ublished by Elsevier Inc. doi:10.1016/j.jacc.2005.10.065
American College of Cardiology Foundation
w3nsiesuawftecs4aasc
P
Iwptiwfi9
atients with acute coronary syndromes (ACS) present withnstable angina, acute myocardial infarction, and suddenoronary death. Most of the ACS are thought to be theesult of sudden luminal thrombosis (1–5). Luminal throm-osis occurs from three different pathologies: plaque rup-ure, erosion, and calcified nodules. Plaque rupture isefined as a lesion consisting of a necrotic core with anverlying thin ruptured fibrous cap that leads to luminalhrombosis because of contact of platelets with a highlyhrombogenic necrotic core. Plaque erosion shows a luminalhrombus with an underlying base rich in proteoglycans andmooth muscle cells with minimal inflammation. Mostrosion lesions are devoid of a necrotic core, but whenresent, the core does not communicate with the lumenecause of a thick fibrous cap. The least common of allesions is the calcified nodule. The calcified nodule shows annderlying calcified plate with superimposed bony noduleshat result in discontinuity of the fibrous cap and is devoidf endothelial cells with overlying luminal thrombus.We have examined over 400 cases of sudden death that
ave been published in the last 15 years highlightingifferences in type of thrombi; influence of race, age, andender; and the role of risk factors on plaque morphologies1–12). The frequency of thrombi in sudden death is 60%
From the *CVPath, International Registry of Pathology, Gaithersburg, Maryland; andhe †U.S. Food and Drug Administration, CDRH-ODE-DCD-ICDB, Rockville,
aryland. The opinions or assertions contained herein are the private views of theuthors and are not to be construed as official or reflecting the views of the Departmentf the Army, the Department of the Air Force, or the Department of Defense. Dr.
illiam A. Zoghbi acted as guest editor.
oManuscript received June 16, 2005; revised manuscript received October 10, 2005,
ccepted October 24, 2005.
ith underlying etiology in 55% to 60% plaque rupture, in0% to 35% plaque erosion, and in 2% to 7% calcifiedodule. In the case of myocardial infarction, an autopsytudy has shown that only 20% to 25% of acute myocardialnfarcts occurring in hospitalized patients are due to plaquerosion (13). In both acute myocardial infarction andudden death, plaque erosion occurs primarily in patientsnder the age of 50 years and represents the majority ofcute coronary thrombi in premenopausal women. Inomen older than 50 years, 80% of coronary thrombi occur
rom plaque rupture; when they occur in women youngerhan 50 years, there is a strong association with hyperlipid-mia. Plaque ruptures occur in men at all ages, but, as is thease with all types of thrombosis, their relative incidence inudden coronary death decreases with advancing age. In0% of sudden coronary death patients, no acute thrombire observed; however, healed infarction and total occlusionsre observed in the vast majority with only 15% dying ofevere coronary narrowing in the presence or absence ofardiomegaly.
LAQUE RUPTURE AS THE BASIS OF ACS
t has been postulated that thin cap fibroatheroma (TCFA),hich resemble the plaque rupture in morphology, are therecursor lesion of plaque rupture. A necrotic core charac-erizes plaque rupture with an overlying thin-ruptured capnfiltrated by macrophages (Fig. 1). Smooth muscle cellsithin the cap are absent or few. The thickness of thebrous cap near the rupture site measures 23 � 19 �m, with5% of the caps measuring �65 �m (1). It has been
bserved that some plaques at other sites in the coronary
tbvrtlc
2fficplpvoohiwdntthwi�pa
tt
LL
IotFt7nTsnt
woiih(�wdiatda
RI
Tttci
Fw�n
C14 Virmani et al. JACC Vol. 47, No. 8 Suppl CPathology of the Vulnerable Plaque April 18, 2006:C13–8
ree resemble the rupture plaque but lack a luminal throm-us: these lesions have been designated as TCFA orulnerable plaques (4). The term vulnerable plaque should beeserved for plaques that resemble all three causes of luminalhrombosis, and these morphologies include TCFA, patho-ogic intimal thickening, thick cap fibroatheroma, andalcified plaque with luminal calcified nodules.
