The new engl and jour nal of medicine
n engl j med 383;9  nejm.org  August 27, 2020846
Review Article
From Fondazione Policlinico Universitario
A. Gemelli IRCCS (R.V., F.C.), and Università
Cattolica del Sacro Cuore (F.C.)
— both in Rome. Address reprint requests
to Prof. Crea at Dipartimento
di Scienze Cardiovascolari e Pneumologiche,
Università Cattolica del Sacro
Cuore, Largo Agostino Gemelli 8, 00168,
Rome, Italy, or at ­filippo​.­crea@​­unicatt​.­it.
N Engl J Med 2020;383:846-57.
DOI: 10.1056/NEJMra2000317
Copyright © 2020 Massachusetts Medical Society.
A
therosclerotic plaques typically develop over a period of years
or decades. In contrast, the thrombotic complications of atherosclerotic
disease occur suddenly, often without warning.1
The notion that acute
coronary syndromes develop from the rupture or superficial erosion of an atherosclerotic
plaque is an oversimplification of a process involving plaque activity,
blood thrombogenicity, and healing.2,3
Pathological studies have shown that many
(if not most) atherosclerotic plaques destabilize without resulting in a clinical
syndrome.4,5
The occurrence of an acute coronary syndrome probably depends on
the disruption of a balance between instability (“activation”) and healing (“passivation”)
of an atherosclerotic plaque. During the past 30 years, research efforts have
mostly been focused on the mechanisms of plaque instability.2,3
Yet the risk of
acute myocardial infarction or sudden death from coronary causes remains difficult
to predict,6
suggesting that other pathogenic mechanisms should also be investigated.
Recently, the notion that plaque healing may play a key role in the
natural history of atherosclerotic disease has been gaining attention, in part because
of the development of new imaging techniques, allowing in vivo study of the
morphologic features of atherosclerotic plaque.7,8
This review examines the mechanisms
of atherosclerotic plaque healing, their role in the progression of atherosclerotic
disease and in the development of acute coronary syndromes, and the
clinical and potential therapeutic implications of the healing process.
Mechanisms of Plaque Rupture, Erosion, and Healing
Atherosclerotic plaque consists of extracellular lipid particles, foam cells, and debris
that have accumulated in the intima of the arterial wall and formed a lipid or
necrotic core. The core is surrounded by a layer of collagen-rich matrix and
smooth-muscle cells covered by endothelial cells, known as the fibrous cap
(Fig. 1A). Inflammatory cells (mainly T cells and macrophages) infiltrate the lesion
and are involved in plaque progression and thrombosis, leading to an acute
coronary syndrome.1-3
The two most frequent causes of thrombosis are plaque
rupture and superficial erosion. Plaque rupture occurs when the fibrous cap covering
the necrotic core fissures, exposing the highly thrombogenic core to flowing
blood. The thin-cap fibroatheroma, a plaque with a large necrotic core covered by
a thin (<65-μm) fibrous cap infiltrated by activated macrophages, is considered the
prototype of the rupture-prone plaque.1-3,9
Plaque erosion is caused by endothelial
damage or denudation and overlying thrombosis in the absence of frank cap rupture.
Plaques subject to erosion tend to be proteoglycan-rich and lipid-poor and
usually lack prominent inflammatory infiltrates.2,3,9
When plaque rupture or erosion
occurs in a prothrombotic milieu, subocclusive or occlusive thrombosis results,
causing a symptomatic acute coronary event; otherwise, if thrombosis-resisting
factors prevail, thrombus formation is contained, and plaque healing occurs.1,10
John A. Jarcho, M.D., Editor
Atherosclerotic Plaque Healing
Rocco Vergallo, M.D., Ph.D., and Filippo Crea, M.D.​​
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n engl j med 383;9 nejm.org August 27, 2020 847
Atherosclerotic Plaque Healing
Atherosclerotic plaque healing is a dynamic
process that takes place after disruption of the
plaque and prevents the formation of a thrombus,
promotes plaque repair, and restores the
integrity of the vessel. This process, which involves
circulating blood cells, soluble mediators,
local plaque cells, and extracellular matrix, has
three main, overlapping phases: thrombus lysis,
granulation­tissue formation, and vessel re­endothelialization.
