Acute coronary-syndromes-circulation

STATEOFTHEART
Circulation. 2017;136:1155–1166. DOI: 10.1161/CIRCULATIONAHA.117.029870 September 19, 2017 1155
Filippo Crea, MD
Peter Libby, MD
ABSTRACT: Well into the 21st century, we still triage acute myocardial
infarction on the basis of the presence or absence of ST-segment
elevation, a century-old technology. Meanwhile, we have learned a great
deal about the pathophysiology and mechanisms of acute coronary
syndromes (ACS) at the clinical, pathological, cellular, and molecular
levels. Contemporary imaging studies have shed new light on the
mechanisms of ACS. This review discusses these advances and their
implications for clinical management of the ACS for the future. Plaque
rupture has dominated our thinking about ACS pathophysiology for
decades. However, current evidence suggests that a sole focus on plaque
rupture vastly oversimplifies this complex collection of diseases and
obscures other mechanisms that may mandate different management
strategies. We propose segmenting coronary artery thrombosis caused
by plaque rupture into cases with or without signs of concomitant
inflammation. This distinction may have substantial therapeutic
implications as direct anti-inflammatory interventions for atherosclerosis
emerge. Coronary artery thrombosis caused by plaque erosion may be
on the rise in an era of intense lipid lowering. Identification of patients
with of ACS resulting from erosion may permit a less invasive approach to
management than the current standard of care. We also now recognize
ACS that occur without apparent epicardial coronary artery thrombus or
stenosis. Such events may arise from spasm, microvascular disease, or
other pathways. Emerging management strategies may likewise apply
selectively to this category of ACS. We advocate this more mechanistic
approach to the categorization of ACS to provide a framework for future
tailoring, triage, and therapy for patients in a more personalized and
precise manner.
Acute Coronary Syndromes
The Way Forward From Mechanisms to Precision Treatment
© 2017 American Heart
Association, Inc.
Correspondence to: Peter Libby,
MD, Brigham and Women’s
Hospital, Harvard Medical School,
77 Ave Louis Pasteur, NRB-741-G,
Boston, MA 02115. E-mail plibby@
bwh.harvard.edu
IN DEPTH
Key Words: erosion
◼ inflammation ◼ microvessels
◼ myocardial infarction ◼ plaque
◼ plaque, atherosclerotic
◼ thrombosis
byguestonSeptember18,2017http://circ.ahajournals.org/Downloadedfrom

Crea and Libby
September 19, 2017 Circulation. 2017;136:1155–1166. DOI: 10.1161/CIRCULATIONAHA.117.0298701156
W
illem Einthoven introduced electrocardiogra-
phy at the dawn of the 20th century. Well into
the 21st century, we still triage acute myocar-
dial infarction on the basis of this venerable technology:
ST segments up or not. Although this approach remains
the appropriate evidence-based strategy today, aiming
toward the future goal of more individualized therapy,
can we apply a more pathophysiologically based cat-
egorization of the acute coronary syndromes (ACS)? In-
deed, we have learned much about the mechanisms of
ACS since we last reviewed this topic in these pages.1,2
Moreover, the human disease of atherosclerosis has
evolved considerably in the interim.3–5
This review aims
to work toward a categorization of the ACS that reach-
es beyond equating all ACS with plaque rupture or fis-
sure, guided by the latest insights into the underlying
mechanisms of ACS, and points a way forward toward
the eventual clinical application of these considerations.
