Basic Science Review

Atherosclerosis as Inammation
Philip S. Mullenix, MD,1 Charles A. Andersen, MD,2 and Benjamin W. Starnes, MD,2 Tacoma, Washington

Atherosclerosis has traditionally been attributed to disordered cholesterol metabolism with associated accumulation of lipid substrate in the arterial wall. It is now believed that systemic and local inammatory events mediate all phases of plaque development, progression, and degeneration. No longer regarded as a bland, mechanical process, plaque evolution is now best understood as a pitched battle between proinammatory and anti-inammatory cellular and molecular elements. Not unlike models of chronic wound healing or ischemia-reperfusion, the biologic state of a plaque at any given time is transient and mutable, reecting a dynamic balance of numerous local and circulating inammatory forces. Dreaded complications of the disease such as myocardial infarction and stroke result from acute shifts in this balance in favor of plaque instability and vulnerability over stable states of chronic inammation. The purpose of this article is (1) to review the inammatory pathogenesis of atherosclerosis on a molecular basis, (2) describe several of the emerging inammatory biomarkers currently being investigated with particular interest in their possible roles as direct mediators of vascular disease, and (3) identify several important implications for diagnosis and therapy.

INTRODUCTION
Originally formulated as an unsophisticated disorder of lipoprotein accumulation, atherosclerosis can now be fundamentally understood as a chronic inammatory disease of the arterial system.1 While endothelial injury and dysfunction remain central to the initiation and pathogenesis of the disease, accumulating evidence suggests that the classically postulated response-to-injury is in fact inammation itself.2,3 Recognition of the inammatory
1 General Surgery Service, Department of Surgery, Madigan Army Medical Center, Tacoma, WA.

Vascular and Endovascular Surgery Service, Department of Surgery, Madigan Army Medical Center, Tacoma, WA. This is an original work by the above authors. The opinions expressed in this article do not necessarily reect those of the United States (US) Government, the US Department of Defense, or Madigan Army Medical Center. Correspondence to: Benjamin W. Starnes, MD, Vascular and Endovascular Surgery Service, Department of Surgery, Madigan Army Medical Center, 9040A Reid Street, Tacoma, WA 98431-1100, USA, Email: benjamin. starnes@nw.amedd.army.mil Ann Vasc Surg 2005; 19: 130-138 DOI: 10.1007/s10016-004-0153-z Annals of Vascular Surgery Inc. Published online: January 11, 2005 130

nature of atherosclerosis is important clinically as only 50% of patients with the disease actually manifest hyperlipidemia, the popular major secondary risk factor targeted for intervention worldwide.4 Furthermore, the prevalence of traditional risk factors such as diabetes, smoking, and hypertension is only slightly higher in patients with documented cardiac or peripheral vascular disease compared to similarly elderly patients without disease.5 Indeed, it appears that it is the degree of inammatory activityand associated morphologic instabilityof a plaque, rather than its degree of stenosis, that denes its propensity to cause an acute coronary syndrome, threatened limb, or stroke.6 The purpose of this brief review is to summarize the immunopathogenesis of the atherosclerotic vascular lesion, and describe a few key implications of this new understanding in terms of diagnosis and therapy.

THE INFLAMMATORY NATURE OF PLAQUE PROGRESSION

Stary has classied the development of the mature atherosclerotic plaque as a six-stage stepwise