Atherosclerotic plaque healing differs
from plaque stabilization; healing follows
plaque disruption and takes place in a limited
Figure 1. Mechanisms of Atherosclerotic Plaque Healing.
Shown are the phases of rupture and healing of an atherosclerotic plaque. The cross-section of a plaque in Panel A shows a central core
containing lipids and necrotic debris (yellow) and macrophage foam cells (pink cells), surrounded by a fibrous cap composed of collagenrich
matrix and smooth-muscle cells. Inflammatory cells, including monocytes (lavender) and macrophages (aqua), infiltrate the intima.
Rupture of the fibrous cap, shown in Panel B, leads to exposure of the highly thrombogenic necrotic core, causing platelet activation and
aggregation and thrombus formation. In the case of plaque erosion, thrombus formation takes place in the presence of endothelial denudation,
which is more characteristic of plaques without a necrotic core. In a patient with an efficient endogenous fibrinolytic system,
rupture or erosion of the fibrous cap triggers a cascade of enzymatic processes such as the release of tissue plasminogen activator (t-PA)
and urokinase plasminogen activator (u-PA) from endothelial cells and the release of elastase and cathepsin G from neutrophils and
monocytes, facilitating fibrin breakdown and lysis of thrombus. In Panel C, the release of growth factors such as platelet-derived growth
factor BB (PDGF-BB) and transforming growth factor β (TGF-β) and the increased expression of P-selectin and stromal cell–derived factor
1α (SCDF-1α) stimulate a proliferative response of local plaque smooth-muscle cells and homing of smooth-muscle cells from the
underlying media, as well as bone marrow–derived smooth-muscle cell progenitors from circulating blood. The proliferating smoothmuscle
cells, in turn, synthesize proteoglycans and type III collagen, which form a provisional extracellular matrix. As shown in Panel D,
when plaque healing is complete, type I collagen gradually replaces type III collagen, and re-endothelialization occurs. This process prevents
the rapid development of occlusive thrombus but can cause the slow progression of a nonocclusive, lipid-rich plaque to a stenotic,
more fibrous lesion.
A
Atherosclerotic plaque
Endothelial
cell
Proteoglycans Type III
collagen New
endothelium
Collagen isoform conversion
type III type I
Homing of
smooth-muscle
cell progenitors
Smooth-muscle
cell proliferation
and migration
MEDIA
INTIMA
LUMEN
Type 1
collagen
Fibrous cap
Platelets
and fibrin
Fibrin
breakdown
Smooth-muscle
cells
t-PA
u-PA
Lipid
core
Lipid
core
Lipid
core
Thrombus
Fibrous cap
rupture or erosion
Lipid
core
B
C D
Thrombus formation and lysis
Thrombus organization and plaque healing Healed plaque re-endothelialization
BLOOD FLOW
BLOOD FLOW
BLOOD FLOW
BLOOD FLOW
Monocytes
and neutrophils
P-selectin
SCDF-1α
PDGF-BB
TGF-β
Mitogens
(e.g., thrombin)
Plaque
growth
Elastase
Cathepsin G
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n engl j med 383;9  nejm.org  August 27, 2020848
The new engl and jour nal of medicine
time period, whereas stabilization is a progressive
transformation of a lipid-rich plaque into a
more fibrotic and calcific plaque.