Postmortem studies carried out in the 1980s pro-
posed that plaque rupture (also sometimes referred to
as fissure) caused most fatal myocardial infarctions.6
These findings led to the notion of the vulnerable or
high-risk plaque characterized by a large central lipid
core, an abundance of inflammatory cells, a paucity of
smooth muscle cells (SMCs), and a thin fibrous cap.7
These observations spawned the widely accepted con-
cept that instability of coronary atheromata resulted
from fissuring of a thin-capped fibroatheroma caused
by a weakening of its collagen structure wrought by
inflammatory mechanisms.8
This concept stimulated manifold attempts to de-
velop methods to detect the vulnerable plaque, a quest
predicated on the postulate that local interventions
could preclude plaque thrombosis and possibly prevent
ACS. However, attempts to identify vulnerable plaques
proved disappointing because of their low predictive
value.9
Pathological studies of human coronary arter-
ies show that plaque rupture occurs commonly in indi-
viduals without symptomatic ACS.10
Moreover, 5% of
plaques with the features of thin-capped fibroatheroma
as determined by intravascular ultrasound interroga-
tion actually cause clinical events during over 3 years
of follow-up.11
Thus, most thin-capped fibroatheroma
are clinically quite stable, a realization that renders
vulnerable plaque a misnomer. Indeed, plaques with
thin-capped fibroatheroma morphology as assessed
by radiofrequency backscatter data from intravascular
ultrasound (virtual histology) commonly convert to an
apparently more stable character during a 1-year fol-
low-up period.12
Such evolution in plaques may reflect
mutability during the natural history of human athero-
sclerosis but could also reflect adherence of many of
these patients to a contemporary secondary preven-
tion regimen, including smoking cessation, statins, and
agents that target the renin-angiotensin axis.
Moreover, although we have witnessed wide accep-
tance of the formerly controversial concept that inflam-
mation contributes to atherogenesis,13
inflammation
may not drive all transitions from stable atherosclerosis
to acute thrombotic events. In a large study, about half
of ACS occurred in the presence of normal levels of
C-reactive protein (CRP), a marker of inflammation.14
Another recent study using optical coherence tomog-
raphy (OCT) demonstrated that among patients with
ACS and plaque rupture, two thirds of patients had im-
aging evidence of inflammatory cell infiltration in the
region of the ruptured fibrous cap but one third did
not and the latter had lower levels of CRP.15
In addition,
plaque erosion causes up to a third of ACS in the cur-
rent era.16,17
Finally, about one fifth of ACS occur in the
apparent absence of coronary thrombosis, suggesting
that functional alterations beyond thrombus formation
can contribute to ACS pathogenesis.18,19
The ensemble of postmortem studies and in vivo
studies using intravascular imaging point to 4 patho-
logical pathways to ACS. Although these mechanisms
may overlap and coexist in some patients, we present
them separately for heuristic simplicity: plaque rupture
with systemic inflammation, plaque rupture without
systemic inflammation, plaque erosion, and plaque
without thrombus (Figure 1).20
This review considers the causes of these 4 predomi-
nant pathways to ACS. To strive for a more precision
approach, we explore the therapeutic implications of
these distinct mechanisms that provoke ACS. Moreover,
we advocate the future goal to move beyond triage of
therapy based merely on electrocardiographic current
of injury by harnessing the recent advances in arterial
biology and human studies that shed new mechanis-
tic light on ACS pathogenesis. Further improvements
in the appropriate deployment of technologies and in
outcomes should evolve from a more mechanistically
based classification of ACS.
PLAQUE RUPTURE WITH SYSTEMIC
INFLAMMATION
Mechanisms
Several studies have implicated systemic inflammation
in ACS as assessed by the biomarker CRP (Figure 1A).21
Laboratory studies and observations on human plaques
point to inflammatory mechanisms as key regulators of
the fragility of the fibrous cap and of the thrombogenic
potential of the lipid core (Figure 2). Macrophages likely
pave the way for the rupture of the fibrous cap of the
plaque: When activated, these cells elaborate enzymes
that degrade all components of the arterial extracellular
matrix. These enzymes include matrix metalloproteinases
and certain cathepsins. Multiple mechanisms regulate
these matrix-degrading proteinases: transcription, trans-

ACS Mechanisms Inform Management
STATEOFTHEART
lation, activation of zymogen precursors, and balance
with endogenous inhibitors such as the tissue inhibitors
of matrix metalloproteinases or the cystatins. Thus, in-
creased amounts of activated proteinases or reduced lev-
els of their corresponding inhibitors can enhance break-
down of the extracellular matrix of plaque.22
Adaptive immunity also appears altered in coronary
plaque instability.23
Patients with ACS have an increased