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process of cross-sectional morphologic and histologic change.7-9 In this model, a normal arterypresumably situated at an injury-prone locale such as a bifurcation, kink, or curve evolves in childhood from a type I initial lesion through a progressive series of characteristic crosssectional architectures.10 A spectrum of possible advanced lesions can result, ranging from the chronic stable type IV atheroma of adulthood to the complicated type VI plaque of disease. It is now believed that inammatory cellularity and molecular events dominate the pathophysiology at every stage. Even the earliest type I and II areas of fattystreak intimal thickening and lipid accumulation are comprised almost entirely of inammatory cells: activated T lymphocytes and monocyte-derived macrophages.11,12 Likewise, long-standing repetitive inammatory injury appears to be the primary factor driving the transformation of stable mature type IV lesions into type V broatheromas prone to symptomatic luminal stenosis, or degenerated type VI plaques vulnerable to acute rupture, hemorrhage, ulceration, thrombosis, or embolization.13 Despite the reformulation of atherosclerosis as inammation over the last decade, the disruption of normal endothelial homeostasis is still considered the inaugural event in the inammatory process fueling plaque progression and degeneration.14-16 The character of endothelial dysfunction is functionally and morphologically typical despite a diverse group of physiologic insults. These include both local and systemic inciting factors, such as lipid accumulation, mechanical denudation (i.e., angioplasty), advanced glycation end products (AGEs), infectious agents (ranging from remote dental infection to foci of Chlamydia in the plaque itselt), uremia, cigarette toxins, oxidative stress, genetic variability, radiation injury, homocysteinemia, chronic autoimmune conditions, or the rheology of hypertension and shear.17-23 It is important to recognize that even small perturbations in endothelial cell function can be amplied with dramatic systemic effect. This phenomenon becomes easier to understand when one considers the tremendous magnitude of surface area that is associated with the aggregate endothelial cell mass of the human vascular system. Four main elements characterize the endothelial response to injury: adhesiveness, permeability, proliferation, and thrombogenesis (Table I). Dysfunctional endothelial cells lose their critical physiologic property of nonadherence to circulating immune effector cells. Vascular injury induces upregulation of endothelial-derived adhesion mole-

cules such as intracellular adhesion molecule-l (ICAM-1), vascular cell adhesion molecule-1 (VCAM-1), and platelet-endothelial cell adhesion molecule-1 (PECAM-1), integrins, and L, E, and P selectins. These molecules mediate the attachment and accumulation of monocytes, macrophages, T lymphocytes, and platelets on the vessel wall, which in turn become activated and release proinammatory cytokines, membrane receptors, and enzymes including interleukins (IL) 1, 2, 6, 7, 8, and 18, tumor necrosis factor-a (TNF-a), interferon-a (IFN-a), monocyte chemotactic protein (MCP-1), MCP-4, CD40 ligand (CD40L), parathyroid hormone-related protein (PTHrP), osteopontin, cyclooxygenase-2 (COX-2), and matrix metalloproteinases (MMP).24-26 A proinammatory positive feedback loop is thus established, as these mediators (1) locally recruit additional cytokinereleasing immune cells, (2) promote low-density lipoprotein (LDL)-receptor expression causing injurious aggregation of oxidized LDI particles on the endothelial surface, and (3) promote the release of hepatic acute-phase reactants with attendant activation of the systemic inammatory cascade. The endothelial layer also dramatically increases its permeability in response to injury, even as its histiologic architecture remains intact. Endothelial passage of adherent oxidized LDL, for example, in turn results in the substrates immunogenic and deleterious subintimal deposition. Circulating macrophages then exploit the increased adherence and permeability of the endothelium and proceed to sequester, modify, and phagocytose these accumulating lipid antigens.29 Resultant lipidladen foam cell macrophages typify the histology of early lesions. Unfortunately, this protective mechanism is itself inammatory in nature and can affect a disproportionate recruitment of additional monocytes, macrophages, T lymphocytes, and mast cells with attendant cytokine and chemokine release.30 It activates the classical and alternative complement pathways of the immune system and stimulates the local proliferation of vascular smooth muscle cells (VSMC).31,32 Elaborated chemokines including RANTES (regulated on activation, normally T-cell expressed and secreted) and MCP-1 promote the retention of recruited leukocytes and monocytes in the plaque itself.33 A smoldering vicious cycle of inammatory activity in the vessel wall is established and a progressive and potentially complicated lesion is formed. Activated dysfunctional endothelium is synthetic and proliferative in nature, in many ways functioning as an endocrine tissue. The production

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Table I. Molecular and cellular inammatory elements of endothelial dysfunction and associated biologic effects
Endothelial dysfunction Mediators after vascular injury Cellular elements Inflammatory response Biologic effect

