Pathophysiology of Native Coronary, Vein Graft, and In-Stent Atherosclerosis PDF

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Pathophysiology of native coronary,

vein graft, and in-stent atherosclerosis
Kazuyuki Yahagi1, Frank D.Kolodgie1, Fumiyuki Otsuka1, Aloke V.Finn2, Harry R.Davis1,
Michael Joner1 andRenu Virmani1
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 <50years, and eruptive
calcified nodules, which are occasionally identified in older individuals. Various treatments for
patients with coronary artery disease, such as CABG surgery and interventional therapies, have
led to accelerated atherosclerosis. These processes occur within months to years, compared with
the decades that it generally takes for native disease to develop. Morphological identifiers of
accelerated atherosclerosis include macrophage-derived foam cells, intraplaque haemorrhage,
and thin fibrous cap. Foam-cell infiltration can be observed within 1year of a saphenous vein graft
implantation, with subsequent necrotic core formation and rupture ensuing after 7years in over
one-third of patients. Neoatherosclerosis occurs early and with greater prevalence in drug-eluting
stents than in bare-metal stents and, although rare, complications of late stent thrombosis from
rupture are associated with high mortality. Comparison of lesion progression in native
atherosclerotic disease, atherosclerosis in saphenous vein grafts, and in-stent neoatherosclerosis
provides insight into the pathogenesis of atheroma formation in natural and iatrogenic settings.
CVPath Institute, Inc.,

19 Firstfield Road,
Gaithersburg,
MD20878, USA.
2
Department of Medicine,
Emory University Hospital,
550 Peachtree Street,
Nebraska, Atlanta,
GA30308, USA.
1
Correspondence toR.V.
rvirmani@cvpath.org
doi:10.1038/nrcardio.2015.164
Published online 27 Oct 2015
Coronary artery disease (CAD) remains the major

cause of morbidity and mortality throughout the world,
despite many and continued advances in medical therapies. Although the survival rate of patients with CAD has
been steadily improving, cardiovascular disease (CVD)
accounted for 17.3million deaths worldwide in 2012,
and this number is expected to grow to >23.6million by
20301. Recent estimates show that one-third of adults in
the USA (approximately 71.3million) have some form
of CVD, including >17million with CAD and 10million
with angina pectoris2,3. Advancing age is the strongest
risk 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. After
40years of age, the lifetime risk of coronary heart disease
is 49% in men and 32% in women, according to findings
from the Framingham HeartStudy 5.
CABG surgery is the standard of care for patients
with three-vessel disease or left main disease with
reduced ejection fraction, as supported by many studies
showing a reduction in morbidity and mortality relative
to percutaneous coronary intervention6. Of the graft
options vein graft versus internal mammary arteries
(IMAs) the latter have the better long-term patency 7;
however, only 510% of patients receive bilateral IMAs,
because of the increased perioperative morbidity, mortality, duration of operation, and risk of sternal wound
problems that are reported for this type of graft7. Of note,
1025% of saphenous vein grafts (SVGs) occlude from
thrombosis within 1year after CABG surgery 810, and
an additional 12% occlude each year from 1year to
5years after CABG surgery 11. Moreover, 45% occlude
each year from 6years to 10years postoperatively, owing
to accelerated development of atherosclerosis11.
Currently, percutaneous coronary intervention
withstents (either bare-metal stents (BMS) or drug-eluting
stents (DES)) is the most commonly performed procedure for the treatment of patients with symptomatic
CAD. Delayed arterial healing with poor strut coverage is
recognized as the primary substrate for stent thrombosis
attributed to the first-generation DES12,13. However, we
have reported that neoatherosclerosis within the in-stent
segment is another complication of first-generation
and second-generation DES, resulting in late stent failure from restenosis or stent thrombosis induced by
plaque rupture14,15.
The temporal presentation of atherosclerosis in the
form of clinical events differs between native CAD,
which develops over decades, and vein graft atherosclerosis and in-stent neoatherosclerosis, which occur
NATURE REVIEWS | CARDIOLOGY
VOLUME 13 | FEBRUARY 2016 | 79

2016 Macmillan Publishers Limited. All rights reserved
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Key points
The aetiology of luminal thrombosis in native coronary arteries is
predominatelyplaque 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
within months to a few years. This Review is focused on

the structural characteristics of human atherosclerotic
plaques for these three entities, with emphasis on disease
progression where divergent or shared characteristics of
lesion morphology exist. We also provide an updated

classification scheme for atherosclerotic lesions (TABLE1,
FIGS1,2), which should now replace our previous recommendations on lesion classification (the modified AHA
classification) that were published in200016.
Native coronary artery disease

Historical perspective
In the late 1970s, Russell Ross highlighted the importance of smooth muscle cell (SMC) proliferation in
atherosclerotic lesion formation, and hypothesized that
injury to the arterial wall had a major role in plaque
progression17,18. Inflammation was later identified as
the primary driving force for activation and proliferation of SMCs, processes mediated by growth factors19.
Subsequent studies from Libby and Hansson in the late
1990s indicated that the mechanism of disease progression involved a complex interaction between risk factors and inflammation; their work resulted in a move
away from the idea that atherosclerosis was a bland proliferative disorder to the concept of it being a complex
inflammatory disease of the vessel wall2022. During the
same period, Fuster and colleagues observed plaque
progression as staged events: initial involvement of the
Table 1 | Updated classification of atherosclerotic lesions based on morphology

Type of lesion
Subtype of lesion
Morphological description
Nonatherosclerotic
intimal 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, fibrous

cap, or thrombosis.
Pathological intimal
thickening
Plaque rich in smooth muscle cells, with hyaluronan and proteoglycan

matrix and focal accumulation of extracellular lipid. Absence of
thrombosis.
Fibroatheroma
During early necrosis: focal macrophage infiltration into areas of lipid

pools with an overlying fibrous cap. During late necrosis: loss of matrix
and extensive cellular debris with an overlying fibrous cap. With or
without calcification. Absence of thrombosis.
Intraplaque
haemorrhage or
plaque fissure
Large necrotic core (size >10% of plaque area) with haemorrhage,

and plaque area shows presence of angiogenesis. Necrotic core
communicates with the lumen through a fissure. Minimal tear without
obvious thrombus.
Thin-cap
fibroatheroma
A thin, fibrous cap (<65m) infiltrated by macrophages and lymphocytes,

with rare or no smooth muscle cells and relatively large underlying
necrotic core (>10% of plaque area). Intraplaque haemorrhage and/or
fibrin might be present. Absence of thrombosis.
Plaque rupture
Thin-cap fibroatheroma with cap disruption. Thrombosis is present and

might 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.
Nocommunication of the thrombus with the necrotic core.
Calcified nodule
Eruptive (shedding) of calcified nodule with an underlying fibrocalcific

plaque with minimal or no necrosis. Thrombosis is usually not occlusive.
Healed plaque
rupture, erosion, or
calcified nodule
Healed lesion composed of smooth muscle cells, proteoglycans, and

collagen typeIII with or without underlying disrupted fibrous cap,
necrotic core, or nodular calcification. Lesions can contain large areas of
calcification with few inflammatory cells and have a small or no necrotic
core. The fibrotic or fibrocalcific collagen-rich plaque is associated with
significant luminal stenosis. Absence of thrombosis.
Progressive
atherosclerotic
lesions
Lesions with
acutethrombi
Healed lesions
An updated version of the modified AHA classification published in 200016, which was based on the original AHA classification
published in the mid 1990s25.
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Nonatherosclerotic intimal lesions
Intimal
thickening
Intimal
xanthoma
Progressive atherosclerotic lesions

Fibroatheroma
Pathological intimal thickening

Without
macrophage
With
macrophage
Early
Thin-cap
broatheroma
Late
Lesions with acute thrombi

Rupture
Erosion
Underlying pathological
intimal thickening
Calcied nodule
Plaque ssure
Fibrous plaque
Underlying
broatheroma
Complications of haemorrhage and/or thrombus with healing and stabilization

