Journal of Thrombosis and Thrombolysis 17(1), 35–44, 2004.C© 2004 Kluwer Academic Publishers, Manufactured in The Netherlands.

Evolving Concepts in the Triad of Atherosclerosis,Inflammation and Thrombosis

Roberto Corti MD, Randolph Hutter MD, Juan JoseBadimon PhD, Valentin Fuster MD, PhDFrom the Zena and Michael A. Wiener Cardiovascular Institute,The Mount Sinai School of Medicine, New York, NY, USA

Abstract. Recent developments into antherothrombo-sis, the leading cause of morbidity and mortality inWestern Society, may help to change our treatmentstrategy to a more casual approach. The compositionof the atherosclerotic plaque, rather than the per-cent stenosis, appears to be a critical predictor forboth risk of plaque rupture and subsequent thrombo-genicity. A large lipid core, rich in tissue factor (TF)and inflammatory cells including macrophages, and athin fibrous cap with compromise of its structural in-tegrity by matrix degrading enzymes, such as metal-loproteinases (MMPs), render a lesion susceptible torupture and subsequent acute thrombosis. Thrombo-sis may lead to a complete occlusion or, in the case ofmural thrombus or intraplaque hemorrhage, to plaqueprogression.

Disruption of a vulnerable or unstable plaque (typeIV and Va lesions of the AHA classification) with asubsequent change in plaque geometry and thrombo-sis may result in an acute coronary syndrome. Thehigh-risk plaque tend to be relatively small, but softor vulnerable to “passive” disruption because of highlipid content. Inflammatory processes are importantcomponents of all stages of atherosclerotic develop-ment, including plaque initiation and disruption. Assuch the early steps in atherosclerotic lesion forma-tion are the over expression of endothelial adhesiveprotein (i.e. selectins, VCAM and ICAM), chemotacticfactors (MCP-1), growth factors (M-CSF), and cytokines(IL-2) that will facilitate the recruitment, internaliza-tion and survival of blood-borne inflammatory cellsinto the vascular wall. Macrophages, following what ap-pears to be a defense mission by protecting the vesselwall from excess lipid accumulation, may eventuallyundergo apoptosis with release of MMPs and TF. Spe-cific cell recruitment in the vessel wall and build-up ofthe extracellular matrix are coordinated by a wide va-riety of stimulators and inhibitors. Active interactionof immune competent cells within the atheroscleroticlesions appears to play a pivotal role in the controlof atherosclerotic plaque evolution and, therefore, de-serves particular attention from the research commu-nity with the ultimate goal of improving preventive andtherapeutic medical approaches. Inflammation, throm-bosis and atherosclerosis are interdependent and de-fine a triad within the complex pathogenic process ofatherothrombosis.

Key Words. atherosclerosis, inflammation, thrombosis

Introduction

Crucial advances in the understanding of the patho-genesis of atherosclerosis have been achieved duringthe last century. The two major historic pathogenichypotheses, namely the “incrustation” and “lipid” hy-potheses have evolved into new concepts that inte-grate several factors contributing to initiation andevolution of this disease, namely balanced choles-terol transport, accumulation, replication and apop-tosis of macrophages and thrombus formation andreorganization [1–4]. The atherosclerotic and throm-botic processes appear somewhat interdependentand may therefore be integrated under the termatherothrombosis.

Atherothrombosis is a systemic disease affectingthe intima of large- and medium-sized arteries of var-ious vascular beds (such as the aorta, carotid, coro-nary and peripheral arteries). Secondary changesmay occur in the underlying media and adventi-tia, particularly in the more advanced stages of thedisease [5].