The mechanisms of atherosclerotic plaque
healing have been studied in humans and in
experimental models of mechanical injury to the
vessel wall (Fig. 1).11-14
After plaque rupture or
erosion, the exposure of thrombogenic plaque
components (e.g., the necrotic core, tissue factor,
and collagen) provides a potent stimulus for
platelet activation and aggregation and for thrombus
formation2,15
and simultaneously triggers
endogenous fibrinolysis to physiologically preserve
vessel patency10
(Fig. 1B). Data obtained
from both clinical studies and animal models
show that prevention of lasting occlusive thrombus
formation requires an intact and functional
endogenous fibrinolytic system, including the
release of tissue plasminogen activator16-18
and
urokinase plasminogen activator19
from endothelial
cells, the release of elastase and cathepsin
G from neutrophils and monocytes trapped
in the thrombus (which directly break down fi­
brin),17,20
and the dispersing effect of laminar
blood flow.21
The structural properties of fibrin
fibers are another important determinant of
susceptibility to endogenous thrombolysis, with
thick fibers appearing to be more susceptible to
lysis than compact, thin fibers.22
Plaque disruption also activates a proliferative
response in the smooth-muscle cells of the local
plaque, as well as migration of smooth-muscle
cells from the underlying media to the intima
(Fig. 1C). Factors promoting this smooth-muscle
cell response include the release of growth factors
(e.g., platelet-derived growth factor BB and
transforming growth factor β [TGF-β]) and mitogens
(e.g., thrombin) by platelets.23
In addition,
the release of TGF-β stimulates extracellular
matrix production by smooth-muscle cells.13,14
Experimental studies in mice have shown that
activated platelets adhering to and aggregating
over an injured arterial wall can also stimulate
the homing of bone marrow–derived smoothmuscle
cell progenitors from circulating blood
through the expression of P-selectin and stromal
cell–derived factor 1α.12,24,25
At the site of plaque
healing, proliferating smooth-muscle cells synthesize
a provisional extracellular matrix (granulation
tissue), which is rich in proteoglycans
and type III collagen4,26
(Fig. 1C). When plaque
healing is complete, type I collagen gradually
replaces type III collagen, and complete re-endothelialization
of the plaque surface with creation
of a neointima eventually occurs27
(Fig. 1D). After
the healing cycle has been completed, atherosclerotic
plaque may undergo further cycles of
destabilization and subsequent healing, with
accumulation of new granulation tissue.
Prevalence and Phenotype
of Plaque Healing
The reported prevalence of healed plaques varies
greatly (ranging from <5% to >80%), depending
on the method of detection, the vascular bed
assessed, and the clinical presentation.4,5,7,8,28-31
The introduction of new imaging techniques,
such as optical coherence tomography (OCT),
intravascular ultrasonography, and cardiovascular
magnetic resonance imaging (MRI), has enabled
the assessment of atherosclerotic plaque
healing in vivo.7,8,28,30
Studies using these techniques
suggest that the prevalence of healed
plaques is considerably higher among patients
with chronic manifestations of atherosclerotic
disease than among those in whom clinical stability
is frequently interrupted by acute events, in
both coronary7,8,29-31
and noncoronary28
vascular
beds. Pathological studies reveal similar findings.
In histologic studies of nonculprit lesions
in patients who died suddenly from ischemic
heart disease, more than half the lesions were
clinically silent, healed coronary plaques.4,5
Observations
from noncoronary vascular beds are
consistent with these findings. Serial carotid
MRI in patients with a transient ischemic attack
showed healing of plaque rupture or erosion in
almost 90% of patients who had no recurrence
of ischemic symptoms at 12 months of followup,
whereas this tendency toward healing was
less clear in patients with subsequent cerebrovascular
events.28
Why do some ruptured or eroded plaques fail
to heal, resulting in vessel occlusion, whereas
other plaques heal, entering a quiescent phase?
Knowing the phenotypic features of a healed
plaque may help in understanding the mechanisms
that promote plaque healing. On histopathological
evaluation with the use of picrosirius
red staining, healed plaque ruptures are
typically identified as newly synthesized type III
collagen (which appears green under polarized
light) over a disrupted fibrous cap containing
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n engl j med 383;9 nejm.org August 27, 2020 849
Atherosclerotic Plaque Healing
mostly type I collagen (which appears yellow to
white). Such lesions may have multiple layers of
lipid and necrotic core, indicative of previous
episodes of thrombosis and healing (Fig. 2A).4,29
In contrast, healed plaque erosions appear as
distinct layers of dense collagen interspersed
with smooth­muscle cells and proteoglycans,
without evidence of preexisting disruption of the
fibrous cap.4,29
On OCT imaging, healed plaques
appear as heterogeneous signal­rich layers with
optical­signal intensity that is different from the
underlying plaque, creating a characteristic onionlike
appearance, without interruption of the old
fibrous cap or with interruption that is suggestive
of a previous rupture7,8,29
(Fig. 2B through
2F). In a histopathological study by Shimokado
et al., half of the analyzed multilayered lesions
were healed plaque ruptures, and half healed
plaque erosions. These lesions had an underlying
lipid core in about two thirds of cases and
consisted of fibrous plaque in the remaining
third.29
The morphologic features of healed
carotid plaques at autopsy are similar to those
of healed coronary plaques, with multiple layers of
fibrous tissue and a lipid­rich necrotic core.32
Coronary thrombi overlying ruptured or eroded
plaques may also be assessed for evidence of
healing.33
In a pathological study involving 111
patients who died suddenly from coronary
causes, almost half the thrombi overlying plaque
ruptures had no evidence of healing, and the
remaining half showed various phases of healing.