Intraplaque
haemorrhage
Healed rupture
Single layer
Chronic total
occlusion
Multiple layers
Fibrocalcic plaque
(calcied sheet)
Nodular
calcication
Artery wall
Macrophage foam cells
Necrotic core
Angiogenesis
Thrombus
Lumen
Extracellular lipid
Cholesterol clefts
Haemorrhage
Healed thrombus
Smooth muscle cells
Collagen
Calcied plaque
Fibrin
Figure 1 | Human coronary lesion morphologies categorized as nonatherosclerotic intimal

lesions,
progressive
Nature
Reviews
| Cardiology
atherosclerotic lesions, lesions with acute thrombi, and complications of haemorrhage and/or thrombus with
healing and stabilization.
endothelium, which was causally linked to the developing intima, with further injury of the underlying media
in the advanced phases of development. They also recognized that deep plaque fissures and ulcerations resulted
in the manifestation of complex lesions, as a cause of
luminal thrombosis and clinical presentation of acute
coronary syndrome23,24.
An AHA consensus document on atherosclerosis classification was published in the mid1990s 25.
Theclassification involved six distinct categories: typeI,
intimal thickening; typeII, fatty streak; typeIII, transitional or intermediate lesion; typeIV, advanced atheroma with well-defined region of the intima; typeV,
fibroatheroma or atheroma with overlaid new fibrous
connective tissue; and typeVI, complicated plaques with
surface defects, haematoma or haemorrhage, thrombosis, or a combination of these characteristics25. However,
this classification failed to capture two important clinical

aetiologies of coronary thrombus that are distinct from
plaque rupture surface erosion, which accounts for
2530% of thrombosis cases, and the less frequent, but
still important, eruptive calcified nodules, which occur
in <5% of patients. Moreover, in the mid1980s, Davies
had identified active lesions characterized by plaque fissures as yet another form of communication between
the lumen and underlying necrotic core26, which was
not included in the AHA classification 25. We have
since clarified this concept 27, which is best described
as a mechanism of intraintimal rather than true
intraluminal thrombosis.
A second important concept not captured in the
AHA consensus classification28 was the recognition of
precursor lesions that potentially give rise to clinical
events. Identification of important structural plaque

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Foamy
macrophages
Intimal
thickening
Intimal xanthoma
(fatty streak)
Lipid pool arises from

SMC apoptosis and
deposition of proteoglcan,
hyaluronan, and lipid
Pathological
intimal
thickening
Conversion
of lipid pool
to necrotic core
with macrophage
inltration
Infrequent
Fibrocalcic plaque
(with or without
calcied sheets)
Fibroatheroma
Angiogenesis,
inammation, and
calcication leads to
intraplaque haemorrhage
or plaque ssure
Inammation, cell death,

and MMPs contribute to
thinning of the brous cap
Thin-cap
broatheroma
Rupture
(necrotic core)
Erosion
Calcied nodule
Most-common
pathway
Second-mostcommon pathway
Least-common
pathway
Thrombosis
Acute myocardial infarction

or unstable angina,
sudden death
Healing
Healed
rupture
Healed plaque
rupture or erosion
Fibrocalcic plaque
(with calcied sheets)
Healed erosion
>75% area
luminal narrowing
Total occlusion
Nodular
calcication
>75% area
luminal narrowing
Sudden death,
stable angina,
or congestive heart failure
Figure 2 | Simplified scheme for classifying atherosclerotic lesions in human

Reviews
| Cardiology
coronary arteries. Solid arrows indicate the main pathway Nature
of plaque
progression,
and
dashed arrows indicate infrequent pathways. Abbreviations: MMP, matrix
metalloproteinase; SMC, smooth muscle cell.
characteristics conceivably leading to coronary thrombosis would not only provide important mechanistic
insights into understanding lesion progression, but also
support efforts leading to improvements and refinements in diagnostic imaging. The notion of vulnerable
plaque, as a precursor to rupture, also fails to fit precisely
into an orderly numerical classification as set forth by
the AHA25,28. These constraints, therefore, prompted us
to develop a modified scheme16, in which AHA lesion
typesIIV were replaced by descriptive terms of: adaptive intimal thickening, intimal xanthoma (fatty streak),
pathological intimal thickening, and fibroatheroma.
Fibroatheromas were more recently subcategorized
into early stage and late stage plaques, on the basis of
lytic and nonlytic characteristics of the necrotic core29. In
our scheme16, AHA categoriesV and VI were discarded
because they failed to account for the three aetiologies
(rupture, erosion, and calcified nodule) that give rise to

coronary thrombosis. The precursor lesions to plaque
rupture, originally known as vulnerable plaques, were
classified as thin-cap fibroatheroma (TCFA). Additional
terms were also introduced to implicate the sudden
enlargement of plaques from silent episodic thrombosis
(healed plaque rupture (HPR)), and plaque fissures16.
The concept of plaque healing is also not accounted
for in the AHA numerical classification, as HPRs or
healed erosions can eventually give rise to increased
plaque burden, luminal narrowing, and possible negative remodelling, or even silent or symptomatic chronic
total occlusion (CTO)16. Similarly, we added terms that
inferred lesion stability, such as fibrous or fibrocalcific,
and nodular calcification in the absence of thrombosis,
which are more commonly observed in patients presenting with stable CAD, or long-standing diabetes mellitus
and chronic renal failure.
Nonatherosclerotic intimal lesions

Adaptive or diffuse intimal thickening. Adaptive or diffuse intimal thickening (FIG.3a) is often observed in atherosclerosis-prone arteries (the coronary, carotid, and iliac
arteries, as well as the abdominal and descending aorta)30,
and is considered a physiological response to blood flow
rather than an atherosclerotic process. Study of neonates31, and of adolescents and young adults32, has indicated that intimal masses that form near branch points
enlarge with advancing age and might be precursors
to high-risk plaques with the potential to thrombose.
Intimal xanthomas. Intimal xanthomas (FIG. 3b), or
so-called fatty streaks, are lesions primarily composed of
infiltrating macrophage foam cells and, to a lesser extent,
lipid-laden SMCs within the intima33,34. This type of lesion
has been shown to regress, especially in the thoracic aorta
and the right coronary artery in young individuals3537.
Intimal xanthomas do not always convey the mandatory
features of more-advanced atherosclerotic plaques and,
therefore, are not considered progression-prone disease.
Progressive atherosclerotic lesions

Pathological intimal thickening. Pathological intimal
thickening (FIG.4a,b) is the earliest progressive lesion
consisting of SMC remnants within an extracellular
matrix (ECM) composed of proteoglycans and collagen
typeIII with a co-existing lipid pool16. The ECM consists primarily of hyaluronan and proteoglycans biglycan,
decorin, and versican admixed with neutral lipids and
free cholesterol. Remnants of apoptotic SMCs are generally visualized by a thickened basement membrane on
periodic acidSchiff (PAS) staining 38, and are thought
to support continued intimal growth. The lipid pools
show a relative absence of viable SMCs. When present,
resident macrophages in pathological intimal thickening
are often seen localized to the luminal aspect of the lipid
pool, which is likely to indicate a more-advanced stage of
atherogenesis. Typical pathological intimal thickening,
consisting of extracellular lipid under layers of macro
phage-derived foam cells, is found at locations near
branch points39.
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a
to the pathogenesis of inflammation in atherosclerosis,

whereby macrophages are recruited into the lipid pools
where they eventually undergo necrosis.
1.0 mm
b
1.0 mm
Artery wall
Lumen
Smooth muscle cells
Figure 3 | Human coronary lesion morphologies categorized as

Nature Reviews | Cardiology
nonatherosclerotic intimal lesions. Histological and schematic images are shown for
a | intimal thickening, and b | intimal xanthoma. Arrowheads indicate macrophages.
The current view of subendothelial lipid retention

involves the interaction of negatively charged sulphate
groups present in glyocosaminoglycan (GAG) side chains
of proteoglycans with positively charged domains of apolipoproteinB (apoB)3941. The direct attraction between
LDL and proteoglycans is further facilitated by the
activity of lipoprotein lipase42. Dermatan sulphate proteoglycan of the decorin type is not observed in healthy
intima, which is rich in SMCs, but has been reported in
the intima of lesions of adaptive intimal thickening, especially in zones with reduced staining for SMC actin43,
which might facilitate the retention of apoB100 in these
early lesions. Fine crystalline structures of free cholesterol
are also seen in lipid pools, but never in excess. Smith
and Slater found a high percentage of unesterified cholesterol in the deep layers of the lipid pool in early plaques,
and concluded that most of this cholesterol was derived
directly from plasma LDL44. However, the precise origin
of free cholesterol in pathological intimal thickening
remains unknown, but might be derived from membranes of dead SMCs45. Pathological intimal thickening
is also the earliest type of lesion exhibiting calcification;
vonKossa or Alizarin red staining (FIG.5) demonstrates
the presence of microcalcification (0.5m, and typically
<15m) in the lipid pools46.
The ECM is increasingly being recognized as being
important in the early steps of inflammation, particularly through its influence on macrophage phenotype47.
Versican has been shown to promote leukocyte adhesion,
and interference with the incorporation of versican into
ECM blocks monocyte adhesion and dampens inflammatory responses4850. Preliminary studies from our
laboratory indicate greater macrophage infiltration in
pathological intimal thickening highly enriched in versican51. In the context of vascular disease, versican might
be one of the initial amplification steps that contributes
Early and late fibroatheromas. Fibroatheromas (FIG.4c,d)