Adhesiveness

ICAM VCAM-1 PECAM-1 Integrins L, E, and selectins

Monocytes Macrophages T lymphocytes Platelets

Cytokines Receptor expression IL-1, 2, 6, 7, 8, 18 TNF-a IFN-a MCP-1 CD40L PTHrP Osteopontin COX-2 MMP MCP-1 MCP-4 RANTES

Recruit additional cellular elements Promote LDL receptor expression Aggregation of ox-LDL Release of hepatic acute phase reactants

Activate inflammatory cascade

Permeability

ox-LDL

Macrophages Monocytes T lymphocytes Mast cells

Macrophage foam cells (sequestration, modification, and phagocytosis of lipid antigens) Activation of complement VSMC proliferation Cytokine and chemokine release Transformation of early lesion to mature plaque

Proliferation

PDGF IDGF-1 FGF TGF-b IL-1 TNF-a Phospholipase A2 PAI-1 Cigarette toxins Thromboxanes Leukotrienes Serotonin Endothelin-1 Angiotensin II Tissue factor MMP

VSMC

VSMC proliferation VSMC migration Collagen synthesis Matrix deposition Fibrous cap production

Thrombogenesis

Platelets Endothelial cells

Thrombogenic environment

Hemorrhage Plaque rupture Thrombosis Embolization Occlusion

CD40L, CD-40 ligand; COX, cyclooxygenase; FGF, fibroblast growth factor: ICAM, intracellular adhesion molecule; IDGF, insulin derived growth factor; IFN, interferon; IL, interleukin; ox-LDL, oxidized low-density lipoprotein; MCP, monocyte chemotactic protein; MMP, matrix metalloproteinase; PAI, platelet activator inhibitor; PDGF, platelet-derived growth factor; PECAM, platelet-endothelial cell adhesion molecule; PTHrP, parathyroid hormone-related protein; RANTES, regulated on activation, normally T-cell expressed and secreted; TGF, transforming growth factor; TNF, tumor necrosis factor; VCAM, vascular cell adhesion molecule; VSMC, vascular smooth muscle cell.

of platelet-derived growth factor (PDGF), insulinlike growth factor-1 (IDGF-1), broblast growth factor (FGF), transforming growth factor-b (TGFb), IL-1, TNF-a, and other trophic endothelial products promote VSMC proliferation and migration, local vasoconstriction, broblast-mediated collagen synthesis and matrix deposition, brous cap production, and additional immune and

platelet cell recruitment and activation. In aggregate, this process can direct the transformation of an early lesion into a mature plaque, as the artery thickens and becomes less compliant due to the combined effects of the various ongoing inammatory and tissue remodeling activities. If unmitigated, the process will eventually overwhelm compensatory dilatory mechanism and compro-

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mise luminal cross-sectional area, and ow-related distal ischemia syndromes can manifest. Dysfunctional endothelial cells also lose their intrinsic anticoagulant properties. Local inammatory activity; platelet adherence, activation, and degranulation; disordered nitric oxide metabolism; increased phospholipase A2 and plasminogen activator inhibitor-1 (PAI-1) activities; cigarette toxin exposures; release of vasoactive agents such as thromboxanes, leukotrienes, serotonin, endothelin-1, and angiotensin II; and structural denudations in the endothelial layer itselfwith attendant collagen exposure, tissue factor release, and MMP activityare all factors contributing to the thrombogenic microenvironment of endothelial dysfunction.34-38 MMP-mediated areas of ssuring or ulceration that subsequently develop in advanced atherosclerotic plaques are particularly vulnerable to plateletassociated vascular hemorrhage, rupture, thrombosis, embolization, and occlusion. Depending on the vascular bed or end organ involved, these events are generally catastrophic clinically, and include unstable angina, myocardial infarction, stroke, and critical limb or visceral ischemic syndromes.39 Of particular research interest over the last several years is the potential direct pathogenic role in this process of nonspecic circulating acute-phase markers of inammation such as C-reactive protein (CRP), serum amyloid-A, IL-6, TNF-a, PAI-1, and brinogen.40,41 PAI-1 is one key example of such a mediator.42 Tissue plasminogen activator (t-PA) is an important circulating brinolytic component of plasma. The principle inhibitor that mitigates t-PA activity is the platelet- and endothelial cell-derived protein PAI-1. Functionally, PAI-1 promotes extension and stability of newly formed thrombus by forming ternary complexes with t-P A and brin on clot surface, thus preventing the brinolytic activities of t-PA and stabilizing the thrombus from premature lysis.43 High concentrations of PAI-1 levels are found in severely atherosclerotic plaques however, and may be associated with inammatory cell migration, VSMC activation, vascular remodeling, and acute thrombosis following plaque ssuring or rupture.44 Clinically, increased PAI-1 levels and activity have been associated with thrombogenensis, unstable angina, future myocardial infarction, post-transplant coronary artery disease, insulin-resistance and hyper insulinemia, dyslipidemia, and obesity.45-48 Together, these ndings suggest that the protein has potential utility not only as a marker of endothelial dysfunction and atherosclerotic progression