In contrast, more than 85% of thrombi
overlying plaque erosions showed late stages of
healing, characterized by inflammatory­cell degradation,
infiltration of smooth­muscle cells,
proteoglycan deposition, and platelet and fibrin
layering.33
In a study by Geary et al.,34
who analyzed
healing thrombi that developed after experimental
angioplasty of the left iliac artery in
Figure 2. Histologic and Optical Coherence Tomographic (OCT) Images of Healed Coronary Plaques.
In Panel A, a histologic cross-section of human coronary atherosclerotic plaque stained with picrosirius red and
viewed under polarized light shows a healed plaque rupture; the majority of plaque collagen (type I collagen) is yellow–white,
and the new, loosely arranged collagen repairing the disrupted plaque (type III collagen) is green. Panels
B through F show representative in vivo OCT images of human healed coronary plaques with heterogeneous, signal-rich
layers of healing tissue (white double-headed arrows) characterized by a different optical-signal intensity
from the underlying plaque, giving the lesion a characteristic layered, “onion-like” appearance. (Panel A is reprinted
from Mann and Davies5
with the permission of the publisher.)
A B C
E FD
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The new engl and jour nal of medicine
nonhuman primates, thrombus was replaced by
smooth-muscle cells expressing hyaluronan and
an associated protein, versican, which are known
to be specifically involved in the pathogenesis of
erosion.15,35
Taken together, these observations
suggest that plaque erosion may be more likely
to heal than plaque rupture. The ingrowth of
microvessels is a common feature during thrombus
organization and is observed more frequently
in healed plaques than in nonhealed plaques.8
Neoangiogenesis appears to be a crucial step in
thrombus organization (and generally in tissue
repair), as the new microvessels provide oxygen
and nutrients to the healing tissue.36
Inflammation and Plaque
Healing
Although the mechanisms through which inflammation
can precipitate or exacerbate the thrombotic
complications of atherosclerosis have been
extensively investigated, the link between inflammation
and plaque healing remains incompletely
elucidated.1,37
A study of human vascular
smooth-muscle cells showed that exposure to
interferon-γ, secreted by activated type 1 helper
T (Th1) cells, inhibits the ability of smoothmuscle
cells to produce the interstitial collagen
needed to repair the fibrous cap and maintain
its integrity, even when the smooth-muscle cells
are maximally stimulated by TGF-β (Fig. 3).23
In
addition, cross-talk between Th1 cells and macrophages
(through the interaction between the
T-cell–derived cytokine CD40 ligand and the
macrophage receptor CD40) boosts the production
of interstitial collagenases, including matrix
metalloproteinases 1, 8, and 13, which promote
interstitial collagen breakdown, weakening the
fibrous cap.38,39
These phagocytes, known as M1
macrophages, are part of Th1 responses and are
involved in proinflammatory activities.40
In contrast, so-called alternative M2 macrophages
are triggered by type 2 helper T (Th2)
cytokines, including interleukin-4 and interleukin-13,
and secrete antiinflammatory cytokines,
including interleukin-10, which counterbalance
the proinflammatory activity of M1 macrophages
and promote tissue repair (Fig. 3).40,41
M2 macrophages
have been categorized into three subtypes:
M2a, M2b, and M2c.41
M2a macrophages,
traditionally recognized as wound-healing macrophages,
express high levels of scavenger, mannose,
and galactose receptors and produce profibrotic
factors, such as fibronectin, insulin-like
growth factor 1, and TGF-β, which may contribute
to plaque healing.40-42
Studies suggest a potential
role for M2 macrophages in plaque stability
and atherosclerosis regression in mouse models,
as well as in humans.43,44
It has been shown that macrophages are not
terminally differentiated in atherosclerotic disease
but can switch from one phenotype to another
in response to environmental cues.41,45
The
resolution of inflammation in atherosclerosis
is mediated by specialized, proresolving mediators,
such as resolvins, lipoxins, maresins, and
protectins. These mediators modulate the phenotypic
conversion of M1 proinflammatory
macrophages into alternative M2 macrophages,
promote apoptosis and efferocytosis of inflammatory
cells, and may play a role in the resolution
of inflammation during plaque healing.46
Mounting evidence suggests that CD31, an immunoglobulin-like
membrane receptor expressed by
leukocytes, platelets, and endothelial cells, might
play a part in atherosclerotic plaque healing by
regulating platelet activity and modulating T-cell
activation and macrophage phenotypic conver­
sion.47,48
Other studies suggest that smoothmuscle
cells are also not terminally differentiated
during the natural history of atherosclerosis
and can undergo a phenotypic conversion to a
macrophage-like state in response to changes in
the microenvironment. Whether smooth-muscle
cells can switch to an alternative M2 phenotype
and whether some dedifferentiated intimal
smooth-muscle cells can redifferentiate to repair
the fibrous cap during the healing process are
questions that remain largely unexplored.49
OCT
imaging data suggest a higher prevalence of
macrophage infiltration in healed plaques than
in nonhealed plaques,8
but in vivo molecular insights
into the macrophage phenotype in healed
plaques are lacking.