population of particularly proinflammatory CD4+
T cells
characterized by low cell surface expression of CD28, a
costimulatory molecule critically involved in determin-
ing the outcome of antigen recognition by T cells.24
ACS
also profoundly perturb the numbers of 2 other circulat-
ing T-cell subsets: type 17 helper T cells and CD4+
CD25+
regulatory T cells (Tregs
). The net role of interleukin (IL)-17
in atherosclerosis remains controversial, however; some
experimental studies in mice support a predominantly
proatherogenic function for IL-17, yet type 17 helper
T cells activated in plaques promote the formation of
thick collagen fibers, which might increase plaque sta-
bility.25,26
Tregs
normally help to maintain homeostasis of
cells involved in adaptive immunity, including antigen-
presenting cells and effector T cells. Tregs
mediate these
modulatory effects by contact-dependent suppression
or by releasing anti-inflammatory cytokines such IL-
10 or transforming growth factor-β1.27
Patients with
ACS have a reduced number and suppressive function
of circulating Tregs
compared with patients with stable
angina and healthy control subjects.28
The molecular
mechanisms responsible for the T-cell dysregulation in
ACS remain largely unknown. Recent work highlights
the importance of the strength of the stimulation of
the T-cell receptor for antigen in the differentiation of
helper T-cell subsets. The altered activity observed in
ACS of proteins involved in the regulation of upstream
T-cell receptor for antigen signaling such as CD31 and
protein tyrosine phosphatase N22 may modulate T-cell
functions.29,30
Figure 1. Four diverse mechanisms cause acute coronary syndromes (ACS).
A, Plaque rupture, also referred to as fissure, traditionally considered the dominant substrate for ACS, usually associates
with both local inflammation, as depicted by the blue monocytes, and systemic inflammation, as indicated by the gauge
showing an increase in blood C-reactive protein (CRP; measured with a high-sensitivity [hsCRP] assay). B, In some cases,
plaque rupture complicates atheromata that do not harbor large collections of intimal macrophages, as identified by optical
coherence tomography criteria, and do not associate with elevations in circulating CRP. Plaque rupture usually provokes
the formation of fibrin-rich red thrombi. C, Plaque erosion appears to account for a growing portion of ACS, often provok-
ing non–ST-segment–elevation myocardial infarction. The thrombi overlying patches of intimal erosion generally exhibit
characteristics of white platelet-rich structures. D, Vasospasm can also cause ACS, long recognized as a phenomenon in the
epicardial arteries but also affecting coronary microcirculation.

Crea and Libby
Therapeutic Implications
Several anti-inflammatory treatments might provide
benefit in this setting. Colchicine, a time-honored
anti-inflammatory drug, reduced major cardiovascular
events in a medium-sized, unblinded randomized study
in patients with stable ischemic heart disease.31
Two tri-
als underway are evaluating colchicine treatment in pa-
tients with coronary artery disease, although not in the
acute phase.32
A phase III trial is testing the potential
beneficial effects of low-dose methotrexate in patients
after myocardial infarction or with coronary artery dis-
ease and diabetes mellitus or elements of the metabolic
syndrome.33
Targeting proinflammatory cytokines offers an-
other approach. Because of the potentially detrimen-
tal effects on cardiovascular risk profile or the lack of
compelling evidence of benefit in experimental ath-
erosclerosis, monoclonal antibodies that neutralize tu-
mor necrosis factor-α, interferon-γ, or IL-17 may not
prove appropriate for treating atherosclerosis. In a small
(n=182) phase II study, the IL-1 receptor antagonist
anakinra reduced the area under the curve of high-
sensitivity CRP in patients in the 7 days after presenta-
tion with ACS.34
A large (n10 000) phase III trial with
clinical end points that tested a fully humanized anti–
IL-1β monoclonal antibody, canakinumab, in patients
with previous myocardial infarction and CRP levels 2
mg/L showed a significant 15% reduction in the prima-
ry endpoint of MI, stroke, or death, and a 17% fall in
a secondary endpoint that included urgent revascular-
ization. Indeed, revascularization procedures declined
30% in the group that received the interleukin-1β neu-
tralizing antibody canakinumab 150mg subcutaneously
every 3 months. This intervention trial substantiates the
causal contribution of inflammation to atherosclerotic
events.35-37
T-cell activation signaling offers possible targets. A
synthetic CD31-derived peptide can suppresses im-
munity in vivo by restoring an inhibitory pathway to a
CD31-negative T-cell subset.38
Moreover, the develop-
ment of a novel series of inhibitors of the phosphatase
protein tyrosine phosphatase N22 might contribute to
a better understanding of its role in immune dysregula-
tion in patients with ACS.39
Therapeutic strategies that
Figure 2. Imbalance in adaptive immune pathways can modulate atherosclerotic plaque activity.