The TCFAs differ from ruptured plaques (Table 1, Fig.), by having a smaller necrotic core (statistically differentrom ruptured plaques), less macrophage infiltration of thebrous cap, and less calcification. We have quantitated, inross sections of coronary arteries with various types oflaques, the size of the necrotic core, the proportion of the
esion composed of cholesterol clefts, the percent macro-hage infiltration of the fibrous cap, the number of vasaasorum within the atherosclerotic plaque, and the numberf hemosiderin-laden macrophages (Table 2). The numbersf cholesterol clefts in the necrotic core, vasa vasorum, andemosiderin-laden macrophages were significantly greater
n the ruptured plaques than in erosion or stable plaquesith �75% cross-sectional luminal narrowing. Significantifferences between rupture and TCFAs were only seen forecrotic core size, macrophages, and hemosiderin infiltra-ion. Plaque hemorrhages are more common at other sites ofhe coronary tree in cases with plaque ruptures than inearts from patients dying with severe coronary diseaseithout acute ruptures. The mean number of hemorrhages
n the coronary tree of patients with plaque rupture was 2.51.3 versus none in erosion and 0.05 � 0.6 in stable
laques (4). Evidence of prior hemorrhage in TCFA, whennalyzed by glycophorin A staining, is significantly greater
igure 1. Coronary plaque rupture. (A) Low-power view of a circumfereith numerous cholesterol clefts. There is a focal disruption of a thin fib
Abbreviations and AcronymsACS � acute coronary syndromesCRP � C-reactive proteinHDL � high-density lipoproteinMPO � myeloperoxidaseTC � total cholesterolTCFA � thin cap fibroatheroma
20). (B) High-power view of the rupture site showing fibrous cap disruptiecrotic core (Movat Pentachrome, �400).
han in early or late fibroatheromas and correlates with bothhe necrotic core size and extent of macrophage infiltration.
OCATION, LENGTH, AND PERCENTUMINAL NARROWING OF THE TCFA
n a detailed morphometric analysis of ruptured plaques, 80%f necrotic cores were larger than 1.0 mm2, and in nearly 90%,he lipid core comprised �10% of the plaque area (Fig. 3).urthermore, almost 65% of plaque ruptures had �25% area of
he plaque occupied by the necrotic core. In contrast, nearly5% of TCFA have �10% area of the plaque occupied byecrotic core. The mean cross-section area narrowing of theCFA is 71%, and most have 10% to 25% of the cross
ectional area occupied by a necrotic core. The length of theecrotic core in ruptures and TCFAs is similar, varying from 2o 22.5 mm, with mean of 8 and 9 mm, respectively (Table 3) (6).
In 38 hearts with severe coronary luminal narrowing, inhich the coronary arteries had been serially cut from coronarystium to intramyocardial location, the mean luminal narrow-ng was least in sections with thin cap atheroma (59.6%),ntermediate for hemorrhage into a plaque (68.8%), andighest in plaque rupture (73.3%) or healed plaque rupture72.8%) (6). Overall, approximately 75% of the arteries showed75% cross-sectional luminal-narrowing, indicating that sitesith �50% diameter stenosis are the most useful for theetection of vulnerable plaque. Over 50% of the TCFAs occur
n the proximal portions of the major coronary arteries, leftnterior, left circumflex and the right, and another one-third inhe mid portion of these arteries, and the rest are distributed inistal segments (5). A similar distribution is found in rupturesnd healed plaque ruptures.
OLE OF MONOCYTENFILTRATION OF THE OCCLUSIVE THROMBUS
he rupture of the fibrous cap allows platelets and inflamma-ory cells to come in contact with the thrombogenic substrate,he necrotic core. Before the report of Nemerson et al. (14), theore was thought to be the main source of the tissue factor. Its now believed that circulating monocytes, instead of plaque
coronary plaque with fibrous cap rupture. Note the large necrotic corecap (arrow) with an occlusive luminal thrombus (Movat Pentachrome,
ntialrous
on (arrows); the thrombus shows communication with the underlying
FttsA
T
RTp
Mean values represent � SD. Reprinted, with permission, from Kolodgie et al. (5).SMC � smooth muscle cell; TCFA � thin cap fibroatheroma.