are a progressive stage of atherosclerotic disease
characterized by the presence of an acellular necrotic
core generated by macrophage infiltration into lipid
pools. Expression of hyaluronan and the proteoglycans
biglycan, decorin, and versican is decreased in the
lipid pool and necrotic core, probably owing to active
metalloproteinases (MMPs) and/or peptidases of the
ADAMTS (A Disintegrin And Metalloproteinase with
Thrombospondin Motifs) family 16,52. We have defined
two unambiguous phases of the necrotic core formation
relative to early or late necrosis, mainly on the basis of
the relative extent of matrix proteoglycans. Early-phase
necrosis (transition from lipid pool) is associated with
an appreciable decrease in the expression of biglycan,
hyaluronan, and versican within the lipid pool together
with infiltrating macrophages, which are undergoing
necrosis or apoptosis. The necrotic core underlying the
late fibroatheroma is noticeably deficient in ECM and
has more cholesterol clefts, calcification, intraplaque
haemorrhage, and surrounding neoangiogenesis, than
the earlierphase29,53,54.
In our view, these morphological attributes provide
important mechanistic insight into how necrotic cores
initiate and evolve. The presence of accumulated macro
phages within lipid pools coinciding with an appreciable increase in free cholesterol and breakdown of ECM
essentially defines the early necrotic core. Moreover,
macrophage death in tandem with defective phagocytic
clearance of apoptotic macrophages in animal models is
another consistent feature of early necrotic core formation, referenced appropriately by the coined-observation
grave yard of macrophages55. Consistent with this observation, a systematic assessment of progressive coronary
lesions shows the greatest density of apoptotic bodies in
late versus early fibroatheromas, and least in pathological
intimal thickening 51.
Late fibroatheromas also have thick fibrous caps
composed of collagen typeI and III and proteoglycans
interspersed with SMCs. The fibrous cap is the main
structural element responsible for harbouring the athero
matous haemorrhagic contents of the necrotic core, and
is vulnerable to thinning and rupture. Although the precise mechanisms of fibrous cap thinning are not fully
understood, ECM degradation facilitated by MMPs and
ADAMTS proteases secreted by an overabundance of
macrophages are likely to be involved56,57, in addition to
possible deficiencies in repair mechanisms58.
Thin-cap fibroatheromas. The concept of TCFA was
originally developed from observations of ruptured
coronary lesions where the distinguishing morpho
logical features relative to rupture were the absence of
a luminal thrombus along with a disrupted cap. TCFAs
are essentially synonymous with the more widely-used
term vulnerable plaques, referring to precursor lesions
with a tendency to rupture16. Patients with high serum

REVIEWS
total cholesterol level and a high ratio of total:HDL cholesterol, individuals who smoke, women aged >50years,
and patients with elevated levels of Creactive protein
measured by high-sensitivity assay have increased risk
ofTCFA59.
a
LP
1.0 mm
b
LP
100 m
1.0 mm
c
NC
200 m
1.0 mm
d
NC
200 m
1.0 mm
e
Thin brous cap
1.0 mm
Artery wall
Necrotic core
Lumen
Extracellular lipid
Cholesterol clefts
Smooth muscle cells
Collagen
Calcied plaque
Figure 4 | Human coronary lesion morphologies categorized as progressive

Nature
Reviews
atherosclerotic lesions. Histological and schematic images
are shown
for | Cardiology
a|pathological intimal thickening without macrophage infiltration, b | pathological
intimal thickening with macrophage infiltration, c | early fibroatheroma, d | late
fibroatheroma, and e | thin-cap fibroatheroma. Arrowheads indicate macrophages.
Abbreviations: LP, lipid pool; NC, necrotic core. The histological image of the late
fibroatheroma shown in paneld is reprinted with permission from Nature Publishing
Group Otsuka, F. etal. Clinical classification of plaque morphology in coronary disease.
Nat. Rev. Cardiol. 11(7), 379389 (2014).
TCFAs (FIG.4e) generally have a large late necrotic

core, with an overlying thin intact fibrous cap that is
composed predominantly of collagen typeI with varying degrees of macrophages and lymphocytes, and
paucity or absence of SMCs. Fibrous cap thickness
<65m is considered a pathological indicator of lesion
vulnerability, because a study of 113 men with CAD
who died suddenly demonstrated a mean thickness at
the site of rupture of 2319m, with 95% of the ruptured caps measuring <65m60. TCFA is more common
among individuals presenting with acute plaque rupture
than among those with stable plaques or culprit lesions
involving erosions, and than among individuals who
have died from noncardiac causes61. Plaque burden is
highest in patients with diabetes and in those with stable disease, and lowest in plaque erosions61. Individuals
with plaque rupture have smaller lumen area than those
presenting with plaque erosion62.
Particular morphological characteristics might
bevaluable surrogates of lesion instability that couldbe
assessed by invasive or noninvasive imaging techno
logies to improve prediction of TCFAs that are susceptible to rupture63. In a study published in 2013,
histological evaluation of plaque burden demonstrated that 70% of ruptures were associated with >75%
cross-sectional luminal area narrowing, 25% narrowed
by 5075%, and only 5% had <50% narrowing 63. By
contrast, only 40% of TCFAs are associated with >75%
luminal narrowing, approximately 50% of these lesions
are associated with 5075% narrowing of the lumen,
and 10% show <50% narrowing 63. Furthermore, overall
plaque burden was greater for ruptures, and necrotic
core area was generally smaller for TCFAs than for
ruptured plaques. The best morphological parameter
separating TCFAs from ruptures, however, was fibrous
cap thickness, which usually measures 5584m for
TCFAs, and <55m for ruptured plaques63. The extent
of macrophage infiltration was helpful in discriminating between TCFAs and ruptured plaques, although not
as useful as fibrous cap thickness63.
Coronary thrombosis
Incidence and aetiology. In a series of 20 individuals
who experienced sudden coronary death (SCD) published in 1994, the incidence of plaque rupture was
60%, and the remaining 40% showed surface erosion64. Subsequently, in 1996, our laboratory reported
plaque erosions in 44% of patients who died suddenly
as a result of thrombosis; the individuals with erosions
were younger and more often women, and their lesions
had less calcification and inflammation compared with
ruptures62. A 2013 review of autopsy findings for 1,847
cases of hospital-based acute myocardial infarction and
SCD reported a 73% incidence of plaque ruptures or
fissures; the remaining causative lesions were erosions27.
Consistent with our definition of SCD, in our registry,
the mean age of patients without a history of CAD is
relatively young (5212years), in comparison with the
hospital-based population (709years)27. In our 2015
analysis of 442 patients from our registry (TABLE2), the
frequency of coronary thrombosis is similar to previous
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reports16, with plaque ruptures being the most-frequent
cause (65%), followed by erosions (30%), and calcified
nodules (5%)65.
In a clinical study of 126 patients with ACS published
in 2013, the frequency of thrombosis was assessed using
optical coherence tomography (OCT)66. The OCTidentified prevalence of plaque rupture, erosion, and calcified nodule was 43.7%, 31.0%, and 7.9%, respectively.
Patients identified using OCT as having erosion were
younger than those identified as having plaque rupture or
calcified nodule (53.813.1years versus 60.611.5years
and 65.15.0years, respectively; P=0.005)66. Notably,
relative to rupture, the OCT diagnosis of plaque erosion is clinically challenging. The current definition
is dependent on the finding of thrombi attached to an
intact plaque, referred to as definitive plaque erosion,
or luminal irregularities without presenting thrombusor
thrombi in the absence of underlying complications of
lipid or calcium, suggestive of probable plaque erosion.
The diagnosis of erosion by OCT, however, remains controversial and needs further testing and refinement. The
diagnosis of plaque erosion also exists under the umbrella
of intact fibrous cap (IFC), which additionally includes
plaques with a thick fibrous cap with or without necrotic
cores and/or calcium. Further limitations of OCT include
the inability to separate a lipid pool from a necrotic core,
and failure to recognize the presence or absence of
surface endothelium.
Plaque rupture. Plaque ruptures (FIG.6a) consist of a
necrotic core with an overlying disrupted thin fibrous
cap, which is generally infiltrated by macrophages and
Tlymphocytes. The ECM of the fibrous cap is mainly
composed of collagen typeI and contains very few, if
any, SMCs. The luminal thrombus at the site of rupture
is always predominantly composed of platelets (white
thrombus), and might or might not be obstructive.
Propagated (older) thrombi proximal and distal to
rupture sites usually consist of layers of fibrin (lines of
Zahn) interspersed with red blood cells (red thrombus), and tend to move to the nearest side branch,
thus allowing blood to reflow through the collateral
branch. Rupture of the fibrous cap is generally thought
to occur at its weakest point involving shoulder regions.
However, although we have found that this is typically
true at rest, we have observed that during exercise,
ruptures at the mid portion of the fibrous cap occur at
the same frequency as ruptures at shoulder regions67.
Therefore, we speculate that different processes might
lead to the final event of plaque rupture, where select
proteases secreted by macrophages68 might weaken the
fibrous cap, and high shear and tensile stress might also
be involved69. Within the fibrous cap, microcalcifications (>5m) derived from dying macrophages and/or
SMCs might be another possible trigger of plaque rupture, potentially causing stress-induced debonding of
the fibrous cap70,71.
In a previous study, serum analysis of total cholesterol,
HDL cholesterol, ratio of total cholesterol to HDL, and
serum 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 to

