Pathophysiology of native coronary, vein graft, and in-stent atherosclerosis.pdf

8/19/2019 Pathophysiology of native coronary, vein graft, and in-stent atherosclerosis.pdf

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Coronary artery disease (CAD) remains the majorcause of morbidity and mortality throughout the world,despite many and continued advances in medical thera-pies. Although the survival rate of patients with CAD hasbeen steadily improving, cardiovascular disease (CVD)accounted for 17.3 million deaths worldwide in 2012,and this number is expected to grow to >23.6 million by20301. Recent estimates show that one-third of adults inthe USA (approximately 71.3 million) have some formof CVD, including >17 million with CAD and 10 millionwith angina pectoris2,3. Advancing age is the strongestrisk factor for CVD. Heart disease and stroke are the

first and fourth leading causes of death in the USA and,together, accounted for 29.4% of deaths in 20104. After40 years of age, the lifetime risk of coronary heart diseaseis 49% in men and 32% in women, according to findingsfrom the Framingham Heart Study 5.

CABG surgery is the standard of care for patientswith three-vessel disease or left main disease withreduced ejection fraction, as supported by many studiesshowing a reduction in morbidity and mortality relativeto percutaneous coronary intervention6. Of the graftoptions — vein graft versus internal mammary arteries(IMAs) — the latter have the better long-term patency 7;however, only 5–10% of patients receive bilateral IMAs,

because of the increased perioperative morbidity, mor-tality, duration of operation, and risk of sternal woundproblems that are reported for this type of graft7. Of note,10–25% of saphenous vein grafts (SVGs) occlude fromthrombosis within 1 year after CABG surgery 8–10, andan additional 1–2% occlude each year from 1 year to5 years after CABG surgery 11. Moreover, 4–5% occludeeach year from 6 years to 10 years postoperatively, owingto accelerated development of atherosclerosis11.

Currently, percutaneous coronary interventionwith stents (either bare-metal stents (BMS) or drug-elutingstents (DES)) is the most commonly performed pro-

cedure for the treatment of patients with symptomaticCAD. Delayed arterial healing with poor strut coverage isrecognized as the primary substrate for stent thrombosisattributed to the first-generation DES12,13. However, wehave reported that neoatherosclerosis within the ‘in-stent’segment is another complication of first-generationand second-generation DES, resulting in late stent fail-ure from restenosis or stent thrombosis induced byplaque rupture14,15.

The temporal presentation of atherosclerosis in theform of clinical events differs between native CAD,which develops over decades, and vein graft athero-sclerosis and in-stent neoatherosclerosis, which occur

1CVPath Institute, Inc.,

19 Firstfield Road,

Gaithersburg,

MD 20878, USA.2Department of Medicine,

Emory University Hospital,

550 Peachtree Street,

Nebraska, Atlanta,

GA 30308, USA.

Correspondence to R.V.

[email protected]

doi:10.1038/nrcardio.2015.164

Published online 27 Oct 2015

Pathophysiology of native coronary,vein graft, and in-stent atherosclerosisKazuyuki Yahagi 1, Frank D. Kolodgie1, Fumiyuki Otsuka1, Aloke V. Finn2, Harry R. Davis1,

Michael Joner 1 and Renu Virmani 1

Abstract | Plaque rupture, usually of a precursor lesion known as a ‘vulnerable plaque’ or ‘thin-cap

fibroatheroma’, is the leading cause of thrombosis. Less-frequent aetiologies of coronary

thrombosis are erosion, observed with greatest incidence in women aged


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within months to a few years. This Review is focused on

the structural characteristics of human atheroscleroticplaques for these three entities, with emphasis on diseaseprogression where divergent or shared characteristics of

lesion morphology exist. We also provide an updatedclassification scheme for atherosclerotic lesions (TABLE 1,FIGS 1,2), which should now replace our previous recom-mendations on lesion classification (the ‘modified AHAclassification’) that were published in 200016.

Native coronary artery disease

Historical perspective

In the late 1970s, Russell Ross highlighted the impor-tance of smooth muscle cell (SMC) proliferation inatherosclerotic lesion formation, and hypothesized thatinjury to the arterial wall had a major role in plaqueprogression17,18. Inflammation was later identified asthe primary driving force for activation and prolifera-tion of SMCs, processes mediated by growth factors19.Subsequent studies from Libby and Hansson in the late1990s indicated that the mechanism of disease progres-sion involved a complex interaction between risk fac-tors and inflammation; their work resulted in a moveaway from the idea that atherosclerosis was a bland pro-liferative disorder to the concept of it being a complex

inflammatory disease of the vessel wall20–22. During thesame period, Fuster and colleagues observed plaqueprogression as staged events: initial involvement of the