TV
RTES
R0
C15JACC Vol. 47, No. 8 Suppl C Virmani et al.April 18, 2006:C13–8 Pathology of the Vulnerable Plaque
igure 2. Thin-cap fibroatheroma. (A) Low-power view of an eccentric coronary plaque showing a thin fibrous cap overlying a relatively large necrotic core;he vessel was injected with barium (Movat Pentachrome, �20). (B) Immunohistochemical staining reveals numerous CD68-positive macrophages withinhe fibrous cap (rose-red reaction product, �400). (C) Shows a cellular-rich thin fibrous cap with cholesterol clefts. (D) Staining for alpha-actin positive
able 1. Morphologic Characteristics of Plaque Rupture and TCFA
mooth muscle cells within the fibrous cap was virtually negative (�400). (Reproduced with permission from Kolodgie FD, Virmani R, Burke AP, Farb, et al. Pathologic assessment of the vulnerable human coronary plaque. Heart 2004;90:1385–91.)
able 2. Comparison of the Size of the Necrotic Core, Number of Cholesterol Clefts, Macrophage Infiltration, Number of Vasaasorum, and Hemosiderin-Laden Macrophages in Plaque Rupture, TCFAs, Erosion, and Stable Plaques
Plaque TypeNecrotic Core,
%No. of Cholesterol
Clefts, %Macrophage Infiltration,
Fibrous Cap, % Mean Vasa VasorumMean HemosiderinLaden Macrophages
C16 Virmani et al. JACC Vol. 47, No. 8 Suppl CPathology of the Vulnerable Plaque April 18, 2006:C13–8
acrophages, supply tissue factor that trigger and propagatecute thrombi overlying unstable coronary atheroscleroticlaques. We have shown that monocyte infiltration of thehrombus correlates with the presence of an occlusive throm-us (7). Monocytes and neutrophils were identified in thebrous cap by myeloperoxidase (MPO) staining. In clots,cclusive thrombi have greater density of CD68-positive mac-ophage (15.7 � 12.5% vs. 3.0 � 2.7%, p � 0.05) and
PO-positive monocytes (12.2 � 7.5% vs. 5.0 � 2.7%, p �.006) and neutrophils (2.9 � 3.4% vs. 0.36 � 0.50%, p �.03) than in non-occlusive thrombi. Similarly, the length ofhe thrombus showed a positive correlation with the intra-clotensity of macrophages (p � 0.004) and MPO positive cells (p
0.04). In the disrupted fibrous cap the density of MPO-ositive cells was greater in occlusive (5.5%) versus non-cclusive (0.9%); this association was similar for neutrophils0.7% vs. 0.4%) but not for total CD68-positive macrophages13% vs. 20%) (7).
The precise role of MPO in triggering acute coronaryhrombosis is unclear. In addition to providing a pro-oxidantilieu and increasing oxidized low-density lipoprotein choles-
erol, there is evidence that macrophage MPO might beesponsible for the disruption of the fibrous cap by productionypochlorous acid (8).