In the late phases of the healing process, M2
macrophages not only prompt the production of
extracellular matrix but also may promote plaque
calcification by stimulating osteoblastic differentiation
and maturation of vascular smoothmuscle
cells (Fig. 3).50,51
Calcium formation durThe
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n engl j med 383;9 nejm.org August 27, 2020 851
Atherosclerotic Plaque Healing
Figure 3. Inflammatory Pathways Involved in Plaque Instability and Plaque Healing.
A cross-section of a plaque (bottom) shows two phases of the natural history of atherosclerosis (i.e., plaque rupture
with thrombosis on the left, and plaque healing on the right). The panel on the left depicts the key inflammatory
pathways involved in plaque instability. Activated T cells (type 1 helper T [Th1] cells) produce interferon-γ, which
inhibits the synthesis of interstitial collagen by smooth-muscle cells. Th1 cells can also activate M1 macrophages
through a CD40 ligand–CD40 macrophage receptor interaction, stimulating an overproduction of interstitial collagenases,
including matrix metalloproteinases 1, 8, and 13 (MMP-1, -8, and -13), which in turn promote collagen
breakdown. The CD40 ligand–CD40 interaction also induces an overexpression of tissue factor by M1 macrophages.
The decreased synthesis and increased breakdown of interstitial collagen render the fibrous cap more susceptible to
rupture, and the enhanced thrombotic potential due to inflammatory activation triggers thrombus formation over
the disrupted plaque. The panel on the right shows the key antiinflammatory pathways involved in plaque healing.
Alternative M2 macrophages, mainly triggered by type 2 helper T (Th2) cytokines interleukin-4 and interleukin-13,
produce antiinflammatory cytokines, including interleukin-10, and secrete profibrotic factors, including fibronectin,
insulin-like growth factor 1 (IGF-1), and TGF-β, which prompt the production of interstitial collagen and extracellular
matrix by smooth-muscle cells. In the late phases of the healing process, M2 macrophages also induce osteoblast
differentiation and maturation of vascular smooth-muscle cells, promoting plaque calcification.
Plaque instability Plaque healing
MEDIA
INTIMA
Lipid
core
Fibrous cap
rupture with
thrombosis
Th1
cell
Th1
cell
Th2
cell
CD40
Tissue-factor
procoagulant
Increased
collagen degradation
Decreased
collagen production
MMP-1
MMP-8
MMP-13
Smooth-muscle cells
Smooth-muscle cell
maturation and proliferation
Osteoblast
differentiation
Interferon-γ
CD40
ligand
Mannose and
galactose
receptors
Interleukin-4
Interleukin-13
Interleukin-10
TGF-β
Fibronectin
IGF-1
Scavenger
receptor
M1
macrophage
M2
macrophage
Increased
collagen production
Calcium
deposition
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The new engl and jour nal of medicine
ing plaque healing is therefore not merely a
passive degenerative process but rather is the
result of dysregulated deposition and impaired
clearance. Pathological studies have shown that
maximum calcification is present in healed
plaque rupture and in fibrocalcific plaques and
that the calcification area steadily enlarges with
progressive luminal narrowing. Healed plaques
frequently contain diffuse sheets of calcification,
which provide mechanical support for the
healed plaque.52
Role of Plaque Healing
in Clinical Events
Much of the work addressing the mechanisms of
acute coronary syndromes during the past three
decades has focused on the pathogenesis of
plaque instability.1-3
However, recent intracoronary
imaging studies suggest that acute coronary
syndromes may require a “double hit” of
plaque disruption and impaired healing7
(Fig. 4).