be a predictor of acute thrombosis regardless of plaque
aetiology, and plaque rupture correlated with high total
cholesterol, low HDL cholesterol, and an elevated ratio
of total:HDL cholesterol. Furthermore, increased levelsof total c holesterol correlated with a greater number
ofTCFAs.
Erosion. Erosions (FIG.6b,c) occur in the absence of rupture where luminal thrombi are in direct contact with a
denuded intimal surface consisting of SMCs and proteo
glycan matrix 27. The underlying lesion is a pathological
intimal thickening in 16% of patients and an early or late
fibroatheroma in 50% and 34% of patients, respectively 72.
In the majority of erosions, the medial wall is intact and
less inflamed than in ruptures. Additionally, in contrast
to ruptures, which generally show positive remodelling,
erosions involve negative remodelling 73. The majority of
erosions (56%) lack evidence of calcification, although
microcalcification is observed in approximately 40% of
lesions; fragmented calcification and sheets of calcification are rare (<2%)72. The tissuethrombus interface
in erosion often shows activated SMCs embedded in a
proteoglycan-rich matrix consisting primarily of collagen typeIII, hyaluronan, and versican; these histological
features contrast to those of ruptured or stable plaques,
in which the fibrous cap is mainly composed of biglycan,
collagen typeI, and decorin62,74. Currently, no distinct
morphological features suggestive of erosion-prone
lesions have been identified.
Lipid profiles in women and men do not correlate
with erosions60; however, only total cholesterol level
correlated with plaque rupture in women60,75. By contrast, the risk of smoking significantly correlated with
plaque erosion in men and women59,74. In our SCD registry, erosions were more likely to occur in women, at
a young age, and in those with less plaque burden and
stenosis, and with less calcification compared with
ruptured plaques62,75.
At autopsy, the thrombi of eroded plaques often
show a later stage of organization than those of ruptured plaques. Indeed, a 2010 analysis showed an 88%
prevalence of late-stage thrombi in erosion compared
with a 54% prevalence in ruptured plaques (P<0.0001)76.
Fragments of coronary thrombi that embolize downstream are another frequent complication of plaque erosion; intramyocardial microemboli were found in 71% of
patients with erosion, and in only 42% of patients with
ruptured plaque77.
Calcified nodule. The least frequent cause of coronary
thrombosis is the calcified nodule (FIG. 6d), a noted
complication of highly calcified coronary arteries. In
an examination of 236 cases of SCD with acute thrombi
published in 2015, the incidence of calcified nodules was
only 5%65. Although the precise mechanism underlying
the calcified nodule is unknown, one working hypothesis is that mechanical stress might fragment sheets of
calcium, resulting in small nodules that become surrounded by fibrin, which might eventually erupt through
the plaque surface. Intraplaque fibrin is also common

REVIEWS
-SMA
a Movat
PAS
PAS
LP
100 m
von Kossa
100 m
OPG
OPN
50.0 m
50 m
MGP
50.0 m
-SMA
b Movat
100 m
50.0 m
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NC
200 m
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200 m
OPG
OPN
50.0 m
c Movat
50.0 m
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H/E
50.0 m
50.0 m
d H/E
50.0 m
H/E
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NC
NC
500 m
e Movat
50.0 m
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f Movat
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g Movat
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h H/E
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i Movat
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j Movat
100 m
H/E
Bone
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200 m
200 m
100 m
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Figure 5 | Progression of coronary calcification. Nondecalcified arterial segments
(panels a and b; serial sections) and decalcified segments (panels cj). a|Pathological
intimal thickening characterized by LP that lacks SMCs (negative for SMA) and
showing the presence of apoptotic SMCs, which can be identified by prominent
basement membrane that stains positive with PAS (arrows). Early microcalcification is
likely to result from SMC apoptosis, and calcification is detected by vonKossa staining
within the LP (corresponding to the boxed area in the Movat image), where
bone-related proteins such as MGP, OPG, and OPN are detected. b | Early NC not only
lacks SMCs, but is also infiltrated by macrophages that eventually undergo apoptosis
and calcification, which is observed as punctate areas of calcification (>20m). The
microcalcifications in early NC show variable amounts of staining for macrophage CD68
antigen; however, vonKossa staining clearly shows larger punctate areas of calcification
resulting from macrophage cell death within the NC than microcalcification of dying
SMCs (<10m). These calcified macrophages show co-localization of bone-related
proteins. c | A substantial amount of macrophage calcification can be observed in early
NC. d | The degree ofcalcification in NC typically increases towards the medial wall
where fragmented calcifications can be seen. e | Microcalcification resulting from
macrophage or SMC death can also be detected within a thin fibrous cap and might be
associated with plaque rupture. f|Calcification generally progress within the
surrounding area of the NC. g,h | This process leads to the development of sheets of
calcification where both collagen matrix and NC itself are calcified. i | Nodular
calcification can occur within the plaque in the absence of luminal thrombus and is
characterized by breaks in calcified plates with fragments of calcium separated by
fibrin. j | Ossification can occur at the edge of an area of calcification. Abbreviations:
SMA, smooth muscle actin; H/E, haematoxylin and eosin; LP, lipid pool; MGP, matrix
Gla protein; NC, necrotic core; OPG, osteoprotegerin; OPN, osteopontin; PAS, periodic
acid Schiff; SMC, smooth muscle cell; Thr, thrombus. Reprinted with permission from
Otsuka, F. etal. Has our understanding of calcification in human coronary
atherosclerosis progressed? Arterioscler. Thromb. Vasc. Biol. 34(4), 724736 (2014).
in noneruptive nodular calcification, potentially arising from surrounding capillaries that are leaky and/or
damaged, given that no communication exists with the
lumen. Eruptive calcified nodules typically occur in
eccentric lesions in which protrusion causes disruption
of the overlying luminal endothelium, which is likely to
trigger platelet adherence. Calcified nodules are more
commonly found in the mid-right coronary artery or
left anterior descending artery, where torsion stress is
maximal16. Calcified nodules are more commonly found
in older individuals. Eruptive calcified nodules should
not to be confused with nodular calcification, because
the latter does not involve luminal thrombi, although
it can cause medial wall disruption with rare extension
into the adventitia.
Mechanisms of lesion progression

Episodic rupture and healing. In the early 1990s, Mann
and Davies introduced the concept of plaque progression
through the identification of episodic rupture and healing (FIG.7a,b) in coronary arteries from patients who had
died as a result of unstable angina or acute myocardial
infarction. On average, individuals had 2.4episodes of
coronary thrombosis described as minor nonocclusive
thrombi, which seemed to contribute to luminal narrowing 78. Microscopic analysis of Picrosirius Red staining
viewed under polarized light identified HPRs as breaks
in the fibrous cap showing disrupted collagen typeI,
together with an overlying repair reaction consisting of
SMCs, proteoglycans, and varying amounts of different
types 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 ruptures or erosions, and the thrombus will organize with
granulation tissue and subsequent infiltration by SMCs
with 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 characterized
by the initial accumulation of proteoglycans and collagen typeIII, which is later replaced by collagen typeI.
Although the prevalence of silent ruptures in the general population remains unknown, Mann and Davies
reported an incidence of HPRs of 16% in plaques with
20% diameter stenosis, 19% with 2150% diameter
stenosis, and 73% for plaques with >50% diameter stenosis; the difference in the numbers of HPRs in lesions
with stenosis <50% and in lesions with 51% stenosis
was highly significant (P<0.001)78. In a later study, a
61% prevalence of subclinical ruptures in SCD was
reported80. The incidence was highest in culprit lesions
of stable plaque (80%), followed by acute rupture (75%)
and plaque erosion (9%)80. Multiple HPRs with layering were more common in proximal segments with the
underlying percentage luminal narrowing for acute ruptures exceeding that for HPRs (7915% versus 6614%;
P=0.0001), suggesting that SCD with thrombosis was
the culmination of the multiple previous silentevents.
Table 2 | Distribution of culprit plaques by sex and age in sudden coronary death
Subpopulation
Acute thrombi (n=236)
No acute thrombi
(stable severe CAD) (n=206)
Total
Rupture
Erosion
Calcified
nodule
Organized
thrombi*
No thrombi
Men aged <50years
82 (48%)
34 (20%)
3 (2%)
16 (9%)
36 (21%)
171
Men aged 50years
59 (31%)
14 (7%)
6 (3%)
46 (24%)
63 (34%)
188
All men
141 (39%)
48 (13%)
9 (3%)
62 (17%)
99 (28%)
359
Women aged <50years 3 (6%)
16 (36%)
0 (0%)
4 (9%)
21 (48%)
44
Women aged 50years 10 (26%)
6 (15%)
3 (8%)
8 (21%)
12 (31%)
39
All women
13 (16%)
22 (27%)
3 (4%)
12 (14%)
33 (40%)
83
Total population
154 (35%)
70 (16%)
12 (3%)
74 (17%)
132 (30%)
442
*Chronic total occlusion. Organized thrombi with healed myocardial infarction=62/74 (84%). No thrombi (stable plaque) with healed
myocardial infarction=71/132 (54%). Abbreviation: CAD, coronary artery disease. Reprinted from Yahagi, K. etal. Sexdifferences in
coronary artery disease: pathological observations. Atherosclerosis 239(1), 260267 (2015), with permission from Elsevier.