To varying degrees, atherothrombotic plaques arecomposed of a lipid-rich core (containing crystallinecholesterol, cholesteryl esters, and phospholipids), acap of fibrous tissue, vascular smooth-muscle cellsand connective tissue extracellular matrix (includ-ing collagen, proteoglycans and fibronectin elasticfibers), inflammatory cells (such as monocyte-derivedmacrophages, T-lymphocytes and mast cells) thatproduce various enzymes and procoagulant factors[6–8]. Varying proportions of these components occurin different plaques, thus giving rise to a spectrumof lesions. The vulnerability of a coronary lesion isdetermined by the critical mass of the lipid-core, thethickness of the fibrous cap and high macrophagecontent [9].

Acute coronary syndromes (ACS) often result fromdisruption of mildly stenotic vulnerable plaques lead-ing to thrombotic complication [10]. In contrast tocoronary vulnerable plaques, the disruption-prone

Address for correspondence: Valentin Fuster, Mount SinaiSchool of Medicine, Box 1030, New York, NY 10029, USA.E-mail: valentin.fuster@mssm.edu

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36 Corti et al.

plaques of the carotid arteries are severely stenotic.Therefore, in atherothrombotic disease, the term“high-risk” plaque, rather than the classic term “vul-nerable” plaque that only implies the presence ofa lipid-rich core, is more appropriate to define thedisruption-prone plaques.

Since there is striking heterogeneity in the com-position of human atherothrombotic plaques evenwithin the same individual, reliable noninvasiveimaging tools able to detect early atherothromboticdisease in the various regions and characterize thecomposition of the plaques are clinically desirable[11]. Such tools will improve our understanding ofthe pathophysiological mechanisms underlying theatherothrombotic processes and allow us to bet-ter risk-stratify the disease. Additionally, such toolsmay permit optimal tailoring of treatment and allowdirect monitoring of the vascular response.

Classification of the AtherothromboticLesions

According to a proposed modification of the criteriaset forth by the American Heart Association Com-mittee on Vascular Lesions, plaque progression canbe subdivided into the five phases shown in Figure 1[12,13].

Phase 1 plaques are small, are common in peo-ple under the age of 30 years and may progressover a period of years. Their content is characterized

Fig. 1. Modified AHA classification of lesion morphology of coronary atherosclerosis according to gross pathological and clinicalfindings.

by macrophage-derived foam cells that contain lipiddroplets (type I), macrophages, smooth-muscle cellsand extracellular lipid deposits (type II), and smooth-muscle cells surrounded by extracellular connectivetissue, fibrils and lipid deposits (type III).

Phase 2 plaques, although not necessarilystenotic, may be prone to disruption because of theirhigh lipid content and thin fibrous cap. These lesionsmay consist of confluent cellular lesions with a greatdeal of extracellular lipid intermixed with fibrous tis-sue (type IV) or extracellular lipid core covered by athin fibrous cap (type Va). Phase 2 plaques can evolveinto acute phase 3 and 4 plaques, and either of thesecan evolve into fibrotic phase 5 plaques.

Phase 3 consists of acute “complicated” type VI le-sions; disruption of a type IV or Va lesion leads tothe formation of a mural thrombus. Changes in thegeometry of a disrupted plaque, as well as organiza-tion of the mural thrombus by connective tissue, canlead to the more occlusive and fibrotic lesions char-acteristic of phase 5 type Vb or Vc lesions. Type Vb orVc lesions may cause angina; however, because thepreceding stenosis and ischemia can stimulate thedevelopment of protective collateral circulation, a fi-nal occlusion may be silent or clinically unapparent.

Lesions of phase 4, rather than being character-ized by a small mural thrombus (as in phase 3), con-sist of an occlusive thrombus and can result in anacute coronary syndrome.

Upon disruption, even the minimally stenoticlesions may lead to acute occlusive thrombosis.

Evolving Concepts in the Triad of Atherosclerosis, Inflammation and Thrombosis 37

Additionally, occlusive thrombi may results fromseverely stenotic lesions in the presence of a hyper-coagulable state. Both phase 3 and phase 4 plaquescan develop into the occlusive and fibrotic type Vb orVc lesions of phase 5.