The acute destabilization of an atherosclerotic
plaque by either rupture or erosion (the first hit)
leads to thrombosis and an acute coronary syndrome
in patients with an impaired healing capacity
(the second hit). In contrast, in patients
with an effective healing system, the first hit is
contained, the unstable plaque is “pacified,” and
the healing process promotes the development
of a more fibrous, stable plaque.
Repeated cycles of thrombosis and healing
lead to progressive encroachment on the arterial
lumen, with silent, stepwise stenotic progression
possibly leading to high-grade coronary occlusion
in the absence of acute coronary events. In
a seminal pathological study by Mann and
Davies,5
only approximately 16% of coronary
lesions with 0 to 20% diameter stenosis (the
percentage of cross-sectional diameter lost to
stenosis) and approximately 19% of coronary
lesions with 21 to 50% diameter stenosis had
healed disruption, whereas approximately 73%
of lesions with more than 50% diameter stenosis
had a healed disruption pattern. In vivo, healed
coronary plaques detected on OCT imaging have
been consistently associated with a significantly
smaller luminal area,7,8,30
and the prevalence of
healed plaques steadily increases with a greater
degree of stenosis.30
The clinical significance of plaque healing is
still a matter of debate.7,8,30
In a study from our
group, impaired healing was associated with
recurrent acute coronary syndromes, whereas
the presence of healed plaques was a predictor
of long-term clinical stability.7
Whether plaque
healing, through the silent progression of stenosis,
may translate into more frequent revascularization
procedures warrants investigation. Recent
data suggest that patients with OCT evidence of
healed plaques in nonculprit coronary segments
may have higher rates of revascularization in the
absence of acute events than patients without
evidence of healed plaques.53
Taken together,
these observations suggest that plaque healing
may protect patients with atherosclerotic disease
from the occurrence of acute coronary syndromes,
instead leading to a chronic coronary
syndrome (Fig. 4).
Ther apeutic Implications
and Future Perspectives
Both established and experimental therapeutic
interventions may influence plaque healing and
thereby reduce the risk of acute coronary syndromes
(Table 1). In rabbits with atherosclerosis
induced through balloon injury of the thoracic
aorta and an atherogenic diet, subsequent dietary
lipid lowering reduced the proteolytic activity of
matrix metalloproteinases and increased interstitial
collagen within the fibrous cap of the
plaque,54
reduced oxidative stress and endothelialcell
activation,55
and reduced tissue factor expression
and activity,56
rendering atheroma less
susceptible to disruption and thrombosis.
Lipid-lowering medication also has beneficial
effects on plaque healing. Statin therapy has
been shown to increase the number of intimal
smooth-muscle cells and the expression of type
I procollagen and to reduce the proliferation and
activation of macrophages, as well as tissue factor
expression, in atherosclerotic lesions in
Watanabe heritable hyperlipidemic rabbits.57,58
In
a recent study by Schuster et al., treatment of
APOE*3Leiden.CETP mice with neutralizing monoclonal
antibodies against proprotein convertase
subtilisin–kexin type 9 (PCSK9) resulted in a
reduction in macrophage infiltration within aortic
plaques and an increase in the numbers of
endothelial progenitor cells and circulating angiogenic
cells.59
Lipid lowering by conditional
inactivation of the gene encoding the microsomal
triglyceride transfer protein (MTTP) has
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n engl j med 383;9 nejm.org August 27, 2020 853
Atherosclerotic Plaque Healing
been associated with an increase in collagen
deposition, as well as a reduction in cholesterol
and CD68+ macrophage content within atherosclerotic
plaques in low­density lipoprotein receptor–deficient
mice.60
In vivo OCT imaging studies
suggest that coronary plaques undergo an
increase in fibrous­cap thickness and a reduction
in lipid content and macrophage infiltration
after the initiation of statin therapy61,62
or other
lipid­lowering therapies.63,64
A similar response
Figure 4. Role of Plaque Healing in the Natural History of Ischemic Heart Disease.