Key points

• The aetiology of luminal thrombosis in native coronary arteries is

predominately plaque rupture, but can also be surface erosion and, least frequently,

calcified nodules

• The main precursor lesion with potential for rupture is identified as a ‘vulnerable

plaque’ or ‘thin-cap fibroatheroma’, and is considered an appropriate therapeutic

target for patients at risk of future coronary events

• Native coronary disease develops over decades, whereas accelerated atherosclerosis

is observed in saphenous vein grafts and in stents within months to years

• In saphenous vein grafts and stents, accelerated atherosclerosis is likely to develop

from resident macrophage-derived foam cells, which undergo apoptosis and form

necrotic cores; pathological intimal thickening is rarely observed

• By contrast, native coronary disease is thought to progress from lipid pools associated

with pathological intimal thickening; necrotic cores arise from macrophage

infiltration of these lipid pools

• Important morphological identifiers of accelerated plaque progression include

macrophage foam cells, intraplaque haemorrhage, and fibrous cap thickness

Table 1 | Updated classification of atherosclerotic lesions based on morphology

Type of lesion Subtype of lesion Morphological description

Nonatheroscleroticintimal lesions

Intimal thickening Natural accumulation of smooth muscle cells in the absence of lipid,macrophage foam cells, and thrombosis.

Intimal xanthoma Superficial accumulation of foam cells without a necrotic core, fibrouscap, or thrombosis.

Progressiveatheroscleroticlesions

Pathological intimalthickening

Plaque rich in smooth muscle cells, with hyaluronan and proteoglycanmatrix and focal accumulation of extracellular lipid. Absence ofthrombosis.

Fibroatheroma During early necrosis: focal macrophage infiltration into areas of lipidpools with an overlying fibrous cap. During late necrosis: loss of matrixand extensive cellular debris with an overlying fibrous cap. With orwithout calcification. Absence of thrombosis.

Intraplaquehaemorrhage orplaque fissure

Large necrotic core (size >10% of plaque area) with haemorrhage,and plaque area shows presence of angiogenesis. Necrotic corecommunicates with the lumen through a fissure. Minimal tear withoutobvious thrombus.

Thin-capfibroatheroma

A thin, fibrous cap (10% of plaque area). Intraplaque haemorrhage and/orfibrin might be present. Absence of thrombosis.

Lesions withacute thrombi

Plaque rupture Thin-cap fibroatheroma with cap disruption. Thrombosis is present andmight or might not be occlusive. The luminal thrombus communicates

with the underlying necrotic core.Plaque erosion Can occur on pathological intimal thickening or on a fibroatheroma.

Thrombosis is present and might or might not be occlusive.No communication of the thrombus with the necrotic core.

Calcified nodule Eruptive (shedding) of calcified nodule with an underlying fibrocalcificplaque with minimal or no necrosis. Thrombosis is usually not occlusive.

Healed lesions Healed plaquerupture, erosion, orcalcified nodule

Healed lesion composed of smooth muscle cells, proteoglycans, andcollagen type III with or without underlying disrupted fibrous cap,necrotic core, or nodular calcification. Lesions can contain large areas ofcalcification with few inflammatory cells and have a small or no necroticcore. The fibrotic or fibrocalcific collagen-rich plaque is associated withsignificant luminal stenosis. Absence of thrombosis.

An updated version of the modified AHA classification published in 200016, which was based on the original AHA classificationpublished in the mid 1990s25.

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endothelium, which was causally linked to the develop-ing intima, with further injury of the underlying mediain the advanced phases of development. They also recog-nized that deep plaque fissures and ulcerations resulted

in the manifestation of complex lesions, as a cause ofluminal thrombosis and clinical presentation of acutecoronary syndrome23,24.

An AHA consensus document on atherosclero-sis class ification was published in the mid-1990s25.The classification involved six distinct categories: type I,intimal thickening; type II, fatty streak; type III, tran-sitional or intermediate lesion; type IV, advanced ath-eroma with well-defined region of the intima; type V,fibroatheroma or atheroma with overlaid new fibrousconnective tissue; and type VI, complicated plaques withsurface defects, haematoma or haemorrhage, thrombo-sis, or a combination of these characteristics25. However,

this classification failed to capture two important clinicalaetiologies of coronary thrombus that are distinct fromplaque rupture — surface erosion, which accounts for25–30% of thrombosis cases, and the less frequent, but

still important, eruptive calcified nodules, which occurin


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characteristics conceivably leading to coronary throm-bosis would not only provide important mechanisticinsights into understanding lesion progression, but alsosupport efforts leading to improvements and refine-

ments in diagnostic imaging. The notion of vulnerableplaque, as a precursor to rupture, also fails to fit preciselyinto an orderly numerical classification as set forth bythe AHA25,28. These constraints, therefore, prompted usto develop a modified scheme16, in which AHA lesiontypes I–IV were replaced by descriptive terms of: adap-tive intimal thickening, intimal xanthoma (fatty streak),pathological intimal thickening, and fibroatheroma.Fibroatheromas were more recently subcategorizedinto ‘early’ stage and ‘late’ stage plaques, on the basis oflytic and nonlytic characteristics of the necrotic core29. Inour scheme16, AHA categories V and VI were discardedbecause they failed to account for the three aetiologies