Initiation of Atherothrombotic Diseaseand Inflammation

Several risk factors such as hyperlipoproteinemia,diabetes, hypertension, inflammation, smoking andaging, have been recognized as main triggers in thedevelopment and progression of atherosclerosis [3].The endothelium is a metabolically active organ sys-tem that, by virtue of its geographical location, mag-nitude and metabolic activity, plays a pivotal rolein maintaining vascular homeostasis by regulatinghemostatic, inflammatory and reparative responsesto local injury. Endothelial dysfunction has been rec-ognized to be the promoter of the atherothromboticdisease as it may promote inflammation, oxidationof lipoproteins, smooth-muscle cell proliferation, ex-tracellular matrix deposition or lysis, lipid accumu-lation, platelet activation and thrombus formation.Disturbed endothelial function, induced by manynoxious stimuli (including oxidized LDL-cholesterol,glycation end-products, smoking, hypertension, ele-vated homocystein and others) can induce the surfaceexpression of two classes of adhesion molecules, theselectins and the immunoglobulin gene superfamily.

These adhesion molecules appear to be a commonendothelial response to a variety of atherogenic stim-uli and result in expression of their counterligands,leucocyte integrins, and the attraction and adherenceof monocytes and T-lymphocytes to the endothelium[14]. Selectins mediate the first step in adhesion,characterized by rolling and tethering of leukocytesto the endothelial surface (and to platelets and otherleukocytes) [15]. Firm adhesion is then facilitated byinteraction between the integrins on leukocyte sur-face and VCAM-1 and ICAM-1, the prototypic mem-bers of the immunoglobin superfamily [14]. Recently,VCAM-1, but not ICAM-1, was found to have an im-portant role in initiation of early atherosclerotic le-sions in an LDL receptor knockout murine model[16].

An altered balance between lipoprotein influxand efflux, intraplaque hemorrhage as well as thedevelopment of the extracellular matrix promotesprogression of early atherosclerotic lesions. A de-crease in lipoprotein influx (such as by risk factormodification thus improving endothelial function)will probably result in a predominance of lipopro-tein efflux and final scarring. However, an increaseof lipoprotein influx can predominate over the ef-flux and scarring, resulting in the lipid-rich type IVand type Va plaques that are prone to disruption[2].

Recent data have highlighted the important roleof the tunica media and adventitia in athero-genesis. The adventitia has long be exclusivelyconsidered a supporting tissue with the main func-tion of provide adequate nourishment to the mus-cle layers of the tunica media. This concept has dra-matically changed due to the evidence accumulatedwith experimental models of atherosclerosis. It hasbeen demonstrated that fibroblasts from the adven-tia have an important partnership with the residentmedial smooth-muscle cells in term of phenotypicconversion, proliferation, apoptotic, and migratoryproperties the result of which is neointima formationand vascular remodeling [17].

Disruption of High-Risk, Lipid-RichCoronary Plaques and Inflammation

Type IV and type Va plaques are commonly com-posed of an abundant crescentic mass of lipids, sepa-rated from the vessel lumen by a discrete componentof extracellular matrix covered by the endothelium(fibrous cap, Fig. 2) [8,18].

Fairly small coronary lesions may be associatedwith acute progression to severe stenosis or total oc-clusion and may eventually account for as many astwo-thirds of the ACS patients [18]. Plaque disrup-tion seems to depend on both a passive and an ac-tive phenomenon. Related to physical forces, passiveplaque disruption occurs most frequently where thefibrous cap is thinnest, most heavily infiltrated byfoam cells, and therefore weakest.

The process of plaque disruption is, however, notpurely mechanical. Inflammation, for instance, playsa pivotal role in plaque disruption. Atherectomyspecimens from patients with ACS reveal areas veryrich in macrophages [9], and these cells are capableof degrading extracellular matrix by secretion of pro-teolytic enzymes, such as matrix metalloproteinases(MMPs, collagenases, gelatinases, stromelysins, andothers).