but also as a potential target for therapeutic inhibition or receptor blockade. CRP is a 206-amino acid polypeptide quantitatively secreted into the bloodstream by the liver in the context of various nonspecic etiologies of inammation ranging from self-limited acute infection to chronic autoimmune disease. A key hepatic stimulus of CRP production is the presence of IL-6 in the bloodstream. Historically, CRP has been considered a nonspecic downstream inammatory marker variously involved in immune cell chemotaxis, macrophage phagocytosis, complement activation, platelet stimulation, and the clearance of immune complexes, cellular necrotic material, and bacterial debris. In addition to its functions as a component of the generalized hepatic response to acute inammation, however, CRP also appears to be produced locally in atherosclerotic plaques by resident macrophages and vascular smooth muscle cells and may be involved in several important steps in plaque genesis and progression.49 CRP up-regulates endothelial cell permeability, promotes endothelial adhesion protein expression, is present in disproportionate concentrations in subintimal plaque, xes complement, recruits monocytes and macrophages to foci of endovascular inammation, and stimulates local platelet activity and thrombogenesis.50-52 CRP may also be involved in foam cell generation, as it binds oxidized LDL with high afnity, and the resultant CRP-LDL aggregates are actively absorbed by macrophages in vitro.53,54 In aggregate, these ndings suggest that CRP may directly mediate vascular tissue injury at the level of the plaque by amplifying and exacerbating ongoing local inammatory processes.

DIAGNOSTIC AND THERAPEUTIC IMPLICATIONS

To date, the premise that atherosclerosis and its complications result primarily from chronic endovascular inammatory tissue injury has directed clinical research in two main directions: (1) identifying patients at risk, and (2) the development of potential therapeutic targets for intervention. Current surveillance efforts are focused on assessing the utility of monitoring serum levels of various candidate inammatory markers in an attempt to identify patients with occult atherosclerosis, characterize the rate of progression, and risk-stratify those with known and potentially vulnerable disease.

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Table II. Circulating markers of atherosclerotic inammation under current investigation

Putative marker

hs-CRP ox-LDL Phospholipase A2 PAI-1 Homocysteine IL-1, 2, 6, 7, 8, 18 Myeloperoxidase TNF-a D-dimer IFN-a MCP-1 CD40L PTHrP MMP-9 MCP-1, 4 Endothelin-1 Angiotensin II Fibrinogen Serum amyloid-A TGF-b ICAM Lipoprotein (a) Leukotrienes Peroxisome proliferator-activated receptors
CRP, C-reactive protein; CD40L, CD-40 ligand; COX, cyclooxygenase; IFN, interferon; IL, interleukin; ICAM, intracellular adhesion molecule; MCP, monocyte chemotactic protein; MMP, matrix metalloproteinase; ox-LDL, oxidized low-density lipoprotein; PAI, platelet activator inhibitor; PDGF, platelet derived growth factor; ox-LDL, oxidized low density lipoprotein cholesterol; PTHrP, parathyroid hormone-related protein; TGF, transforming growth factor; TNF, tumor necrosis factor.