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Necrotic core expansion. In the 1960s, Constantinides
and colleagues initially described the notion of cracks
or fissures (FIG.9a) originating from the luminal surface
as an entryway of blood into the lesions81. This concept
was expanded upon in the 1980s by Michael Davies, who
defined the term plaque fissure as an eccentric collection of blood, giving rise to fibrin deposition within
the necrotic core82. As highlighted by Davies, fissures
and plaque ruptures are distinct entities; the latter are
always accompanied by an appreciable luminal thrombus, whereas fissures generally have an intra-intimal
a
Th
NC
2.0 mm
200 m
Th
Th
200 m
1.0 mm
c
Th
Th
NC
200 m
1.0 mm
d
Th
Nodular
Ca2+
2.0 mm
200 m
Artery wall
Necrotic core
Angiogenesis
Lumen
Extracellular lipid
Cholesterol clefts
Fibrin
Smooth muscle
cells
Collagen
Calcied plaque
Thrombus
Figure 6 | Human coronary lesion morphologies categorized

lesions| Cardiology
with acute
NatureasReviews
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 panelsa, b, and d reprinted from
Falk, E. etal. Update on acute coronary syndromes: the pathologists view. Eur. Heart J.
34(10), 719728 (2013) by permission of Oxford University Press and the European
Society of Cardiology.
thrombus consisting of fibrin and platelets with scattered

erythrocytes and, if present, luminal thrombi associated
with fissures are generally very small. Rather than being
an overt breech of the fibrous cap and superimposed
thrombus, as seen in ruptures, a lateral or marginal tear
in an eccentric plaque with underlying small necrotic
core characterizes the plaque fissure. The separation line
of the fissure begins in the necrotic core and extends into
the lumen. The path is lined by few macrophages and red
blood cells and/orfibrin.
The more-dominant mechanism of intraplaque haemorrhage (FIG.9b), however, occurs through intraplaque
vasa vasorum, which extend into the intima from the
adventitia. Kumamoto and colleagues demonstrated that
intraplaque haemorrhages are 28fold more common
than plaque fissures83. The extent of neovascularization
correlated with luminal stenosis and inflammation, and
vascular density was reduced in extensively hyalinized
and calcified arteries.
Advanced necrotic cores typically show an abundance of free cholesterol. This free cholesterol is unlikely
to be derived from macrophages, given that cholesterol
is present in an esterified form in macrophages84. Red
blood cell membranes contain more free cholesterol
than any other cell in the body; therefore, intraplaque
haemorrhage is a more logical origin of the free cholesterol seen in advanced necrotic cores. Using glycophorinA, a specific marker for extravasated red blood
cells, together with iron staining for haemoglobin, we
showed that intraplaque haemorrhage in lesions from
cases of SCD was more common in ruptured plaques,
TCFAs, and fibroatheromas with late necrotic cores than
in early plaques. Moreover, the extent of glycophorinA
immunostaining was proportional to the size of the
necrotic core, which also showed greater macrophage
infiltration29,85. Intraplaque haemorrhage was also shown
to be likely to occur from leaky vasa vasorum. Unlike in
the adventitia, the endothelium of neoangiogenic vessels found within the plaque lack competent junctions,
and exhibit membrane blebs, intra-cytoplasmic vacuoles, and basement membrane detachments53,86. Poorly
formed, leaky endothelial junctions frequently show
an association with inflammation, particularly with
macrophages and Tlymphocytes53, and are highly susceptible to extravasation of red blood cells contributing
to intraplaque haemorrhage87.
Notably, intraplaque haemorrhage is considered to be
one of three factors contributing to the sudden increase
in lesion size (the others being luminal thrombus and
plaque fissure) that can cause the onset of acute coronary syndromes. The concept of plaque enlargement as
a consequence of collections of erythrocytes and fibrin
within the necrotic core is mainly supported by autopsy
and clinical MRI studies29,88,89.
Calcification in advanced plaques

In post-mortem angiography, calcification in advanced
lesions can be present in speckled, fragmented (linear or
wide, single focus of calcium >2mm in diameter),or diffuse (5mm segment length of continuous calcification)
forms (FIG.10)90,91. Speckled calcification is most frequent
REVIEWS
a
NC
1.0 mm
b
NC
200 m
1.0 mm
c
200 m
Artery wall
Necrotic core
Angiogenesis
Lumen
Cholesterol clefts
Haemorrhage
Collagen
Calcied plaque
Healed thrombus
Naturetotal
Reviews
| Cardiology
Figure 7 | Episodic rupture and healing can lead to chronic
occlusion.
Histological and schematic images are shown for a | single-layer healed plaque rupture,
b | multiple-layer healed plaque rupture, and c | chronic total occlusion. Arrowheads
indicate neoangiogenesis. Abbreviation: NC, necrotic core. Histological image in panela
reprinted with permission from Nature Publishing Group Otsuka, F. etal. Clinical
classification of plaque morphology in coronary disease. Nat. Rev. Cardiol. 11(7), 379389
(2014). Histological image in panelc reprinted from Yahagi,K. etal. Sex differences in
coronary artery disease: pathological observations. Atherosclerosis 239(1), 260267
(2015), with permission from Elsevier.
in plaque ruptures whereas fragmented or diffuse calcification is more common in HPRs. In an autopsy study of
individuals dying with severe coronary disease, calcification was dependent on the age of the patient and is seen
by radiography in 46% of individuals aged <40years,
79% of men and women aged 5060years, and 100%
of those aged >60years61. Compared with men, women
showed a 10year lag in coronary calcification, until
the extent of calcification equalized in the eighth decade61. The incidence of calcification in postmenopausal
women aged >50years is at least threefold higher than
in premenopausal women aged <50years92. Additionally,
when stratified by decade, total coronary calcification
scores were consistently higher in white individuals who
had experienced SCD than in black individuals, in every
decade oflife46.
Coronary calcification has been shown to have a linear relationship with total plaque burden, but not with
percent stenosis. Also, calcification as detected using CT
can improve Framingham Risk Score93. Calcification of
atherosclerotic plaque is observed in 80% of SCD cases,
and significantly more calcification is seen in stable than

in unstable plaque46. Lesion calcification is likely to be a
consequence of multiple risk factors, including ageand
sex 94, renal function, diabetes92, vitaminD levels and
other aspects of bone metabolism95, and genetic markers96. A healthy lifestyle in young adults is associated
with decreased risk of developing coronary calcification,
and unhealthy lifestyle is linked with increased risk of
developing calcification by the age of 20years97.
Coronary calcification can be observed in patho
logical intimal thickening, the earliest form of progressive
lesions (FIG.5)46,98. Microcalcification is common in lipid
pools accompanied by SMC loss from apoptosis. Moreadvanced lesions typically show large calcified granules
derived from apoptotic macrophages, especially in early
fibroatheromas. Calcium fragments are also observed at
the periphery of necrotic core, usually near the media.
Sheets (FIG.11a) or plates of calcium that encompass
both the surrounding intimal SMCs and collagen with
or without a necrotic core might also be present. These
larger fragments of calcium can be visualized by standard
imaging techniques, such as radiography or CT. Nodular
calcification (FIG.11b) is the least-common form in the coronary vasculature, and is typically observed in tortuous
arteries of older individuals or in patients with diabetes
or chronic renal failure. The finding of ossification with
intervening marrow formation in coronary arteries israre.
Summary of native coronary atherosclerosis

Coronary atherosclerosis begins with early intimal hyperplasia near branch points. These lesions can be found
from birth and progress to pathological intimal thickening. The invasion of lipid pools by macrophages transition these plaques into early and late fibroatheromas with
large necrotic cores. Necrotic cores further develop and
expand, sometimes rapidly through intraplaque haemor
rhage from leaky vasa vasorum principally from
intimal microvessels originating within the adventitia
accompanied by free cholesterol derived from erythrocyte
membranes and secondary m
acrophages response.
The fibrous cap above the necrotic core is a critical
structural component. Infiltrating macrophages and
release of active proteases unbalanced by regulatory control can result in thinning of the fibrous cap. Continued
fibrous cap thinning can result in asymptomatic or
symptomatic plaque rupture, which is the most-frequent
cause of acute coronary thrombosis. Not all thin caps
eventually go on to rupture; mechanical stress is probably critical to this process. Silent ruptures can result in
continued luminal narrowing through episodic coronary
thrombosis and healing.
In contrast to ruptures, erosions occur in lesions with
pathological intimal thickening or in early fibroatheromas,
where a luminal surface rich in hyaluronan and proteo
glycan matrix lead to de-endothelializationandplatelet
thrombosis. Typically, the extent of luminal narrowing in erosion is mild to moderate, with the least damage to the media; the overlying platelet-rich thrombus
is found in various stages of organization. Evidence for
repeat episodes of erosion and healing exists; negative
remodelling results.