MMPs are expressed in atherosclerotic lesionsmainly in the areas more prone to rupture (Fig. 3),colocalizing with macrophages, and thereby support-ing the hypothesis of their role in plaque instability[19].

These enzymes may weaken the fibrous cap andpredispose it to rupture [4] or digest the internal elas-tic lamina. Indeed, the MMPs and their co-secretedtissue inhibitors of metalloproteinases TIMP-1 andTIMP-2 are critical for vascular remodeling. Recentdata suggest that MMPs are directly involved in pro-moting aneurysm formation by degrading the elasticlamina and could also be involved in modulating theability of macrophages to invade the plaque [20]. Thehypothesis that the expression of MMPs within theplaque may affect macrophages migration and accu-mulation is of interest, suggesting that they could be

38 Corti et al.

Fig. 2. High-risk plaques of the coronary artery are characterized by large lipid core and thin fibrous cap. Note the features ofpositive remodeling of the eccentric growing plaque. (Courtesy of Dr. E. Falk).

involved in the early stages of atherogenesis, foamcell formation and inflammatory cell penetration, aswell as in the later steps of plaque complication:plaque growth and rupture, and aneurysm formation[19].

Interestingly, disruption of the internal elasticlamina has recently been correlated with the in-tegrity of human atherosclerotic plaques (Fig. 4) [21].Disrupted atherosclerotic plaques have larger plaquearea and lipid content, higher incidence of inter-nal elastic lamina, and thinner fibrous cap whencompared to non-disrupted plaque [21].

The continuing infiltration of monocytes/ macrop-hages within plaques is partly dependent on factorssuch as endothelial adhesion molecules (i.e., VCAM-1), monocyte chemotactic protein (MCP-1), monocytecolony stimulating factor (M-CSF), and interleukin-2for lymphocytes.

Macrophages, following what appears to be a de-fense mission by protecting the vessel wall from ex-cess accumulation of lipoproteins, may eventuallyundergo apoptotic death. Interestingly, the distribu-tion of apoptosis is heterogeneous within the plaque,being more frequent in regions rich in inflamma-tory cells and proinflammatory cytokines (such as the

lipid core) [22]. Although it is still uncertain whetherapoptotic death triggers the release of MMPs, thisphenomenon leads to the shedding of membrane mi-croparticles causing exposure of phosphatidylserineon the cell surface and conferring a potent procoagu-lant activity. The shed particles account for almost allthe tissue factor (TF) activity present in plaque ex-tract and may be a major contributor in initiation ofthe coagulation cascade after plaque disruption [22].

Thrombotic Complication

(1) As result of plaque disruptionPlaque disruption with a subsequent change inplaque geometry and thrombosis results in a com-plicated lesion (Figs. 1 and 5). Such a rapid changein atherosclerotic plaque geometry may result inacute occlusion or subocclusion with clinical mani-festations of unstable angina or other ACS. More fre-quently, however, the rapid changes seem to result inmural thrombus without evident clinical symptoms.Such thrombus may be a main contributor to theprogression of atherosclerosis. More specifically, atthe time of coronary plaque disruption, a number of

Evolving Concepts in the Triad of Atherosclerosis, Inflammation and Thrombosis 39

Fig. 3. Detail of a cross-section from the infrarenal aorta in the experimental atherosclerotic rabbit model stained for MMP-1. Tonote, the localization of the MMP positive areas at the shoulder regions of the plaque and surrounding the lipid-rich core whereasthe normal vessel wall does not stain for MMP-1.

local and systemic circulating factors may influencethe degree and the duration of thrombus deposition(Table 1) [23]. Such a thrombus may then either bepartially lysed or become replaced in the process oforganization by the vascular repair response.