Over the last decade, CRP has been featured prominently in these efforts and remains the best studied of the novel inammatory biomarkers (Table II).55,56 Elevated CRP has been associated with undiagnosed peripheral, coronary, and cerebral artery disease; differentiates patients with unstable versus stable angina; predicts future myocardial infarction, stroke, and sudden cardiac death in patients with coronary artery disease; correlates with myocardial infarct size; and predicts development of graft failure in heart transplant patients.57-62 It predicts the presence, degree, and symptomatology of carotid stenosis; early morbidity and late mortality following coronary artery bypass grafting; and late restenosis following percutaneous cardiac interventions.63-68 Numerous other associations of the protein with endovascular disease and outcomes have been reported and are currently being evaluated, making CRP a potentially valuable adjunct to traditional vascular risk

factor assessment efforts. A major advantage of CRP over the other emerging inammatory biomarkers being studies is evidence that its diagnostic yield independently adds to both lipid screening and the Framingham Risk Score.69 Furthermore, a precise, standardized, commercially available assay designed for cardiovascular risk assessment is widely available, complete with accepted normal ranges and screening guidelines from the American Heart Association and the Centers for Disease Control (high-sensitivity CRP, or hs-CRP).70 Markers of proven utility in atherosclerosis are being reevaluated in the context of inammation as well. High-density lipoprotein (HDL) cholesterol is now known to have vascular anti-inammatory, anticoagulant, antioxidant, and brinolytic properties in addition to its traditional roles in peripheral cholesterol mobilization.71 Furthermore, it appears that these benecial properties of HDL are attenuated when the protein is exposed to oxidative stress or is otherwise damaged or dysfunctiona1.72 Low-dose insulin infusion reduces CRP and serum amyloid-A levels in patients with acute myocardial infarction, reduces the number and size of atherosclerotic plaques in animal models, mitigates oxidative stress, and promotes vasodilation and platelet inhibition at the cellular leve1.73 Associations of elevated brinogen, leukotrienes, and homocysteine with vascular disease are other markers of interest and point to an interesting link between the inammatory and coagulation cascades in the progression of atherosclerosis. Understandably, research interest in antiinammatory therapies directed at new atherosclerotic biomarkers is signicant. Drugs directed at putative mediators, including CRP, leukotrienes, IL-6, MCP-1, IL-8, homocysteine, phospholipase A2 angiotension II, MMPs, soluble CD40L, PAI-1, peroxisome proliferator-activated receptors, and other, are in various stages of investigational or clinical evaluation.74-76 Anecdotally, at our own institution a patient experienced near complete regression of documented high-grade carotid stenosis with dramatic reduction in baseline CRP levels incidental to high-dose steroid treatment for rheumatoid arthritis, suggesting a possible role for immunosuppressive drug therapy.77 Biologic modalities such as the use of bone marrow-derived vascular progenitor cells, COX-2 inhibitors, exogenous cytokine infusion, antimicrobial drugs directed at putative bacterial and viral etiologies, monoclonal antibodies, anti-inammatory polyherbals, and gene therapy involving the antiinammatory cytokine IL-10 are also being investigated.78,79

