Inflammation Status

Saif Anwaruddin and Eric J. Topo!

KEY POINTS

■ Inflammation should be considered a risk factor for coronary atherosclerosis and acute coronary syndromes (ACS).

■ Molecular biomarkers may help to define the inflammatory state and to describe characteristics such as plaque morphology and acute thrombosis.

■ Within interventional cardiology, despite technologic advances, inflammation still remains a limiting factor in terms of restenosis, stent thrombosis, microembolization, and so on.

■ Adjuvant medical therapy has improved outcomes in interventional cardiology, and this may, in part, be due to potent anti-inflammatory properties of these drugs.

■ The optimal timing of pretreatment with adjuvant medical therapy in both elective and emergent percutaneous coronary intervention (PCI) has been shown to be of significance and may be related to controlling the inflammatory response to injury from PCI.

■ Future directions in interventional cardiology will focus on device-based therapies, but there will also be a need to discover newer drug therapies that allow for more effective and efficient methods of modulating inflammation.

Although atherosclerosis and acute coronary syndromes (ACS) are related, they remain distinct entities from both a pathophysiologic and a clinical standpoint. Many patients develop severe atherosclerotic disease of coronary vessels but never experience an ACS, whereas others die of an ACS without symptomatic evidence of significant antecedent coronary atherosclerosis. This heterogeneity probably reflects differences in genetic heritability and environmental factors that, in turn, contribute to differences in both the predisposition and the response to injury.1 As our understanding of these entities improves, evidence supporting the role of inflammation as a central component of both of these processes continues to accumulate.

Inflammation appears to be integral in the induction and propagation of atherogenesis and athero-thrombosis. The perpetuation of atherosclerosis by inflammation is also a concept that has important implications, both for the identification of patients at risk and in the treatment of clinically apparent disease. The presence of clinically detectable levels of inflammation in otherwise asymptomatic patients should be considered a harbinger of potentially adverse outcomes.

Current emphasis on risk factor modification focuses primarily on the traditional coronary artery disease risk factors, including smoking, dyslipidemia, hypertension, and the presence of diabetes. Despite affecting the response of patients with atherosclerosis and ACS to various therapies and ultimately dictating their clinical course, inflammation has emerged as a risk factor that needs to be addressed and modi-

fied. How to accomplish this task is a question is of tremendous value, not only in terms of preventive strategies, but also for currently available percutaneous coronary interventions (PCl).

Controversy exists regarding the best way to define inflammation as a risk factor in otherwise healthy patients and in those with preexisting coronary artery disease. Although C-reactive protein (CRP) has been extensively studied, both as an independent marker of risk and as an active participant in the process, some researchers have questioned the clinical value of this marker.

The focus on a single vulnerable plaque is only the tip of the proverbial iceberg. The ACSs seem to be driven by inflammation, a process that more globally affects the entire coronary tree. Although treating individual "unstable" plaques remains enticing, a more complete approach to interventional therapy must be employed, with an emphasis on treating the vulnerable lesion in the context of the broader inflammatory component. As details of the underlying molecular and genetic mechanisms become more apparent, treatment of atherosclerosis and ACS may ultimately become more individually tailored.

Understanding the connection between inflammation and thrombosis is vital to achieving an appreciation of the pathophysiology behind ACS and coronary artery disease. To better serve our patients with this information, viable methods of quantifying arterial inflammation as a modifiable risk factor need to be developed and utilized. Ultimately, this information can help rationalize treatment strategies in order to overcome current obstacles within interventional

Markers of inflammatory status in coronary disease

IL-18

MMPs

Th1/Th2 balance

Marker of plaque vulnerability Plaque morphology

Development of plaque instability

Evidence of acute thrombosis

Proinflammatory vs anti-inflammatory balance

Systemic inflammatory state

Figure 1-1. Markers of inflammatory status in coronary disease. CRP, C-reactive protein; HGF, hepatocyte growth factor; IL-18, interleukin-18; MMPs, matrix metalloproteinases; MPO, myeloperoxidase; Th, helper T cells.

cardiology. With the use of drug-eluting stents (DES) and adjuvant medical therapy, this process is already underway, but it continues to evolve. The challenge is to overcome the limitations, including restenosis and thrombosis, that have important inflammatory underpinnings. This chapter provides an overview of the complex inflammatory components that contribute to atherothrombosis and how percutaneous strategies induce or are influenced by arterial inflammation.

INFLAMMATION, ATHEROSCLEROSIS, AND ATHEROTHROMBOSIS

Quantifying Inflammatory Status

The evaluation and modification of clinical predictors in patients with known coronary atherosclerosis, or in those at risk for developing atherosclerosis or atherothrombosis, is well established. The limitation of these traditional clinical predictors lies in their inability to adequately incorporate other elements, such as inflammation. Attempts to quantify the degree of inflammation and its significance require understanding of the underlying molecular factors involved in the inflammatory and thrombotic processes (Fig. 1-1).