In the “double hit” theory of atherosclerosis, the first hit is the acute disruption of an atherosclerotic plaque (rupture
or erosion), and the second hit is an impaired healing capacity. In patients with a double hit of plaque disruption
and failed healing, occlusive or subocclusive thrombosis and an acute coronary syndrome will develop. In contrast,
the first hit is contained in patients with an effective healing system, and the healing process promotes evolution to
a more fibrous, stable plaque, often accompanied by constrictive remodeling. Repeated cycles of thrombosis and
healing lead to progressive luminal loss with stepwise stenotic progression in the absence of acute events.
Thin-cap
fibroatheroma
Fibrous
plaque
Plaque instability (first hit)
Large
lipid pool
Fibrous
tissue
Thin
fibrous cap
Thrombus
Plaque rupture Superficial
erosion
Failed healing (second hit)
Rapidly occlusive thrombosis Progressive lumen narrowing
Occlusive
thrombus
Effective healing
Acute coronary syndrome Chronic coronary syndrome
Healing
tissue
Repeat episodes
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The new engl and jour nal of medicine
to lipid-lowering therapy has been observed in
carotid plaques.65,66
Intensive antiplatelet therapy with newer P2Y12
inhibitors has proved effective in stabilizing
plaque erosion, with a progressive reduction in
the thrombotic burden at 30 days and complete
healing at 1 year.67,68
Whether patients with
impaired healing capacity may benefit from
prolonged antiplatelet regimens is currently
unknown and may warrant investigation in
larger-scale, randomized studies.
A number of studies are evaluating the effect
of antiinflammatory therapies, including the
interleukin-1β antagonist canakinumab and lowdose
colchicine, in reducing the risk of a recurrent
acute coronary syndrome.69,70
Although the
potential role of these antiinflammatory agents
in plaque healing has not been directly assessed,
their positive effects on clinical outcomes
might be due not only to the prevention of both
atherosclerotic progression and its acute thrombotic
complications but also to an improvement
in plaque healing capacity. Interleukin-1β stimulates
the expression of tissue factor and adhesion
molecules recruiting leukocytes on endothelial
cells, including intercellular adhesion
molecule 1 and vascular-cell adhesion molecule
1.71
Moreover, smooth-muscle cell stimulation
by interleukin-1β strongly induces the production
of interleukin-6, which in turn elicits an
acute-phase response culminating in the synthesis
of acute-phase reactants by hepatocytes,
including fibrinogen and plasminogen activator
inhibitor.72
Blockade of interleukin-1β may therefore
indirectly favor plaque healing by inhibiting
leukocyte adhesion, reducing thrombosis,
and promoting fibrinolysis. Similarly, a recent
study suggests that low-dose colchicine favorably
modifies the morphologic features of coronary
plaques, producing a more stable, fibrous
phenotype.73
What about new therapeutic targets? Modulation
of macrophage polarization (the process of
preferential differentiation into the M1 or M2
Table 1. Therapeutic Interventions That Might Enhance Atherosclerotic Plaque Healing.*
Therapy Potential Favorable Effects on Plaque Healing
Lipid-lowering diet (e.g., low-cholesterol,
low-fat diet)
Reduces expression and proteolytic activity of interstitial collagenase (MMP-1)
Increases interstitial collagen content within fibrous cap
Reduces oxidative stress
Reduces endothelial-cell activation
Reduces tissue factor expression and activity (reduces thrombotic potential)
Lipid-lowering drugs (e.g., statins,
PCSK9 inhibitors)
Reduce expression and proteolytic activity of interstitial collagenase (MMP-1)
Increase smooth-muscle cells and interstitial collagen within fibrous cap
Reduce proliferation and activation of macrophages
Reduce oxidative stress
Reduce endothelial-cell activation
Up-regulate endothelial progenitor cells and circulating angiogenic cells
Reduce tissue factor expression and activity (reduce thrombotic potential)
Reduce plasminogen activator inhibitor 1 levels (increase fibrinolytic
potential)
Antiinflammatory drugs (e.g.,
interleukin-1β antagonists,
­colchicine)
Reduce expression of adhesion molecules and leukocyte recruitment on
endothelial cells
Reduce tissue factor expression (reduce thrombotic potential)
Reduce fibrinogen and plasminogen activator inhibitor 1 levels (reduce
thrombotic potential, increase fibrinolytic potential)
CD31-targeting therapies (e.g., agonist
peptides, antibodies, recombinant
proteins)
Polarize macrophages toward an alternative M2 phenotype
Epigenetic therapies targeting macrophage
polarization (e.g., DNA
methylation, histone modifications,
miRNAs, lnc-RNAs)
Polarize macrophages toward an alternative M2 phenotype
PI3Kc–CXCL10 axis inhibitors Increase re-endothelialization after vascular injury
*	CXCL10 denotes C-X-C motif chemokine ligand 10, lncRNAs long noncoding RNAs, miRNAs microRNAs, MMP-1 matrix
metalloproteinase 1, PCSK9 proprotein convertase subtilisin–kexin type 9, and PI3Kc phosphatidylinositol 3-kinase,
catalytic domain.