REVIEWS
200 m
1.0 mm
Artery wall
Lumen
Collagen
Figure 8 | Nonocclusive propagated thrombi that heal can

contribute
the
Nature
Reviewsto
| Cardiology
formation of fibrous plaques. Histological and schematic images are shown for a
fibrous plaque.
Advanced lesions involving HPRs are supported by

a microenvironment that fosters lesion calcification and
fibrosis. In fibrocalcific plaques, calcium presents as crescent-shaped sheets. Mechanical factors within heavily
calcified tortious vessels can lead to fragmentation giving rise to nodular calcification or calcified nodule with
luminal thrombosis, but this outcome is rare. In contrast
to rupture or erosion, thrombus propagation with organization eventually results in luminal narrowing from
neointimal tissue that is fibrotic incomposition.
Diabetes has been linked to a higher incidence of
coronary artery disease with greater macrophage and
Tlymphocyte infiltrates in atherosclerotic plaques, as
well as larger necrotic cores compared with plaques in
individuals without diabetes99. A higher incidence of
HPRs and healed myocardial infarction is found among
individuals with type2 diabetes, together with greater
plaqueburden.
a
200 m
1.0 mm
b
200 m
1.0 mm
Artery wall
Necrotic core
Haemorrhage
Lumen
Cholesterol clefts
Fibrin
Calcied plaque
Collagen
Angiogenesis
Figure 9 | Plaque morphologies that can lead to necroticNature

core expansion.
Reviews | Cardiology
Histological and schematic images are shown for a | plaque fissure, and b|intraplaque
haemorrhage. Arrowheads indicate neoangiogenesis.
In an acute coronary syndrome that is, unstable angina, myocardial infarction (with or without
ST-segment elevation) or sudden death the contributing lesion is associated with >75% luminal narrowing
and probably a luminal thrombus, which might or might
not be occlusive, together with intraplaque haemorrhage
and/or plaque fissure. We have reported the highest incidence of TCFA in patients presenting with acute rupture,
followed by those presenting with HPR, stable plaque
and, least frequently, in plaque erosion and deaths from
a noncoronary cause61. By contrast, patients presenting
with stable angina generally have lesions with severe
luminal narrowing in one or more coronary arteries with
morphologies of HPR or fibrocalcific plaques.
Accelerated atherosclerosis
Atherosclerosis in saphenous vein grafts
Compared with native coronary arteries, SVGs are
more susceptible to atherosclerosis, and the development of this pathology occurs on an accelerated time
scale. Within the first year after implantation, all vein
grafts show intimal thickening, an adaptive response
to systemic circulation and surgical handling. Intimal
hyperplasia in SVGs consists of a concentric distribution
of SMCs, proteoglycans, and collagen typeIII. The earliest atherosclerotic change in SVGs is reported around
1year and is characterized by foam-cell accumulation
followed by the development of a necrotic core, which
is observed between 2 and 5years after surgery. SVG
implants aged >5years often show necrotic core expansion through intraplaque haemorrhage, which is likely
to arise from the lumen and/or leaky neoangiogenic
vessels100102. Haemorrhagic events might contribute to
plaque rupture, which typically occurs between 5 and
10years after surgery 101. The clinical SVG attrition rate
from the first to the seventh postoperative year is 2% per
year, which increases to 5% per year from the seventh
to the twelfth year 103; at 10years, only 3845% of SVGs
remain patent 104.
A section-based analysis of SVGs implanted for
8.55.9years (range 222years; FIG.12) performed in
our laboratory showed 56.5% total cross-sections with
intimal thickening contributing to an overall mean percent stenosis of 3415%101. Lesions with exclusive foamcell infiltration (intimal xanthomas or fatty streaks)
were observed in 18.8% of sections with a percent stenosis of 379%101. Fibroatheromatous lesions with necrotic
cores were observed in 11.9% of sections, demonstrating a mean stenosis of 4617%. Complications
of intraplaque haemorrhage into a necrotic core were
observed in 7.5% of sections101. The least frequent lesion
morphology of plaque rupture and thrombosis was
observed in 6.3% ofsections, with a mean stenosis of
7524%101.
Circumferential intimal thickening is an early adaptive response in all SVGs. Intimal xanthomas or fatty
streaks, lesions with multilayered foam cells, are typically
present beyond 1year. In contrast to native coronary
disease, however, early SVG lesions typically express
varying degrees of macrophage apoptosis, which result
in necrotic cores that cause nominal expansion of the
REVIEWS
RCA
Fragmented
LAD
LCX
Diuse LOM
Speckled
LD
b 2.0
Mean calcication area (mm2)
LM
1.6
1.2
0.8
0.4
Fibrocalcic
plaques
TCFA
T
Fi
ca br
lc oi
c
at Fib
he ro
ro m
a
TC
F
ha Ru A
em pt
or ure
rh /
a
He ge
ru a
pt led
ur
e
oc To
cl ta
us l
i
Er on
os
io
n
PI
Fi
br
A I ous
T /
0.0
Acute ruptures
Healed ruptures
None
Speckled
Erosions
Fragmented
Diuse
Figure 10 | Histological pattern of coronary calcification in progressive and stable plaques. a | Post-mortem
radiograph from a case of sudden coronary death after removal of the coronary vasculature from
the heart shows
calcification as speckled, fragmented, or diffuse. b | Bar graph shows the meanSEM area of calcification in various lesion
morphologies, as measured from histological sections. c | Frequency of various types of radiographically identified
calcification in various lesion morphologies. Radiographically identified calcification is categorized as none, speckled,
fragmented (single focus of calcium >2mm in diameter), or diffuse (5mm segment of continuous calcium). Abbreviations:
AIT, adaptive intimal thickening; LAD, left anterior descending artery; LCX, left circumflex artery; LD, left diagonal artery;
LM, left main coronary artery; LOM, left obtuse marginal branch; PIT, pathological intimal thickening; RCA, right coronary
artery; TCFA, thin-cap fibroatheroma. Panela reprinted with permission from Otsuka, F. etal. Has our understanding of
calcification in human coronary atherosclerosis progressed? Arterioscler. Thromb. Vasc. Biol. 34(4), 724736 (2014).
Panelsb and c modified with permission from Burke, A.P. etal. Pathophysiology of calcium deposition in coronary arteries.
Herz 26(4), 239244 (2001), with permission from Springer Science and Business Media.
plaque105; lipid pools are not involved in this process.

Typical SVG atherosclerosis is often concentric and diffuse, with a less well-defined fibrous cap than in native
coronary disease; the cap seems fragile and vulnerable
to rupture106.
Critical factors underlying rapid neointimal growth
in SVGs result from endothelial injury and excessive mechanical stretching of the vein under arterial
pressure. Arterialization with fibrointimal thickening
is a consistent adaptive change that occurs in SVG
implants aged <1year, and is generally accompanied
by <50% cross-sectional area narrowing; only <10%
of lesions demonstrate severe narrowing from excessive neointimal growth107. A predisposition of higher
systolic and diastolic blood pressure are considered
important predictors of severe neointimal thickening and possible occlusion; other factors include SVG
diameter, grafting to the right coronary artery, and
target-vesselcharacteristics108.
Ruptured SVG lesions typically contain lipid-laden
macrophages localized to the disrupted fibrous cap and
underlying necrotic core. The necrotic core is generally
large, with numerous cholesterol clefts. If present, complications of intraplaque haemorrhage and focal calcification are usually found close to the vein wall; however,
the lesions might not show severe narrowing 101. The
fibrous cap of ruptured SVGs is discontinuous and
thinner than lesions with intraplaque haemorrhage
(8242m versus 214162m; P=0.002), but is
not as thin as the ruptured caps observed in native
disease (2319m)60,101. Onestudy found that the
overall mean longitudinal length of plaque rupture in
SVGs was 6.67.2mm101. Overall, 10 of 31 ruptures
showed thin fibrous caps overlying large haemorrhagic
necroticcores101.
Cardiovascular risk factors also apply to SVG disease. A study from our laboratory demonstrated a good
correlation between total cholesterol and the development of vein-graft atherosclerosis101. Compared with
a moderate (39%) reduction in SVG atherosclerosis
when LDL-cholesterol levels are reduced to a range
of 132136mg/dl, aggressive statin therapy achieving
LDL-cholesterol levels in a range of 9397mg/dl signifi
cantly reduces SVG atherosclerosis (27%)109. Similarly, a