(rupture, erosion, and calcified nodule) that give rise tocoronary thrombosis. The precursor lesions to plaquerupture, originally known as ‘vulnerable plaques’, wereclassified as ‘thin-cap fibroatheroma’ (TCFA). Additionalterms were also introduced to implicate the suddenenlargement of plaques from silent episodic thrombosis(healed plaque rupture (HPR)), and plaque fissures16.

The concept of plaque healing is also not accountedfor in the AHA numerical classification, as HPRs orhealed erosions can eventually give rise to increasedplaque burden, luminal narrowing, and possible nega-tive remodelling, or even silent or symptomatic chronictotal occlusion (CTO)16. Similarly, we added terms thatinferred lesion stability, such as ‘fibrous’ or ‘fibrocalcific’,and ‘nodular calcification in the absence of thrombosis’,which are more commonly observed in patients present-ing with stable CAD, or long-standing diabetes mellitusand chronic renal failure.

Nonatherosclerotic intimal lesions

Adaptive or diffuse intimal thickening. Adaptive or dif-

fuse intimal thickening (FIG. 3a) is often observed in ather-osclerosis-prone arteries (the coronary, carotid, and iliacarteries, as well as the abdominal and descending aorta)30,and is considered a physiological response to blood flowrather than an atherosclerotic process. Study of neo-nates31, and of adolescents and young adults32, has indi-cated that intimal masses that form near branch pointsenlarge with advancing age and might be precursorsto high-risk plaques with the potential to thrombose.

Intimal xanthomas. Intimal xanthomas (FIG. 3b), orso-called ‘fatty streaks’, are lesions primarily composed ofinfiltrating macrophage foam cells and, to a lesser extent,lipid-laden SMCs within the intima33,34. This type of lesionhas been shown to regress, especially in the thoracic aortaand the right coronary artery in young individuals35–37.Intimal xanthomas do not always convey the mandatoryfeatures of more-advanced atherosclerotic plaques and,therefore, are not considered progression-prone disease.

Progressive atherosclerotic lesions

Pathological intimal thickening. Pathological intimalthickening (FIG. 4a,b) is the earliest progressive lesionconsisting of SMC remnants within an extracellularmatrix (ECM) composed of proteoglycans and collagentype III with a co-existing lipid pool16. The ECM con-sists primarily of hyaluronan and proteoglycans biglycan,

decorin, and versican admixed with neutral lipids andfree cholesterol. Remnants of apoptotic SMCs are gen-erally visualized by a thickened basement membrane onperiodic acid–Schiff (PAS) staining38, and are thoughtto support continued intimal growth. The lipid poolsshow a relative absence of viable SMCs. When present,resident macrophages in pathological intimal thickeningare often seen localized to the luminal aspect of the lipidpool, which is likely to indicate a more-advanced stage ofatherogenesis. Typical pathological intimal thickening,consisting of extracellular lipid under layers of macro-phage-derived foam cells, is found at locations nearbranch points39.

Intimalthickening

Pathological

intimalthickening

Rupture(necrotic core)

Fibrocalcific plaque

(with or withoutcalcified sheets)

Healed plaquerupture or erosion

Nodularcalcification

Acute myocardial infarctionor unstable angina,

± sudden death

Total occlusion

Sudden death,stable angina,

or congestive heart failure

Thin-capfibroatheroma

Angiogenesis,inflammation, andcalcification leads tointraplaque haemorrhageor plaque fissure

Inflammation, cell death,and MMPs contribute tothinning of the fibrous cap

Foamymacrophages

InfrequentLipid pool arises fromSMC apoptosis anddeposition of proteoglcan,hyaluronan, and lipid

Conversionof lipid pool

to necrotic corewith macrophage

infiltration

Second-most-common pathway

Most-commonpathway

Least-commonpathway

>75% arealuminal narrowing

Fibroatheroma

Erosion Calcified nodule

Healing

Intimal xanthoma(fatty streak)

Fibrocalcific plaque(with calcified sheets)

Thrombosis

Healedrupture

Healed erosion>75% area

luminal narrowing

Figure 2 | Simplified scheme for classifying atherosclerotic lesions in human

coronary arteries. Solid arrows indicate the main pathway of plaque progression, and

dashed arrows indicate infrequent pathways. Abbreviations: MMP, matrix

metalloproteinase; SMC, smooth muscle cell.