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Expanded applications for established drugs such as antiplatelet and 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors (statins) are even more promising. Aspirin and statins reduce both CRP levels and the incidence of future myocardial infarction and stroke, and interestingly appear to do so independent of their respective antiplatelet and lipid-lowering effects. Statin agents in particular appear to have numerous anti-inammatory properties, and have recently been shown to reduce IL-6 synthesis, inhibit VSMC proliferation, prevent complement activation, inhibit PTHrP activity, and favorably modulate nitric oxidederived oxidants.80-83 Interestingly, the magnitude of benet of anti-platelet and statin therapy correlates quantitatively with the degree of baseline CRP elevation, suggesting that numerous additional anti-inammatory mechanisms of action of these drugs are yet to be elucidated. The role of athersclerosis as a component of the metabolic syndrome of obesity, insulin resistance, essential hypertension, and inammation has also renewed interest in drugs directed at these disorders. For example, thiazolidinediones (TZDs), historically used as glucose control agents in type 2 diabetic, are now known to also promote endothelial function, inhibit vascular inammation, and reduce CRP levels.84 Antihypertensive therapies are similarly pleiotrophic: angiotensin-converting enzyme (ACE) inhibition reduces PAI-I and MMP9 levels, and angiotensin II receptor blockade inhibits CRP, IL-6, and platelet aggregation in vitro.85 Even the time-tested benets of weight loss and exercise have recently been demonstrated to include a reduction in circulating MCP-1, IL-6, IL8, CRP, PAI-1, and TNF levels.86,87 The propensity of aspirin, statins, weight-loss agents, insulin, and TZDs to lower CRP suggests the marker may not only be useful in pretherapy risk-stratication but also as a target for intervention and end point of efcacy in this prevalent and complex syndrome. Radiographic modalities are being developed that reinforce and exploit the concept that plaque inammatory morphology rather than simple cross-sectional area determines its instability and vulnerability to thrombose, embolize, or ruptureand thus produce an acute clinical event.39,88-90 Promising new modalities such as duplex ultrasonographic gray-scale analysis, plaque endolucency scales, intima-media thickness, and volume-ow determination; degree of calcication, surface irregularities, and ulcerations on computed tomographic angiography (CTA); endovascular temperature probes; and new applications of magnetic resonance angiography (MRA) may assist

providers in identifying patients at highest risk and maximal potential therapeutic benet.91-93 Studies attempting to temporally associate radiographic evidence of plaque vulnerability, serum inammatory marker proles, and clinical events suggest that the primary objective of vascular risk factor assessment in the future will focus less on historical and demographic data and more on accurately determining a plaques current biologic state, thus guiding the nature and timing of intervention. Finally, progress in the area of percutaneous coronary vascular interventions utilizing antiinammatory drug-eluting stents has favorably impacted the important problem of in-stent restenosis.94 In-stent restenosis is an inammatory mediated, neointimal hyperplastic process that may ultimately affect up to 50% of the more than one million percutaneous interventions performed each year in the United States.95 It is associated with signicant morbidity, mortality, and health-care expenditure. One of the many agents being studied in this context is the tacrolimus-related compound rapamycin. Rapamycin is an immunosuppressive agent widely used systemically in maintenance regimens among post-transplant patients. With respect to vascular disease, it is known to inhibit Tcell proliferation, VSMC migration, and proliferative changes in the arterial wallwithout destroying cells or causing vessel injury.96 Rapamycin-impregnated stents have been demonstrated in a prospective, double-blind, and randomized fashion to reduce the binary restenosis rate at 1 year to from 26% to 0% when compared to conventional bare metal stents, and do so with corresponding reductions in major adverse cardiac events. Follow-up intravascular ultrasound evaluations in these patients revealed no signicant evidence of volume loss in the stent itself or at its edges, and the need for repeat interventions in the rapamycin group was nearly eliminated.97,98 This technology represents an excellent example of the type of exciting developments that can result from a greater appreciation of the inammatory mechanisms involved in atherosclerosis.

CONCLUSIONS
Atherosclerosis is a chronic inammatory disease of worldwide prevalence. Its complications can be catastrophic, and might best be understood as acute on chronic clinical events associated with the violation of a vessels intrinsic critical threshold for tissue injury and inammatory burden. Molecular and cellular autoimmune activities dominate all stages of plaque initiation, progres-

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sion, and degeneration. Certain mediators and systemic acute-phase reactants implicated in the pathogenesis of the disease in the future may prove to be (1) useful surrogate markers of disease severity and activity, (2) potential targets for intervention, and (3) end points for titration of therapy and timing of intervention. CRP is currently the most important of these biomarkers, and may become more so as it appears to identify asymptomatic patients at risk, directly mediate endovascular tissue injury, and potentially serve as a useful end point of therapeutic response. Traditional vascular risk assessment efforts are being reevaluated in the context of this new understanding of atherosclerosis, and will likely focus more on identifying vulnerable plaques in vulnerable patients, rather than relying primarily on traditional historical and demographic risks.

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