REVIEWS
a
could conceivably cause the thinning of the fibrous

cap, forming a TCFA with complications of rupture
withthrombosis.
Calcification is another feature of neoatherosclerosis generally involving stents with long-term implant
duration. The morphological character of calcification
varies widely from microcalcification to calcified sheet,
200 m
1.0 mm
which can show fragmentation, particularly in BMS.
Calcification in neoatherosclerosis attributed to DES
b
might be associated with persistent fibrin deposition
around stent struts, which is more commonly found in
paclitaxel-eluting stents (PES).
The formation of neoatherosclerosis shares many
similarities with the accelerated atherosclerosis that
develops in SVGs, given that a base of neointimal hyperplasia supports the infiltration of macrophage foam cells.
200 m
1.0 mm
In contrast to native disease, lipid pool lesions of pathological intimal thickening are unusual for neoathero
Artery wall
Cholesterol clefts
Haemorrhage
sclerosis (and for atherosclerosis in SVGs). Overall,
Lumen
Calcied plaque
Fibrin
in-stent neoatherosclerosis presents as macrophage infiltration and apoptosis that leads to the formation of the
Collagen
necrotic core. Calcification within the in-stent neointima
is observed for both BMS and DES, although it is more
Nature
Reviewsas
| Cardiology
Figure 11 | Advanced lesions complicated by calcification
presenting
common in the latter type ofstent.
fibrocalcific and/or nodual calcification can arise from fibroatheromas.
Autopsy studies of explanted stents from our labHistological and schematic images are shown for a | fibrocalcific plaque (calcified sheet),
oratory have confirmed that the overall incidence
andb | nodular calcification.
of neoatherosclerosis is significantly greater in firstgeneration DES than in BMS (31% versus 16%;
reduction in neointimal thickness has been found when P<0.001)14. As demonstrated by the finding that the
serum cholesterol levels are <100mg/dl in the first year duration of stent implantation is significantly less for
after CABG surgery. Aggressive statin therapy or treat- DES than for BMS (median 420days versus 2,160days,
ment with blockers has also been shown to be effective respectively; P<0.001)14, theonset of the development of
in limiting SVG disease at 1year 108,110. Moreover, anti- neoatherosclerosis clearly differs considerably for these
platelet therapy has been shown to reduce thrombosis- two types of stent. The earliest atherosclerotic change
induced graft failure, but not long-term patency 111. We characterized by macrophage foam cells was observed at
have not observed lesions of plaque erosion or calcified 70days for PES and 120days for sirolimus-eluting stents
nodule in vein graft disease; however, when excessive (SES), and much later (900days) for BMS. Necrotic
neointimal thickening occurs at distal anastomotic cores were observed within 1year for PES and SES (at
sites that is, between vein graft and native disease 270days and 360days, respectively), but occurred after
endothelial loss and thrombosis can be seen, probably significantly longer durations in BMS (earliest 900days),
associated with high shear stress108.
more likely through macrophage infiltration of lipid
pools, relative to apoptotic foams cells, as occurs with
Atherosclerosis in stents (neoatherosclerosis)
DES. Moreover, unstable features of neoatherosclerosis
In-stent atherosclerosis or neoatherosclerosis (FIG.13) is (TCFA and in-stent plaque rupture) were identified
histologically identified by the lipid-laden foamy macro within 2years of the implantation of first-generation
phages with or without complications of a necrotic core DES and 5years after BMS implantation14. In BMS, the
and/or calcification within the nascent intima14. In all frequency of neoatherosclerosis was also dependent
cases, necrotic cores of neoatherosclerosis do not com- on location, given that the incidence was significantly
municate with the underlying native plaque. Clusters greater in proximal than in mid-to-distal lesions (27%
of m
acrophage-derived foam cells withinthe peristrut versus 12%; P=0.014), whereas no such differences
regions, or near the luminal surface, are themost- were observed in DES (33% versus 30%; P=0.61).
frequent and earliest lesion of neoatheroscleros is. Multiple logistic regression analysis identified younger
Reminiscent of the rapid atherosclerosis seen in SVGs, individuals, long implant duration, SES and PES usage,
lesional macrophages associated with neoatherosclero and underling unstable plaque, as independent factors
sis are hypothesized to undergo apoptotic cell death to forneoatherosclerosis14.
give rise to necrotic cores and more-advanced fibro
The earliest finding of neoatherosclerosis in secatheromatous plaques. Intraplaque haemorrhage derived ond-generation cobaltchromium everolimus-eluting
from the lumen or, to a lesser extent, leaky adventitial stent (CoCrEES) was detected in 270day implants15,
vasa vasorum near struts with or without fibrin depos- which was later than seen with the first-generation
its might also exist. Similarly to native coronary disease, SES (120days) and PES (70days). The incidence of
infiltration of foamy macrophages within the neointima neoatherosclerosis in CoCrEES (29%), however, did not
REVIEWS
a
1.0 mm
c
Artery wall
Necrotic core
Haemorrhage
Lumen
Collagen
Calcied plaque
Collagen + proteoglycans
Smooth muscle cells
Cholesterol clefts
Thrombus
Figure 12 | Accelerated atherosclerotic disease in saphenous vein grafts. Histological and

schematic
images
are
Nature
Reviews
| Cardiology
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 13years after graft implantation, a necrotic core forms,
resulting in a fibroatheroma. d | After 45years, intraplaque haemorrhage into the lipid core is observed, with
moderate-to-severe luminal narrowing. e | After 510years, 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. etal. Pathology of
drug-eluting versus bare-metal stents in saphenous vein bypass graft lesions. JACC Cardiovasc. Interv. 5(6), 666674
(2012), with permission from Elsevier.
differ significantly from the incidence in SES (35%) and

PES(19%)15. The dominant morphology in CoCrEES
and PES was foamy macrophage clusters (seen in 67% of
CoCrEES and 87% of PES), which was less frequently
observed in SES (32%)15. Notably, unstable features
of neoatherosclerosis recognized as TCFA or plaque
rupture were not observed in CoCrEES. Although
pathological examination showed a higher incidence of
plaques with neoatherosclerosis in restenotic lesions in
first-generation DES than in second-generation DES,
clinical studies indicate a similar prevalence of unstable
lesions in restenotic lesions between first-generation and
second-generationDES112.
In-stent erosion is a rare event that is characterized by an underlying neointima rich in proteoglycan
matrix fully incorporating all struts, and a superimposed
thrombus 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 of

severe stenosis can potentially cause thrombosis, usually
within the first year after stent implantation113. In DES,
however, the rare phenomenon of erosion is likely to
result 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-graft
atherosclerosis and in-stent neoatherosclerosis develop
over a period of months to a few years. This temporal
difference might reflect the morphological diversity
relative to the natural history of progression among
these entities. Adaptive intimal thickening in native
arteries within the first year after stent implantation
parallels the neointimal hyperplasia observed in vein
grafts (FIG.14). SMC proliferation without macrophage
foam cell infiltration is frequently observed in BMS

REVIEWS
a
NC
Th
Th
NC
NC
1.0 mm
1.0 mm
c
Th
Th
1.0 mm
1.0 mm
e
1.0 mm
f
1.0 mm
g
NC
200 m
1.0 mm
h
NC
NC
1.0 mm
1.0 mm
Artery wall
Collagen
Calcied plaque
Thrombus
Lumen
Necrotic core
Angiogenesis
Neointima
Cholesterol clefts
Haemorrhage
Strut
Healed thrombus

REVIEWS
Figure 13 | Causes of late and very late stent thrombosis attributed
to neoatherosclerosis and restenosis (panelsad) and progression of

neoatherosclerosis (panelsei). Histological and schematic images are shown. Very
late stent thrombosis from in-stent plaque rupture with underlying neoatherosclerosis
associated with a | a PES, and b | a BMS. c | Very late stent thrombosis from in-stent
erosion with underlying neoatherosclerosis associated with an SES. d | Late stent
thrombosis from in-stent erosion in the presence of restenosis associated with a BMS.
Foamy macrophage accumulation e | around struts in a cobaltchromium
everolimus-eluting stent, and f | on the luminal surface within a PES. g | Fibroatheroma
with NC within neointima of a PES. h|Late fibroatheroma with intraplaque haemorrhage
within a BMS. i | Chronic total occlusion in a case of restenosis in an SES with underlying
neoatherosclerosis. Abbreviations: BMS, bare-metal stent; M, macrophage; NC,
necrotic core; PES,paclitaxel-eluting stent; SES, sirolimus-eluting stent; Th, thrombus.
Histological image in panelb reprinted from Nakazawa, G. etal. The pathology of
neoatherosclerosis in human coronary implants bare-metal and drug-eluting stents.
J.Am. Coll. Cardiol. 57(11), 13141322 (2011), with permission from Elsevier.
implants, especially in those aged <5years. The most