Molecular biomarkers of inflammation can be used to predict the future risk of clinical events or to evaluate an appropriate response to therapy. Their use may facilitate targeted therapeutic strategies based on a comprehensive molecular risk profile rather than simply on clinical characteristics. The challenge remains in being able to accurately define and measure the inflammatory state. Although many candidates have been considered, only a select number are supported by the available clinical data. Even fewer have been rigorously evaluated in large-

scale clinical studies to ensure their utility and to confirm their value. Candidate markers need to undergo a meticulous process of evaluation to examine their worth in the clinical context, including an assessment of their practicality, their cost-effectiveness, and whether they add information beyond that which is already known. Furthermore, whether specifically targeting these markers with medical therapy affects clinical outcomes remains to be seen.

C-reactive Protein

Traditionally defined as an acute phase reactant, CRP has achieved recognition as a marker of inflammation. The value of high-sensitivity CRP (hsCRP) as a marker of systemic inflammation is in its ability to predict cardiovascular risk. Extensive large-scale epi-demiologic data exist that support the ability of CRP to predict the risk of future cardiovascular events in otherwise healthy individuals,2,3 in those with unstable angina, and in patients who have undergone PCI procedures. The association between CRP and cardiovascular events only strengthens the importance of inflammation in ACS and atherosclerotic disease.

Although CRP is produced in the liver, there is ample evidence to suggest that it is actively involved in atherosclerotic disease. Its role in upregulation of adhesion molecule expression in endothelial cells and in controlling macrophage recruitment lend support to its involvement in atherosclerosis and ACS. In addition, autopsy studies have demonstrated CRP immunoreactivity in plaques with vulnerable morphology.4 Therefore, CRP represents an attractive target for medical therapy, in both primary and secondary prevention strategies. However, studies have not addressed CRP as a treatable risk factor per se, but have focused instead on the secondary effects of treatment on CRP levels. An ongoing study, the Justification for the Use of Statins in Primary Prevention: an Intervention Trial Evaluating Rosuvastatin (JUPITER), is attempting to address this question.5

Platelets: Mediators Of Inflammation and Thrombosis

Platelets are central to the processes of atherosclerosis and ACS, because they provide a link between inflammation and thrombosis. In the context of ACS and PCI, the effect of platelet inhibition probably extends beyond the ability to inhibit thrombosis, involving regulation of platelet-mediated inflammation (Fig. 1-2). The interactions among platelets, endothelium, and leukocytes facilitate the process of platelet-mediated inflammation and thrombosis. Antiplatelet therapy continues to be an effective method of preventing thrombosis; however, a significant benefit may occur through modulation of the inflammatory properties inherent to platelet function.

Considerable interest has been generated for the platelet-derived CD40 ligand (CD40L) and soluble CD40 ligand (sCD40L) in the context of atherosclerosis and ACS. Although it was originally thought to vWF

Figure 1-2. Platelets as mediators of inflammation. aIIb|33, a glycoprotein receptor; CD40 R, CD40 receptor; GP-1b, glycoprotein-Ib; IL-8, interleukin-8; MCP-1, monocyte chemoattractant protein-1; PSGL, P-selectin glycoprotein ligand; sCD40, soluble CD40; vWF, von Willebrand factor. (From Anwaruddin S, Askari A, Topol EJ: Redefining risk in acute coronary syndromes using molecular medicine. J Am Coll Cardiol 2007;49:279-289.)

Figure 1-2. Platelets as mediators of inflammation. aIIb|33, a glycoprotein receptor; CD40 R, CD40 receptor; GP-1b, glycoprotein-Ib; IL-8, interleukin-8; MCP-1, monocyte chemoattractant protein-1; PSGL, P-selectin glycoprotein ligand; sCD40, soluble CD40; vWF, von Willebrand factor. (From Anwaruddin S, Askari A, Topol EJ: Redefining risk in acute coronary syndromes using molecular medicine. J Am Coll Cardiol 2007;49:279-289.)

• Inhibits endothelial repair

• Increased thromboxane levels

• Prevents endothelial cell migration

• Prevents angiogenesis

CD40 R

Adhesion molecules

• Inhibits endothelial repair

• Increased thromboxane levels

• Prevents endothelial cell migration

• Prevents angiogenesis

CD40 R

Adhesion molecules be involved in cellular development within the context of humoral immunity, CD40L has been found on other cell types, including eosinophils, T cells, basophils, and monocytes, in both bound and soluble forms. Commensurate with its widespread distribution is the myriad of functions CD40L participates in related to atherogenesis and ACS.