LAQUE EROSION AS THE BASIS OF ACS
laque erosion is defined as an acute thrombus in direct contactith the intima, in an area of absent endothelium (Fig. 3). The
ntimal plaque underlying plaque erosion is rich in smoothuscle cells and proteoglycan matrix (9). We speculate that
oronary vasospasm might be involved in the pathophysiologyf erosion. This hypothesis is based on the observation thathere is lack of endothelium and the media in these segmentss intact and is thicker than at sites of plaque rupture (15).here are usually few or absent macrophages and lymphocytes
n plaque erosions. The lesions tend to be eccentric and arenfrequently calcified. The underlying plaque in erosions con-ists of pathologic intimal thickening or fibrous cap atheroma.he most frequent location for both erosion and rupture is theroximal left anterior descending artery (66%) followed by theight (18%) and the left circumflex (14%). Single (56%) vesselisease is twice as frequent as double vessel (26%) disease.laque erosions tend to embolize more frequently than plaque
upture (74% vs. 40%, respectively) (10).Plaque erosion accounts for 20% of all sudden deaths or
0% of coronary thrombi in patients dying suddenly withoronary artery atherosclerosis (1,3,4). The risk factors forrosion are poorly understood and are different from those ofupture. Consistently, plaque erosion is associated with smok-ng, especially in women. On average, patients are youngerhan those with plaque rupture, and there is less severearrowing at sites of thrombosis. Plaque erosion accounts for
igure 3. Coronary plaque erosion. (A) Shows a low-power view of aoronary artery obstructed by a luminal thrombus (Th) with no establishedommunication with the deep underlying plaque consistent with plaquerosion (Movat Pentachrome, �20). The plaque substrate shows a largeipid pool (Lp) with superficial smooth muscle cells and proteoglycansbluish-green stain). (B) Eroded lesions with a necrotic core (Nc). Theres a non-occlusive luminal thrombus with partial organization. (C) High-ower view of the plaque/thrombus (Th) interface in the lesion shown inanel A, showing an absence of endothelium and a substrate rich inmooth muscle cells and proteoglycan matrix (�400). (Figure 3A iseproduced form Kolodgie FD, Burke AP, Farb A, et al. Arheriosclerhrom Vasc Biol 2002;22:1642–8. Figures 3B and 3C are reproduced withermission from Kolodgie FD, Burke AP, Wight TN, et al. Curr Opin
ver 80% of thrombi occurring in women �50 years of age.
C
Tha(bfitstwcf
C
Cbcmadboaedtg
cdcrsdsgerl(saw(dv4mocw
CF
Wp
FP
C17JACC Vol. 47, No. 8 Suppl C Virmani et al.April 18, 2006:C13–8 Pathology of the Vulnerable Plaque
ALCIFIED NODULE AS THE BASIS OF ACS
he least frequent lesion of thrombosis shows a plaque that iseavily calcified consisting of calcified plates and surroundingrea of fibrosis in the presence or absence of a necrotic coreFig. 4). The luminal region of the plaque shows presence ofreaks in the calcified plate, bone formation, and interspersedbrin with a disrupted surface fibrous cap and an overlyinghrombus. There is often fibrin present in between the bonypicules along with osteoblasts and osteoclasts and inflamma-ory cells (4). It is more common in older male individuals thanomen. We believe that these lesions are commoner in the
arotid arteries than the coronary and might be related to therequent occurrence of plaque hemorrhage.
ORONARY CALCIFICATION
oronary calcification correlates highly with plaque burden,ut its effect on plaque instability is less evident. The earliestalcification in coronary lesions occurs in apoptotic smoothuscle cells, which form membrane-bound vesicles that
ctively calcify. With coalescence of microscopic calciumeposits, large granules and plates of calcium form that cane visualized by standard imaging techniques. Calcificationf coronary arteries increases with aging of the population,nd women show a 10-year lag compared with men, withqualization by the 8th decade (11). In a series of suddeneath cases, over 50% of TCFA showed a lack of calcifica-ion or only speckled calcification on postmortem radio-raphs of coronary arteries (12). In the remaining lesions,
Table 3. Approximate Sizes of Necrotic Coreand Acute Plaque Rupture
DimensionFibrous Cap Atheroma
(n � 17)
Mean length, mm (range) 6 (1–18)Necrotic core area, mm2 1.2 � 2.2Necrotic core, % 15 � 20
Reprinted, with permission, from Burke et al. (11).
igure 4. Calcified nodule. (A) Low-power view coronary artery showing a hentachrome, �20). (B) Higher-power view of the plaque surface of the lesion
alcification was almost equally divided into fragmented oriffuse, suggesting a large variation in the degree of calcifi-ation within the “TCFA.” In contrast, 65% of acuteuptures show speckled calcification, with the remainderhowing fragmented or diffuse. Plaque erosion is almostevoid of calcification or, when present, there is onlypeckled calcification. Calcified nodules are lesion with thereatest amount of calcification relative to plaque area withven bone formation. This type of lesion, however, onlyarely triggers thrombosis and tends to occur in the right oreft anterior descending coronary artery of older individuals4). It has been reported that calcification is greater inudden coronary death victims than in those dying withcute myocardial infarction or unstable angina in arteriesith 76% to 100% cross-sectional luminal narrowing
16,17). In our experience, however, calcification is depen-ent on the age of the patient in sudden coronary deathictims; radiographic coronary calcification is present in6% of men and women under the age of 40 years, 79% ofen and women ages 50 to 60 years, and 100% of those
lder than 60 years (11). For women, the degree ofalcification shows a 10-year lag compared with that of men,ith equalization by the eighth decade (11).