The degree of plaque disruption (ulceration, fis-sure or erosion) or substrate exposure is a key fac-tor for determining thrombogenicity at the local ar-terial site. In an experimental setting in which dis-rupted human aortic plaques were exposed to flowingblood at high shear rate, among the various plaquecomponents the lipid core was found to be the mostthrombogenic. The lipid core also demonstrated themost intense TF staining compared with other com-ponents [24,25]. Residual mural thrombus appearsalso to be highly thrombogenic [26].

TF, a small-molecular-weight glycoprotein, initi-ates the extrinsic clotting cascade and is believedto be a major regulator of coagulation, hemostasis,and thrombosis [27]. Colocalization analysis of coro-nary atherectomy specimens (culprit lesions) frompatients with unstable angina showed a strong re-lation between TF and macrophages [28]. This rela-tion suggests a cell-mediated thrombogenicity in pa-tients with unstable angina and ACS. Interestingly,a significant increase in smooth-muscle cell apopto-sis has been described in coronary endarterectomyspecimens of patients with ACS when compared withstable angina [29]. Furthermore, recent observationsof human coronary and carotid artery specimensshowed that TF often co-localizes with macrophageapoptotic death and released microparticles, rather

40 Corti et al.

Fig. 4. High power histological detail of a disrupted class VI human atherosclerotic plaque showing the interface area with ruptureof the internal elastic lamina (arrow). Disrupted atherosclerotic plaques, which are characterized by eccentric expansion, havelarger plaque areas and higher incidence of disruption of the internal elastic lamina, suggesting an active role of the internal elasticlamina in the pathophysiology of vascular remodeling in complex atherosclerotic lesions. (Courtesy of Dr. P. Moreno).

Fig. 5. Plaque disruption and the overlying thrombus formation are the most often cause of acute coronary syndromes. A:cross-section macro-pathology of a disrupted lipid-rich coronary plaque. B: macro-pathology of a coronary non-occlusive, muralthrombus on top of an ulcerated plaque. (Courtesy of Dr. E. Falk).

Evolving Concepts in the Triad of Atherosclerosis, Inflammation and Thrombosis 41

Table 1. Factors Modulating Platelet-Arterial WallInteraction

Local Fluid Dynamics• Shear stress• Tensile stressNature of the Exposed Substrate• Degree of injury (mild vs. severe arterial injury)• Composition of atherosclerotic plaque• Residual mural thrombusSystemic Trhombogenic Factors• Hypercholesterolemia• Diabetes• Smoking• Catecholamines (smoking, cocaine, stress, etc.)• Homocysteine• Lipoprotein (a)• Hyperchoagulable state (Fibrinogen, vWF, TF, Factor VII)• Defective fibrinolytic state, etc.

TF: tissue factor, vWF: von Willebrand Factor.

than with viable macrophages (Fig. 6) [30,31]. Spe-cific inhibition of vascular TF by recombinant TFpathway inhibitor (rTFPI) was associated with a sig-nificant reduction of acute thrombus formation inlipid-rich plaques [32]. Such observations documentthe role of TF activity in acute arterial thrombosis af-ter atherosclerotic plaque disruption and may lead tothe development of a new strategy in the preventionof ACS.

(2) As a result of hyperthrombogenicityIn one third of ACS, particularly in sudden coronarydeath, there is no disruption of a small lipid-richplaque but just a superficial erosion of a markedlystenotic and fibrotic plaque [33]. Thus, thrombusformation in such cases may depend on a sys-temic hyperthrombogenic state triggered by sys-temic factors (Table 1). Indeed, systemic factors,including elevated LDL-cholesterol, cigarette smok-ing, hyperglycemia, hemostasis, and others are as-sociated with increased blood thrombogenicity. Re-cent studies suggested that the endothelial cells thatcover the atherosclerotic plaques may also becomeprocoagulant after apoptosis induction [22].

Cardiovascular Risk Factorsand Hyperthrombogenicity

Elevated LDL cholesterol levels and diabetes in-crease blood thrombogenicity and growth of throm-bus under defined rheology conditions [34,35].Platelets from patients with diabetes have increasedreactivity and hyper-aggregability and expose a va-riety of activation-dependent adhesion proteins [36].