The New England Journal of Medicine
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n engl j med 383;9  nejm.org  August 27, 2020 855
Atherosclerotic Plaque Healing
phenotype) through CD31-targeting molecules
or epigenetic therapies may provide additional
opportunities for therapeutic intervention in the
near future. A drug-suitable CD31 agonist peptide
was recently shown to promote macrophage
polarization toward a reparative M2 phenotype
in experimental models of arterial injury.47,74
Neele et al. found that the histone demethylase
JMJD3 reprograms macrophages to the M2 phe­
notype.75
Similarly, systemic deletion or myeloidspecific
deletion of histone deacetylases 9 and 3
has been shown to promote M2 macrophage po­
larization.76,77
Inhibition of microRNAs (miRNAs)
such as miRNA-33 was found to polarize macrophages
toward an M2 phenotype78
; miRNA-146a
and miRNA-27a also had an atheroprotective effect
mediated by an alternative M2 macrophage
activation.79,80
In a study assessing the detailed
expression patterns of long noncoding RNAs
(lncRNAs) in macrophage polarization, Huang
et al. found that knockdown of the lncRNA
TCONS_00019715 can switch isolated human
monocyte-derived macrophages from a proinflammatory
M1 phenotype to an alternative M2
phenotype.81
An elegant study using an in vivo model of
endovascular injury in mice recently revealed that
a phosphatidylinositol 3-kinase c (PI3Kc)–dependent
T-cell response stimulates production of the
interferon-inducible C-X-C motif chemokine ligand
10 (CXCL10) by smooth-muscle cells, which
in turn inhibits endothelial healing. In this study,
both ubiquitous genetic inactivation of PI3Kc
and hematopoietic cell–specific PI3Kc deletion,
as well as CXCL10 neutralization, improved reendothelialization
of the injured carotid artery
in mice.82
These novel findings might pave the
way for new therapeutic strategies to promote
endothelial healing, which may be particularly
effective when a superficial erosion occurs in the
absence of a frank rupture of the fibrous cap. An
anti-CXCL10 antibody and a highly specific PI3Kc
inhibitor have been developed and are being
evaluated in clinical trials for the treatment of
noncardiovascular diseases.83,84
Conclusions
We have learned a great deal about mechanisms
governing plaque instability, and this knowledge
has driven the traditional approaches to therapy
for atherosclerosis. The notion that plaque healing
contributes to the natural history of atherosclerotic
disease, rooted in keen pathological
observations in the past century, has been undergoing
a research renaissance in recent years,
primarily owing to the availability of new invasive
imaging tools that permit the study of atherosclerosis
in vivo. We now understand that
healed plaques are not merely innocent bystanders.
In particular, the evolution of coronary artery
disease appears to be more stable in patients
with healed plaques than in patients with unhealed
plaques. It is unclear why some patients
have a good capacity for healing and others do
not. A better insight into the pathophysiology of
plaque healing might allow the implementation
of strategies to transform poor healing into good
healing, thus further reducing the residual burden
of cardiovascular disease.
Disclosure forms provided by the authors are available with
the full text of this article at NEJM.org.
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