ORRELATION OF RISKACTORS WITH ACS PATHOLOGY
e have reported our findings relating coronary plaque mor-hology and risk factors in sudden coronary death. Thin-cap
eavily calcified eccentric plaque with eruptive calcified nodules (Movatin A, showing eruptive nodules with accumulated fibrin (�400).
fiwwtcm�pirrptAdochscscscpCinmcni�
C
TpdesdlTttahhrti
RCG
R
1
1
1
1
1
1
1
1
1
1
C18 Virmani et al. JACC Vol. 47, No. 8 Suppl CPathology of the Vulnerable Plaque April 18, 2006:C13–8
broatheromas are a frequent finding in men dying suddenlyith coronary thrombosis and are most frequent in patientsith high total cholesterol (TC) and TC/high-density lipopro-
ein (HDL) cholesterol ratio (�210 mg/dl and TC/HDLholesterol ratio �5) (1). The incidence of TCFA in women isost frequent in women �50 years and also in those with TC210 mg/dl (2). Smoking shows a positive correlation with
resence of thrombosis in sudden coronary death and more son women patients with plaque erosion as compared withupture (2). Plaques of premenopausal women demonstrateelatively little necrotic core and calcification compared withost-menopausal women and men, which might be because ofhe relatively high rate of plaque erosion in young women (2).nother risk factor that has been reported to predict theevelopment of ACS is C-reactive protein (CRP) (lower limitf normal is �3 mg/ml). The increased relative risk of suddenardiac death associated with CRP is seen only in those in theighest quartile, who were at a 2.78-fold increased risk ofudden cardiac death (95% confidence interval 1.35 to 5.72)ompared with men in the lowest quartile (18). We havehown that the median CRP was significantly higher in suddenoronary death victims dying of plaque rupture, erosion, ortable plaque than control subjects dying of noncoronaryonditions (control CRP 1.4 �g/dl vs. sudden death 2.7 �g/dl,
� 0.0001), and by multivariate analysis, log-transformedRP levels were associated with plaque burden (p � 0.03),
ndependent of age, gender, smoking, and BMI (19). Immu-ohistochemically, CRP was localized to necrotic core andacrophages and was strongest in patients with high CRP as
ompared with those with low CRP. In addition, meanumber of thin-cap atheromas was most frequent (3.0 � 0.3)
n patients with high CRP than in those with lower CRP (0.950.22) (19).
ONCLUSIONS
he TCFA has been postulated to be the precursor lesion oflaque rupture and is most frequently observed in patientsying with acute plaque rupture and least frequent in plaquerosion. It usually occurs with lesions showing �50% diametertenosis and is mostly observed in the proximal left anteriorescending, left circumflex, and right coronary arteries, fol-
owed by mid and is least frequent in distal coronary arteries.hin-cap fibroatheroma lesion differ from plaque ruptures in
hat they have smaller necrotic core, less macrophage infiltra-ion of the thin-fibrous cap that is �65 �m in thickness andre less calcified. Risk factors include high TC, low HDLs, aigh TC/HDL ratio, and a high high-sensitivity CRP level;owever, the direct relationship between TCFA and plaqueupture needs to be proven in prospective randomized clinicalrials once we have modalities to recognize the lesion by
nvasive or non-invasive means.
eprint requests and correspondence: Dr. Renu Virmani,VPath, International Registry of Pathology, 19 Firstfield Road,aithersburg, Maryland 20878. E-mail: [email protected].
EFERENCES
1. Burke AP, Farb A, Malcom GT, et al. Coronary risk factors andplaque morphology in men with coronary disease who died suddenly.N Engl J Med 1997;336:1276–82.
2. Burke AP, Farb A, Malcom GT, et al. Effect of risk factors on themechanism of acute thrombosis and sudden coronary death in women.Circulation 1998;97:2110–6.