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The current view of subendothelial lipid retentioninvolves the interaction of negatively charged sulphategroups present in glyocosaminoglycan (GAG) side chainsof proteoglycans with positively charged domains of apo-lipoprotein B (apoB)39–41. The direct attraction betweenLDL and proteoglycans is further facilitated by theactivity of lipoprotein lipase42. Dermatan sulphate pro-teoglycan of the decorin type is not observed in healthyintima, which is rich in SMCs, but has been reported inthe intima of lesions of adaptive intimal thickening, espe-cially in zones with reduced staining for SMC α-actin43,which might facilitate the retention of apoB-100 in theseearly lesions. Fine crystalline structures of free cholesterolare also seen in lipid pools, but never in excess. Smithand Slater found a high percentage of unesterified choles-terol in the deep layers of the lipid pool in early plaques,and concluded that most of this cholesterol was deriveddirectly from plasma LDL44. However, the precise originof free cholesterol in pathological intimal thickeningremains unknown, but might be derived from mem-branes of dead SMCs45. Pathological intimal thickeningis also the earliest type of lesion exhibiting calcification;

von Kossa or Alizarin red staining (FIG. 5) demonstrates

the presence of microcalcification (≥0.5 μm, and typically


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total cholesterol level and a high ratio of total:HDL cho-lesterol, individuals who smoke, women aged >50 years,and patients with elevated levels of C-reactive proteinmeasured by high-sensitivity assay have increased riskof TCFA59.

TCFAs (FIG. 4e) generally have a large ‘late’ necroticcore, with an overlying thin intact fibrous cap that iscomposed predominantly of collagen type I with var-ying degrees of macrophages and lymphocytes, andpaucity or absence of SMCs. Fibrous cap thickness


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reports16, with plaque ruptures being the most-frequentcause (65%), followed by erosions (30%), and calcifiednodules (5%)65.

In a clinical study of 126 patients with ACS publishedin 2013, the frequency of thrombosis was assessed usingoptical coherence tomography (OCT)66. The OCT-identified prevalence of plaque rupture, erosion, and cal-cified nodule was 43.7%, 31.0%, and 7.9%, respectively.Patients identified using OCT as having erosion wereyounger than those identified as having plaque rupture orcalcified nodule (53.8 ± 13.1 years versus 60.6 ± 11.5 yearsand 65.1 ± 5.0 years, respectively; P = 0.005)66. Notably,relative to rupture, the OCT diagnosis of plaque ero-sion is clinically challenging. The current definitionis dependent on the finding of thrombi attached to anintact plaque, referred to as ‘definitive’ plaque erosion,or luminal irregularities without presenting thrombus orthrombi in the absence of underlying complications oflipid or calcium, suggestive of ‘probable’ plaque erosion.The diagnosis of erosion by OCT, however, remains con-troversial and needs further testing and refinement. The

diagnosis of plaque erosion also exists under the umbrellaof intact fibrous cap (IFC), which additionally includesplaques with a thick fibrous cap with or without necroticcores and/or calcium. Further limitations of OCT includethe inability to separate a lipid pool from a necrotic core,and failure to recognize the presence or absence ofsurface endothelium.

Plaque rupture. Plaque ruptures (FIG. 6a) consist of anecrotic core with an overlying disrupted thin fibrouscap, which is generally infiltrated by macrophages andT lymphocytes. The ECM of the fibrous cap is mainlycomposed of collagen type I and contains very few, ifany, SMCs. The luminal thrombus at the site of ruptureis always predominantly composed of platelets (‘whitethrombus’), and might or might not be obstructive.Propagated (older) thrombi proximal and distal torupture sites usually consist of layers of fibrin (lines ofZahn) interspersed with red blood cells (‘red throm-bus’), and tend to move to the nearest side branch,thus allowing blood to reflow through the collateralbranch. Rupture of the fibrous cap is generally thoughtto occur at its weakest point involving shoulder regions.However, although we have found that this is typicallytrue at rest, we have observed that during exercise,ruptures at the mid portion of the fibrous cap occur atthe same frequency as ruptures at shoulder regions67.

Therefore, we speculate that different processes mightlead to the final event of plaque rupture, where selectproteases secreted by macrophages68 might weaken thefibrous cap, and high shear and tensile stress might alsobe involved69. Within the fibrous cap, microcalcifica-tions (>5 μm) derived from dying macrophages and/orSMCs might be another possible trigger of plaque rup-ture, potentially causing stress-induced debonding ofthe fibrous cap70,71.