Improving the glycemic control of diabetic pa-tients reduces the blood thrombogenicity [37]. Reduc-

ing LDL-cholesterol levels using statins decreasedthrombus growth by approximately 20% [35]. Thequestion is, to what extent do such antithromboticeffect contributes to the reduction of total vascu-lar events, including death, coronary events, andstroke, by therapy with statins as documented inlarge prospective clinical trials [38,39].

Smoking increases catecholamine release, whichmay potentiate platelet activation and increase thelevels of fibrinogen. Catecholamine-dependent ef-fects in the circulating blood could explain the in-crease in the incidence of sudden death and acutecardiovascular events after emotional and physicalstress.

Tissue Factor and Blood Thrombogenicity

Recent observations indicate that the hyperthrom-bogenic states associated with high LDL-cholesterol,cigarette smoking, and diabetes may share a com-mon biological pathway. That is, an activation ofleukocyte-platelet interactions associated with re-lease of TF and thrombin activation. Specifically,more leukocyte-platelet aggregates circulate in theblood of patients with diabetes and diabetic vascu-lopathy. Increased procoagulant activity in diabetesis attributed to leukocytes, which may in part acti-vate the TF-pathway [40] and contribute to the highblood thrombogenicity in diabetic patients [36].

Increased levels of circulating TF antigen havebeen documented in patients with cardiovasculardisease. Circulating TF has been associated withincreased blood thrombogenicity in patients withunstable angina [41] and chronic coronary artery dis-ease [42]. Blood levels of TF have been shown to pre-dict outcome in patients with unstable angina [43].As described, lipid-rich atherosclerotic plaques havehigh TF content that colocalizes with macrophages[25] and may account, in large part, for the highthrombogenicity of these lesions. In addition, TFhas also been identified within thrombi formed incoronaries and specific inhibition of the TF-pathwayusing r-TFPI significantly reduces plaque thrombo-genicity [32]. Local production of TFPI may regulatepro-coagulant activity and thrombotic events withinatherosclerotic plaques [44].

Aside from apoptotic macrophages and micropar-ticles from atherosclerotic plaques, activated mono-cytes in the circulating blood seem to be a sourceof TF microparticles and may represent the re-sult of the activation by the above-mentioned riskfactors and others, thus contributing to throm-botic events. Within the context of such possible“pro-inflammatory” or “pro-thrombotic” effect uponthe circulating blood exerted by high LDL choles-terol, cigarette smoking, and diabetes, there is evolv-ing evidence that circulating monocytes and whiteblood cells may be involved in TF expression and

42 Corti et al.

Fig. 6. This detail of a lipid-rich human carotid atherosclerotic lesion shows colocalization of apoptosis (caspase-3 positive cells, A),tissue factor (B) and macrophages (CD-68 positive cells, C) as indicated by the arrows.

Evolving Concepts in the Triad of Atherosclerosis, Inflammation and Thrombosis 43

thrombogenicity [45]. Indeed, the predictive value forcoronary events of high levels of C-reactive protein(CRP) may be a manifestation of such systemic phe-nomena [46].

CRP, like fibrinogen, is a protein of the acute-phase response and a sensitive marker of low-grade inflammation. Increased levels of CRP havebeen reported to predict acute coronary events [46].Whether CRP reflects the inflammatory componentof atherosclerotic plaques or of the circulating blood,and whether it is a surrogate marker or a biolog-ically active element in the process of plaque de-velopment of thrombus formation at the site of theatherosclerotic vessel is not known [47]. However, re-cent studies support that CRP is an activator of bloodmonocyte and vessel wall endothelial cells [48]. Thisencourages further investigation into the effect ofcertain risk factors in the activation of “inflamma-tion” of the vessel wall and circulating blood, and theactive role of TF and CRP as local and systemic keyfactors in the process of atherothrombosis.

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