recognized feature of atherosclerosis common to vein
grafts and stents is macrophage infiltration, which best
resembles fatty streaks. Rather than individual foam
cells interspersed throughout the intima, macrophages
in vein grafts and stents have a tendency to accumulate as surface clusters or in peristrut regions, which is
different from native disease. Another important distinction is that intimal xanthomas or fatty streaks in
native arteries might regress and are considered nonprogressive lesions16,36, whereas foamy macrophage
clusters in stents or SVGs seem to progress to form
necrotic cores through cell death. In native coronary
disease, pathological intimal thickening with lipid pools
are common and considered a passageway to lesion
progression; however, pathological intimal thickening
is rarely present in vein grafts or DES, but can be seen in
BMS (FIG.14 and TABLE3). In native disease, lipid pools
and necrotic cores are localized to the deep intimal layers. The necrotic cores in neoatherosclerosis are more
frequently superficial and, consequently, rarely present as early fibroatheromas; they instead occur as late
Native coronary
atherosclerosis
Vein-graft
atherosclerosis
In-stent atherosclerosis
(neoatherosclerosis)
AIT
AIT
Neointimal formation
PIT
Intimal xanthoma
(luminal)
Intimal xanthoma
(peristrut and luminal)
PIT
(BMS)
Early broatheroma
Fibroatheroma
Fibroatheroma
TCFA
TCFA
TCFA
Plaque rupture
Plaque rupture
Plaque rupture
Late broatheroma
6570% of thrombi
>95% of late thrombi
100% of late thrombosis in BMS and
caused by plaque rupture caused by plaque rupture 33% in DES caused by plaque rupture
Figure 14 | Plaque progression and frequency of plaqueNature

ruptureReviews
in native
| Cardiology
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, thincap fibroatheroma.
fibroatheromas or, in some cases, TCFAs. Similarly to

native disease, intraplaque haemorrhage is also a complication of neoatherosclerosis, particularly from blood
entering from the luminal side presenting as fissure or
rupture, as opposed to extension of neoangiogenic
vessels originating from the adventitia.
Coronary thrombi in neoatherosclerosis are primarily associated with plaque rupture; in-stent erosions are
rarely observed in BMS and DES, although erosions in
this setting might not always be directly tied to the entity
of neoatherosclerosis. Plaque erosion in vein grafts is a
rare event and has been mostly observed at distal anasto
motic sites. Moreover, eruptive calcified nodules, a rare
cause of native coronary thrombosis, have not been seen
in vein grafts or instents.
Episodic HPRs are rare in neoatherosclerosis
occurring within stents and, given the high incidence
of total occlusion, are likely to be a complication of
post-thrombotic events that can heal silently or present as acute coronary syndromes or sudden death80.
As a caveat, chronic total occlusion lesions consisting
of organized thrombi within the stent can originate
from plaque rupture associated with neoatherosclerosis
(in addition to thrombi that develop as a consequence
of incomplete healing of the stent). Late calcification of
in-stent neoatherosclerosis, however, can present as
microcalcification, calcified sheets, or calcified fragments; this calcification is similar to that seen in native
coronary atherosclerosis, except when fibrin becomes
calcified inDES.
Conclusions
Natural causes of luminal thrombosis in native coronary
disease predominantly occur from plaque rupture, but
also occur as a result of erosion and, least frequently, eruptive calcified nodules. Although currently no rationale
exists for this approach, interventional cardiologists have
suggested that the precursor lesion of plaque rupture,
identified as vulnerable plaque or TCFA, is an appropriate target for interventional treatment irrespective
of the extent of luminal narrowing.
Accelerated atherosclerosis in SVGs or occurring
within stents (known as neoatherosclerosis) is typically identified by macrophage foam cell infiltration,
intraplaque haemorrhage, and a thin fibrous cap, which
are well-recognized in clinical and/or autopsy studies as important markers of future coronary events.
Morphological studies suggest divergent pathways with
respect to necrotic core formation in the accelerated
plaques and native coronary atherosclerotic disease,
because apoptosis of lipid-rich macrophages is thought
to give rise directly to necrosis in accelerated disease,
rather than transitioning through pathological intimal
thickening, as occurs in nativedisease.
Within the past 5years, neoatherosclerosis has been
identified as a contributing factor to late thrombosis
attributed to percutaneous coronary intervention with
stents. The incidence of neoatherosclerosis is more
frequent and rapid in DES than in BMS. Moreover,
the incidence of neoatherosclerosis is similar among
first-generation and second-generationDES.

REVIEWS
Table 3 | Prevalence of lesion morphologies in native coronary, vein-graft, and in-stent atherosclerosis
Lesion morphology
Native coronary
atherosclerosis
Vein-graft
atherosclerosis
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.
Notably, in both SVG atherosclerosis and in-stent

neoatherosclerosis, disease progression occurs within
months to a few years, and actual plaque rupture with
clinical events takes between 2 and 10years. In native
coronary disease, this process occurs over decades.
The morphological comparison of the patho
physiology of atherosclerotic plaque progression,
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Acknowledgements
CVPath Institute Inc., a private non-profit research organization, provided major support for this work, which was also
partially supported by National Institutes of Health grant
R01DK09443401A1.
Author contributions
K.Y. and F.D.K. contributed equally to this work. K.Y.,F.D.K.,

F.O., and R.V. substantially contributed todiscussion of content. K.Y., F.D.K., F.O., and R.V. wrotethe manuscript. F.D.K.,
F.O., A.V.F., H.R.D., M.J.,and R.V. reviewed and edited the
manuscript before submission.
Competing interests statement
F.O. has received speaking honoraria from Abbott Vascular,

Bayer, Merck, and Terumo Corporation. A.V.F. receives
research support from Boston Scientific and Medtronic, and is
a consultant to St.Jude Medical. M.J. is a consultant for
Biotronik and Cardionovum, and has received speaking honoraria from Abbott Vascular, Biotronik, Medtronic, and St.Jude
Medical. R.V. receives research support from 480 Biomedical,
Abbott Vascular, Atrium, Biosensors International, Biotronik,
Boston Scientific, Cordis Johnson &Johnson, GSK, Kona,
Medtronic, Microport Medical, OrbusNeich Medical, ReCor,
SINO Medical Technology, Terumo Corporation, and W. L.
Gore; has speaking engagements with Merck; receives honoraria from 480 Biomedical, Abbott Vascular, Biosensors
International, Boston Scientific, CeloNova BioSciences, Claret
Medical, Cordis Johnson &Johnson, Lutonix Bard, Medtronic,
Terumo Corporation, and W. L.Gore; and is a consultant to 480
Biomedical, Abbott Vascular, Medtronic, and W. L. Gore.
Theother authors declare no competing interests.

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REVIEWS

Pathophysiology of native coronary,

CVPath Institute, Inc.,

Coronary artery disease (CAD) remains the major

NATURE REVIEWS | CARDIOLOGY

VOLUME 13 | FEBRUARY 2016 | 79

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

lesion morphology exist. We also provide an updated

Native coronary artery disease

Table 1 | Updated classification of atherosclerotic lesions based on morphology

Natural accumulation of smooth muscle cells in the absence of lipid,

Superficial accumulation of foam cells without a necrotic core, fibrous

Plaque rich in smooth muscle cells, with hyaluronan and proteoglycan

During early necrosis: focal macrophage infiltration into areas of lipid

Large necrotic core (size >10% of plaque area) with haemorrhage,

A thin, fibrous cap (<65m) infiltrated by macrophages and lymphocytes,

Thin-cap fibroatheroma with cap disruption. Thrombosis is present and

Can occur on pathological intimal thickening or on a fibroatheroma.

Eruptive (shedding) of calcified nodule with an underlying fibrocalcific

Healed lesion composed of smooth muscle cells, proteoglycans, and

80 | FEBRUARY 2016 | VOLUME 13

Progressive atherosclerotic lesions

Pathological intimal thickening

Lesions with acute thrombi

Complications of haemorrhage and/or thrombus with healing and stabilization

Macrophage foam cells

Smooth muscle cells

Figure 1 | Human coronary lesion morphologies categorized as nonatherosclerotic intimal

this classification failed to capture two important clinical

NATURE REVIEWS | CARDIOLOGY

VOLUME 13 | FEBRUARY 2016 | 81

Lipid pool arises from

Inammation, cell death,

Acute myocardial infarction

Figure 2 | Simplified scheme for classifying atherosclerotic lesions in human

(rupture, erosion, and calcified nodule) that give rise to

Nonatherosclerotic intimal lesions

Progressive atherosclerotic lesions

82 | FEBRUARY 2016 | VOLUME 13

to the pathogenesis of inflammation in atherosclerosis,

Smooth muscle cells

Macrophage foam cells

Figure 3 | Human coronary lesion morphologies categorized as

The current view of subendothelial lipid retention

Early and late fibroatheromas. Fibroatheromas (FIG.4c,d)

NATURE REVIEWS | CARDIOLOGY

VOLUME 13 | FEBRUARY 2016 | 83

Thin brous cap

Macrophage foam cells

Smooth muscle cells

Figure 4 | Human coronary lesion morphologies categorized as progressive

TCFAs (FIG.4e) generally have a large late necrotic

84 | FEBRUARY 2016 | VOLUME 13

present in 96.5% of individuals60. Smoking was found to

NATURE REVIEWS | CARDIOLOGY

VOLUME 13 | FEBRUARY 2016 | 85

86 | FEBRUARY 2016 | VOLUME 13

2016 Macmillan Publishers Limited. All rights reserved

Mechanisms of lesion progression

Acute thrombi (n=236)

Men aged <50years

Men aged 50years