In a previous study, serum analysis of total cholesterol,HDL cholesterol, ratio of total cholesterol to HDL, andserum thiocyanate (a surrogate marker for smoking)was assessed in 113 men after SCD60. Risk factors were

present in 96.5% of individuals60. Smoking was found tobe a predictor of acute thrombosis regardless of plaqueaetiology, and plaque rupture correlated with high totalcholesterol, low HDL cholesterol, and an elevated ratioof total:HDL cholesterol. Furthermore, increased lev-els of total cholesterol correlated with a greater numberof TCFAs.

Erosion. Erosions (FIG. 6b,c) occur in the absence of rup-ture where luminal thrombi are in direct contact with adenuded intimal surface consisting of SMCs and proteo-glycan matrix27. The underlying lesion is a pathologicalintimal thickening in 16% of patients and an early or latefibroatheroma in 50% and 34% of patients, respectively 72.In the majority of erosions, the medial wall is intact andless inflamed than in ruptures. Additionally, in contrastto ruptures, which generally show positive remodelling,erosions involve negative remodelling73. The majority oferosions (56%) lack evidence of calcification, althoughmicrocalcification is observed in approximately 40% oflesions; fragmented calcification and sheets of calcifi-

cation are rare (


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in noneruptive nodular calcification, potentially aris-ing from surrounding capillaries that are leaky and/ordamaged, given that no communication exists with thelumen. Eruptive calcified nodules typically occur ineccentric lesions in which protrusion causes disruptionof the overlying luminal endothelium, which is likely totrigger platelet adherence. Calcified nodules are morecommonly found in the mid-right coronary artery orleft anterior descending artery, where torsion stress ismaximal16. Calcified nodules are more commonly foundin older individuals. Eruptive calcified nodules shouldnot to be confused with ‘nodular calcification’, becausethe latter does not involve luminal thrombi, althoughit can cause medial wall disruption with rare extensioninto the adventitia.

Mechanisms of lesion progression

Episodic rupture and healing. In the early 1990s, Mannand Davies introduced the concept of plaque progressionthrough the identification of episodic rupture and heal-ing (FIG. 7a,b) in coronary arteries from patients who haddied as a result of unstable angina or acute myocardialinfarction. On average, individuals had 2.4 episodes ofcoronary thrombosis described as minor nonocclusivethrombi, which seemed to contribute to luminal narrow-ing78. Microscopic analysis of Picrosirius Red staining

viewed under polarized light identified HPRs as breaksin the fibrous cap showing disrupted collagen type I,together with an overlying repair reaction consisting ofSMCs, proteoglycans, and varying amounts of differenttypes of collagen, dependent on the time since rupture78.

Silent luminal thrombi are usually nonocclusive,but if occlusive, chronic total occlusion occurs (FIG. 7c).Nonocclusive thrombi can result from silent plaque rup-tures or erosions, and the thrombus will organize withgranulation tissue and subsequent infiltration by SMCswith deposition of proteoglycans and collagen79. However,

the thrombus propagates proximally and distally and,when they heal, it converts into a fibrous plaque (FIG. 8).

Progressive healing of silent ruptures is characterizedby the initial accumulation of proteoglycans and colla-gen type III, which is later replaced by collagen type I.Although the prevalence of silent ruptures in the gen-eral population remains unknown, Mann and Daviesreported an incidence of HPRs of 16% in plaques with≤20% diameter stenosis, 19% with 21–50% diameterstenosis, and 73% for plaques with >50% diameter ste-nosis; the difference in the numbers of HPRs in lesionswith stenosis


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Necrotic core expansion. In the 1960s, Constantinidesand colleagues initially described the notion of cracksor fissures (FIG. 9a) originating from the luminal surfaceas an entryway of blood into the lesions81. This conceptwas expanded upon in the 1980s by Michael Davies, whodefined the term ‘plaque fissure’ as an eccentric collec-tion of blood, giving rise to fibrin deposition withinthe necrotic core82. As highlighted by Davies, fissuresand plaque ruptures are distinct entities; the latter arealways accompanied by an appreciable luminal throm-bus, whereas fissures generally have an intra-intimal

thrombus consisting of fibrin and platelets with scatterederythrocytes and, if present, luminal thrombi associatedwith fissures are generally very small. Rather than beingan overt breech of the fibrous cap and superimposedthrombus, as seen in ruptures, a lateral or marginal tearin an eccentric plaque with underlying small necroticcore characterizes the plaque fissure. The separation lineof the fissure begins in the necrotic core and extends intothe lumen. The path is lined by few macrophages and redblood cells and/or fibrin.