By facilitating direct interaction with endothelial cells, platelet-bound CD40L is pro-inflammatory and has been shown to upregulate cellular adhesion molecules, increase secretion of chemokines,6 and increase tissue factor production. Facilitating the activation of monocytes,7 in combination with its other roles, places CD40L in the center of the atherosclerotic process. In addition to potent pro-inflammatory effects, CD40L regulates the development and stability of thrombus in ACS. Stability is maintained by the interaction between the lysine-argi-nine-glutamic acid domain of the CD40L and the platelet anbp 3 receptor.

Whereas inhibition of CD40L results in more stable plaque morphology, CD40L left unchecked engages in destabilizing activities. When anti-CD40L antibody was administered to apoE -/- mice treated with anti-CD40L, a reduction in plaque lipid and inflammatory content was noted, without any effect on the size of the lesion.9 CD40L is also influential in the production and release of matrix metalloproteinases (MMPs), which are thought to be responsible for degradation of the fibrous cap of the atheromatous plaque. These effects of CD40L support its role in plaque instability and atherothrombosis.

Clinically, the ratio of sCD40L to CD40L provides important prognostic value. In patients presenting with ACS, elevated sCD40L was an independent predictor of death and recurrent myocardial infarction (MI).10 Data from the Dallas Heart Study noted that sCD40L is not a marker of clinically silent atherosclerotic disease, nor is it associated with traditional risk factors for coronary atherosclerosis, suggesting a separate inflammatory process involved in the genesis of an ACS.11 A large, placebo-controlled randomized trial of platelet glycoprotein inhibitors in PCI for ACS showed particular benefit among those patients with elevated sCD40L.12

The interaction and communication among platelets and leukocytes is essential to the process of inflammation and its sequelae. Inasmuch as the interaction between platelets is emphasized in this scenario, leukocyte and platelet interactions are also vital to the development of thrombosis in ACS. One of the key intermediaries between platelets and leukocytes is P-selectin and its interaction with the P-selectin glycoprotein ligand (PSGL). In experimental models, P-selectin was shown to be important to the processes of thrombosis and thrombus stability.13

P-selectin potentially represents an important target for therapy, given its presence in thrombosis. Clinically, in patients presenting with chest pain, elevated levels of P-selectin were predictive of future troponin I positivity.14 In apparently healthy women, P-selectin levels were predictive of future cardiovascular events.15 However, direct measurement of platelet-monocyte aggregates may represent a more sensitive marker than P-selectin, and it remains to be seen whether P-selectin will be of value as a true connection between inflammation and thrombosis.

Leukocytes and Inflammation in Acute Coronary Syndromes and Coronary Atherosclerosis

The inflammatory responses leading to the disruption of plaque in ACS and subsequent events is characterized by a varied cellular presence. The relationship between monocyte-derived macrophages and the pathogenesis of atherosclerotic coronary artery disease has been well studied. The importance of neutrophils, lymphocytes, and mast cells in plaque disruption and thrombosis has become apparent. The value of leukocytosis in acute myocardial infarction may extend beyond simple prognosis and may predict patient response to revascularization strategies.

Mast cell degranulation

Mast cell degranulation

MPO:

• "Marker of vulnerable plaque"

MCP-1: Summons macrophages/monocytes to sites of injury

T Cell

T Cell

VCAMs wlÉ

VCAMs

MPO:

• "Marker of vulnerable plaque"

MCP-1: Summons macrophages/monocytes to sites of injury

Figure 1-3. Leukocyte secretory products. HGF, hepatocyte growth factor; IL-18, interleukin-18; INF-y, interferon-y; LDL, low-density lipoprotein cholesterol; MCP-1, monocyte chemoattractant protein-1; MMPs, matrix metalloproteinases; MPO, myeloperoxidase; NO, nitric oxide; VCAMs, vascular cell adhesion molecules. (From Anwaruddin S, Askari A, Topol EJ: Redefining risk in acute coronary syndromes using molecular medicine. J Am Coll Cardiol 2007;49:279-289.)

Several studies have assessed the prognostic value of leukocytosis in the setting of ACS, supporting a relationship between leukocytosis and adverse cardiac events during hospitalization for acute MI.16 In ACS, the presence of neutrophils is being recognized as an important component of acute plaque rupture. Furthermore, elevated neutrophil counts in those with acute MI are associated with suboptimal angiographic results after fibrinolysis.17 The monocyte-macrophage is central to the events leading to formation of the atherosclerotic plaque and to promoting ongoing inflammation, which may trigger an ACS via an array of leukocyte secretory products. These leukocyte secretory products serve to provide a potential mechanistic link between inflammation and the patho-genesis of atherothrombosis and atherosclerosis (Fig. 1-3).

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