3. Farb A, Tang AL, Burke AP, et al. Sudden coronary death. Frequencyof active coronary lesions, inactive coronary lesions, and myocardialinfarction. Circulation 1995;92:1701–9.
4. Virmani R, Kolodgie FD, Burke AP, Farb A, Schwartz SM. Lessonsfrom sudden coronary death: a comprehensive morphological classifi-cation scheme for atherosclerotic lesions. Arterioscler Thromb VascBiol 2000;20:1262–75.
5. Kolodgie FD, Burke AP, Farb A, et al. The thin-cap fibroatheroma: atype of vulnerable plaque: the major precursor lesion to acute coronarysyndromes. Curr Opin Cardiol 2001;16:285–92.
6. Virmani R, Burke AP, Kolodgie FD, Farb A. Vulnerable plaque: thepathology of unstable coronary lesions. J Interv Cardiol 2002;15:439–46.
7. Burke AP, Kolodgie FD, Farb A, Weber D, Virmani R. Role ofcirculating myeloperoxidase positive monocytes and neutrophils inocclusive coronary thrombi. J Am Coll Cardiol 2002;39:256A.
8. Sugiyama S, Okada Y, Sukhova GK, et al. Macrophage myeloperox-idase regulation by granulocyte macrophage colony-stimulating factorin human atherosclerosis and implications in acute coronary syn-dromes. Am J Pathol 2001;158:879–91.
9. Farb A, Burke AP, Tang AL, et al. Coronary plaque erosion withoutrupture into a lipid core. A frequent cause of coronary thrombosis insudden coronary death. Circulation 1996;93:1354–63.
0. Farb A, Burke AP, Kolodgie FD, et al. Platelet-rich intramyocardialthromboemboli are frequent in acute coronary thrombosis, especiallyplaque erosions. Circulation 2000;102:II774.
1. Burke AP, Virmani R, Galis Z, Haudenschild CC, Muller JE. 34thBethesda Conference: task force 2—what is the pathologic basis fornew atherosclerosis imaging techniques? J Am Coll Cardiol 2003;41:1874–86.
2. Burke AP, Weber DK, Kolodgie FD, et al. Pathophysiology ofcalcium deposition in coronary arteries. Herz 2001;26:239–44.
3. Arbustini E, Dal Bello B, Morbini P, et al. Plaque erosion is a majorsubstrate for coronary thrombosis in acute myocardial infarction. Heart1999;82:269–72.
4. Nemerson Y. A simple experiment and a weakening paradigm: thecontribution of blood to propensity for thrombus formation. Arterio-scler Thromb Vasc Biol 2002;22:1369.
5. Hao H, Gabbiani G, Camenzind E, Bacchetta M, Virmani R,Bochaton-Piallatt ML. Phenotypic modulation of intima and medialsmooth muscle cells in fatal cases of coronary artery lesions. Arterio-scler Thromb Vasc Biol 2006;26:326–32.
6. Kragel AH, Gertz SD, Roberts WC. Morphologic comparison offrequency and types of acute lesions in the major epicardial coronaryarteries in unstable angina pectoris, sudden coronary death and acutemyocardial infarction. J Am Coll Cardiol 1991;18:801–8.
7. Kragel AH, Reddy SG, Wittes JT, Roberts WC. Morphometric analysisof the composition of coronary arterial plaques in isolated unstable anginapectoris with pain at rest. Am J Cardiol 1990;66:562–7.
8. Albert CM, Ma J, Rifai N, Stampfer MJ, Ridker PM. Prospectivestudy of C-reactive protein, homocysteine, and plasma lipid levels aspredictors of sudden cardiac death. Circulation 2002;105:2595–9.
9. Burke AP, Tracy RP, Kolodgie F, et al. Elevated C-reactive protein
values and atherosclerosis in sudden coronary death: association withdifferent pathologies. Circulation 2002;105:2019–23.
![Pathophysiology of Atherosclerosis and Vulnerable Plaque[1].pdf](https://static.documents.pub/doc/80x56/55cf93f7550346f57b9eed83/pathophysiology-of-atherosclerosis-and-vulnerable-plaque1pdf.jpg)