The more-dominant mechanism of intraplaque haem-orrhage (FIG. 9b), however, occurs through intraplaque

vasa vasorum, which extend into the intima from theadventitia. Kumamoto and colleagues demonstrated thatintraplaque haemorrhages are 28-fold more commonthan plaque fissures83. The extent of neovascularizationcorrelated with luminal stenosis and inflammation, and

vascular density was reduced in extensively hyalinizedand calcified arteries.

Advanced necrotic cores typically show an abun-dance of free cholesterol. This free cholesterol is unlikely

to be derived from macrophages, given that cholesterolis present in an esterified form in macrophages84. Redblood cell membranes contain more free cholesterolthan any other cell in the body; therefore, intraplaquehaemorrhage is a more logical origin of the free cho-lesterol seen in advanced necrotic cores. Using glyco-phorin A, a specific marker for extravasated red bloodcells, together with iron staining for haemoglobin, weshowed that intraplaque haemorrhage in lesions fromcases of SCD was more common in ruptured plaques,TCFAs, and fibroatheromas with late necrotic cores thanin early plaques. Moreover, the extent of glycophorin Aimmunostaining was proportional to the size of thenecrotic core, which also showed greater macrophageinfiltration29,85. Intraplaque haemorrhage was also shownto be likely to occur from leaky vasa vasorum. Unlike inthe adventitia, the endothelium of neoangiogenic ves-sels found within the plaque lack competent junctions,and exhibit membrane blebs, intra-cytoplasmic vacu-oles, and basement membrane detachments53,86. Poorlyformed, ‘leaky’ endothelial junctions frequently showan association with inflammation, particularly withmacrophages and T lymphocytes53, and are highly sus-ceptible to extravasation of red blood cells contributingto intraplaque haemorrhage87.

Notably, intraplaque haemorrhage is considered to beone of three factors contributing to the sudden increase

in lesion size (the others being luminal thrombus andplaque fissure) that can cause the onset of acute coro-nary syndromes. The concept of plaque enlargement asa consequence of collections of erythrocytes and fibrinwithin the necrotic core is mainly supported by autopsyand clinical MRI studies29,88,89.

Calcification in advanced plaques

In post-mortem angiography, calcification in advancedlesions can be present in speckled, fragmented (linear orwide, single focus of calcium >2 mm in diameter), or dif-fuse (≥5 mm segment length of continuous calcification)forms (FIG. 10)90,91. Speckled calcification is most frequent

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Figure 6 | Human coronary lesion morphologies categorized as ‘lesions with acute

thrombi’. Histological and schematic images are shown for a | plaque rupture, b | plaque

erosion with underlying pathological intimal thickening, c | plaque erosion with underlying

fibroatheroma, and d | calcified nodule. Arrowheads indicate fibrous cap. Abbreviations:

NC, necrotic core; Th, thrombus. Histological images in panels a, b, and d reprinted from

Falk, E. et al. Update on acute coronary syndromes: the pathologists’ view. Eur. Heart J.

34 (10), 719–728 (2013) by permission of Oxford University Press and the European

Society of Cardiology.

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in plaque ruptures whereas fragmented or diffuse calcifi-cation is more common in HPRs. In an autopsy study ofindividuals dying with severe coronary disease, calcifica-tion was dependent on the age of the patient and is seenby radiography in 46% of individuals aged 60 years61. Compared with men, womenshowed a 10-year lag in coronary calcification, until

the extent of calcification equalized in the eighth dec-ade61. The incidence of calcification in postmenopausalwomen aged >50 years is at least threefold higher thanin premenopausal women aged


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Advanced lesions involving HPRs are supported bya microenvironment that fosters lesion calcification andfibrosis. In fibrocalcific plaques, calcium presents as cres-cent-shaped sheets. Mechanical factors within heavilycalcified tortious vessels can lead to fragmentation giv-ing rise to nodular calcification or calcified nodule with

luminal thrombosis, but this outcome is rare. In contrastto rupture or erosion, thrombus propagation with organ-ization eventually results in luminal narrowing fromneointimal tissue that is fibrotic in composition.

Diabetes has been linked to a higher incidence ofcoronary artery disease with greater macrophage andT lymphocyte infiltrates in atherosclerotic plaques, aswell as larger necrotic cores compared with plaques inindividuals without diabetes99. A higher incidence ofHPRs and healed myocardial infarction is found amongindividuals with type 2 diabetes, together with greaterplaque burden.

In an acute coronary syndrome — that is, unsta-ble angina, myocardial infarction (with or withoutST-segment elevation) or sudden death — the contrib-uting lesion is associated with >75% luminal narrowingand probably a luminal thrombus, which might or mightnot be occlusive, together with intraplaque haemorrhageand/or plaque fissure. We have reported the highest inci-dence of TCFA in patients presenting with acute rupture,followed by those presenting with HPR, stable plaqueand, least frequently, in plaque erosion and deaths froma noncoronary cause61. By contrast, patients presentingwith stable angina generally have lesions with severeluminal narrowing in one or more coronary arteries withmorphologies of HPR or fibrocalcific plaques.

Accelerated atherosclerosis

Atherosclerosis in saphenous vein grafts

Compared with native coronary arteries, SVGs aremore susceptible to atherosclerosis, and the develop-ment of this pathology occurs on an accelerated timescale. Within the first year after implantation, all vein

grafts show intimal thickening, an adaptive responseto systemic circulation and surgical handling. Intimalhyperplasia in SVGs consists of a concentric distributionof SMCs, proteoglycans, and collagen type III. The ear-liest atherosclerotic change in SVGs is reported around1 year and is characterized by foam-cell accumulationfollowed by the development of a necrotic core, whichis observed between 2 and 5 years after surgery. SVGimplants aged >5 years often show necrotic core expan-sion through intraplaque haemorrhage, which is likelyto arise from the lumen and/or leaky neoangiogenic

vessels100–102. Haemorrhagic events might contribute toplaque rupture, which typically occurs between 5 and10 years after surgery 101. The clinical SVG attrition ratefrom the first to the seventh postoperative year is 2% peryear, which increases to 5% per year from the seventhto the twelfth year103; at 10 years, only 38–45% of SVGsremain patent104.

A section-based analysis of SVGs implanted for8.5 ± 5.9 years (range 2–22 years; FIG. 12) performed inour laboratory showed 56.5% total cross-sections withintimal thickening contributing to an overall mean per-cent stenosis of 34 ± 15%101. Lesions with exclusive foam-cell infiltration (intimal xanthomas or ‘fatty streaks’)were observed in 18.8% of sections with a percent steno-sis of 37 ± 9%101. Fibroatheromatous lesions with necroticcores were observed in 11.9% of sections, demon-

strating a mean stenosis of 46 ± 17%. Complicationsof intraplaque haemorrhage into a necrotic core wereobserved in 7.5% of sections101. The least frequent lesionmorphology of plaque rupture and thrombosis wasobserved in 6.3% of sections, with a mean stenosis of75 ± 24%101.

Circumferential intimal thickening is an early adap-tive response in all SVGs. Intimal xanthomas or ‘fattystreaks’, lesions with multilayered foam cells, are typicallypresent beyond 1 year. In contrast to native coronarydisease, however, early SVG lesions typically express

varying degrees of macrophage apoptosis, which resultin necrotic cores that cause nominal expansion of the

Collagen

Lumen

1.0 mm200 μm

Artery wall

Figure 8 | Nonocclusive propagated thrombi that heal can contribute to the

formation of fibrous plaques. Histological and schematic images are shown for a

fibrous plaque.

a

b

1.0 mm

200 μm

1.0 mm

200 μm

Artery wall

Lumen


Collagen

Necrotic core

Cholesterol clefs

Calcified plaque

Angiogenesis

Haemorrhage

Fibrin

Figure 9 | Plaque morphologies that can lead to necrotic core expansion.

Histological and schematic images are shown for a | plaque fissure, and b | intraplaque

haemorrhage. Arrowheads indicate neoangiogenesis.

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plaque105; lipid pools are not involved in this process.Typical SVG atherosclerosis is often concentric and dif-fuse, with a less well-defined fibrous cap than in nativecoronary disease; the cap seems fragile and vulnerableto rupture106.

Critical factors underlying rapid neointimal growthin SVGs result from endothelial injury and exces-sive mechanical stretching of the vein under arterialpressure. Arterialization with fibrointimal thickening

is a consistent adaptive change that occurs in SVGimplants aged


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reduction in neointimal thickness has been found whenserum cholesterol levels are


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differ significantly from the incidence in SES (35%) andPES (19%)15. The dominant morphology in CoCr-EESand PES was foamy macrophage clusters (seen in 67% ofCoCr-EES and 87% of PES), which was less frequentlyobserved in SES (32%)15. Notably, unstable features

of neoatherosclerosis recognized as TCFA or plaquerupture were not observed in CoCr-EES. Althoughpathological examination showed a higher incidence ofplaques with neoatherosclerosis in restenotic lesions infirst-generation DES than in second-generation DES,clinical studies indicate a similar prevalence of unstablelesions in restenotic lesions between first-generation andsecond-generation DES112.

In-stent erosion is a rare event that is character-ized by an underlying neointima rich in proteoglycanmatrix fully incorporating all struts, and a superimposedthrombus on a luminal substrate that lacks endothelium.In erosions in BMS with restenosis, we have shown that

damaged endothelium owing to high shear at sites ofsevere stenosis can potentially cause thrombosis, usuallywithin the first year after stent implantation113. In DES,however, the rare phenomenon of erosion is likely toresult from reoccurring thrombosis and healing.

Comparison of atherosclerotic processes

In contrast to the decades that it takes for atherosclero-sis to develop in native coronary disease, vein-graftatherosclerosis and in-stent neoatherosclerosis developover a period of months to a few years. This temporaldifference might reflect the morphological diversityrelative to the natural history of progression amongthese entities. Adaptive intimal thickening in nativearteries within the first year after stent implantationparallels the neointimal hyperplasia observed in veingrafts (FIG. 14). SMC proliferation without macrophagefoam cell infiltration is frequently observed in BMS

a

c d

e f

b

1.0 mm


Collagen

Cholesterol clefs

Haemorrhage

Collagen + proteoglycans

Artery wall

Lumen

Smooth muscle cells

Necrotic core

Calcified plaque

Thrombus

Figure 12 | Accelerated atherosclerotic disease in saphenous vein grafts. Histological and schematic images are

shown.a | Within the first year, arterialization and fibroinitimal thickening of the vein graft occurs. b | Progressive foam-cell

accumulation follows, resulting in an intimal xanthoma. c | At 1–3 years after graft implantation, a necrotic core forms,resulting in a fibroatheroma. d | After 4–5 years, intraplaque haemorrhage into the lipid core is observed, with

moderate-to-severe luminal narrowing. e | After 5–10 years, plaque rupture of the large necrotic core is accompanied by

haemorrhage, often leading to luminal thrombus. f | Fibroinitimal thickening is commonly observed at the coronary

anastomosis where atherosclerotic disease is uncommon (fibrous plaque). Modified from Yazdani, S. K. et al. Pathology of

drug-eluting versus bare-metal stents in saphenous vein bypass graft lesions. JACC Cardiovasc. Interv .5 (6), 666–674

© (2012), with permission from Elsevier.

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a

c d

e

f

b

Th

NC

1.0 mm

NC

NC

Th

1.0 mm

Th

1.0 mm 1.0 mm

Th

1.0 mm

MΦ

1.0 mm

MΦ

g

NC

1.0 mm

200 µm

h i

NC

1.0 mm

NC

1.0 mm

Calcified plaque

Angiogenesis

Haemorrhage

Artery wall

Lumen


Collagen

Necrotic core

Cholesterol clefs

Thrombus

Neointima

Strut

Healed thrombus

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implants, especially in those aged 95% of late thrombicaused by plaque rupture

100% of late thrombosis in BMS and33% in DES caused by plaque rupture

Figure 14 | Plaque progression and frequency of plaque rupture in native

atherosclerotic disease, vein-graft atherosclerosis, and in-stent neoatherosclerosis.

Abbreviations: AIT, adaptive intimal thickening; BMS, bare-metal stent; DES, drug-eluting

stent; PIT, pathological intimal thickening; TCFA, thin-cap fibroatheroma.

◀

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Notably, in both SVG atherosclerosis and in-stentneoatherosclerosis, disease progression occurs withinmonths to a few years, and actual plaque rupture withclinical events takes between 2 and 10 years. In nativecoronary disease, this process occurs over decades.

The morphological comparison of the patho-physiology of atherosclerotic plaque progression,

as presented in this Review, should help to advanceour understanding of native atherosclerotic disease,SVG atherosclerosis, and the neoatherosclerosis thatoccurs in stents. Further unravelling of the complexi-ties of atherosclerosis is required to aid in the develop-ment of improved strategies for cardiovascular riskmodification and disease prevention.

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Table 3 | Prevalence of lesion morphologies in native coronary, vein-graft, and in-stent atherosclerosis

Lesion morphology Native coronaryatherosclerosis

Vein-graftatherosclerosis

In-stent atherosclerosis(neoatherosclerosis)

Intimal thickening/fibrous plaque ++++ ++++ ++++

Intimal xanthoma (‘fatty streak’) ++++ ++++ ++++

Pathological intimal thickening ++++ – + (BMS)

Fibroatheroma ++++ ++++ +++

Fibroatheroma with haemorrhage ++++ ++++ +++

Thin-cap fibroatheroma ++++ +++ +++

Plaque rupture +++ ++++ ++ to +++

Plaque erosion ++ + +

Calcified nodule + – –

Healed plaque rupture +++ – +

Fibrocalcific plaque ++++ + +++

Chronic total occlusion ++++ ++++ ++

Abbreviations: –, not seen; +, rare; ++, occasional; +++, common; ++++, very common; BMS, bare-metal stent.

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