Subsets of T lymphocytes, major participants in adaptive immunity, can either promote local plaque inflammation (effector T
cells) or, in the case of regulatory T cells (Treg
), suppress inflammation. Although many pathways regulate T-cell functions, the
markers and mechanisms depicted here illustrate the principle that imbalances in T-cell activities can prevail in plaques. Low
levels of expression of the resurface marker CD31 and high activity of protein tyrosine phosphatase N22 (PTPN22; also known
as Lyp) characterize effector T cells. High levels of activation of CREB (cAMP-responsive element binding protein) character-
ize Tregs
that can dampen local adaptive immune responses in the plaque. CCR2 indicates C-C chemokine receptor type 2;
CX3CR1, CX3C chemokine receptor 1; IL, interleukin; IFN-γ, interferon-γ; TGFβ, transforming growth factor-β; and TNF, tumor
necrosis factor.

STATEOFTHEART
target Treg
include administration of low doses of IL-2
and infusion of autologous Tregs
that have undergone
differentiation and expansion in vitro.40
Various vaccina-
tion strategies also can limit experimental atherogen-
esis and may act by augmenting the activity of Treg
.41
PLAQUE RUPTURE WITHOUT
SYSTEMIC INFLAMMATION
Mechanisms
When plaque rupture occurs in the absence of systemic
inflammatory activation, other mechanisms may con-
tribute to pathogenesis, including extreme emotional
disturbance ranging from external events of short dura-
tion such as earthquakes and a beloved team’s loss of a
football (soccer) match to acute manifestations of more
long-term emotional disturbances (Figure 1B). Intense
physical exertion and local mechanical stress at the level
of the artery wall, either increased circumferential stress
or reduced shear stress, may also predispose to plaque
rupture.42
In addition, subclinical inflammation in the
microenvironment of the culprit stenosis might com-
pound the chain of events leading to coronary instabil-
ity, although the triggers for and effectors of such local
inflammation may differ from those that operate in
patients with systemic inflammation.43
Although many
studies have clarified the molecular mechanisms lead-
ing to coronary instability in individuals with systemic
inflammation (eg, gauged by CRP elevations), patients
without systemic inflammation have undergone less
extensive investigation. The precise causes of instability
remain poorly understood, providing a strong stimulus
for further research.
The possible relationship between psychological
stress and plaque rupture may relate to sympathetic
nervous system activation and catecholamine release
associated with an increase in heart rate, blood pres-
sure, and coronary vasoconstriction favoring plaque dis-
ruption and platelet activation, hypercoagulability, and
intense coronary microvascular constriction.44
More-
over, β3
-adrenergic stimulation can stimulate release
from the bone marrow of proinflammatory monocytes
that can home to experimental atheromata and amplify
local inflammation.45
Although physical or emotional
stress per se may not suffice to cause coronary throm-
bosis, it might trigger instability in plaques already pre-
disposed to provoke events.46
Figure 3. Cholesterol crystals activate local innate immune pathways in the atherosclerotic plaque.
Plasma low-density lipoprotein can enter the arterial wall and accumulate in mononuclear phagocytes via scavenger receptors.
Lipid-laden macrophage foam cells can die, contributing to the accumulation of extracellular cholesteryl ester and cholesterol
monohydrate crystals in the lipid-rich necrotic core of the plaque. The dying macrophages can also release apoptotic bodies
and microparticles that contain the potent procoagulant tissue factor (TF+
). The cholesterol crystals can coactivate the inflam-
masome, an intracellular supramolecular structure that generates the biologically active forms of the proinflammatory cyto-
kines interleukin (IL)-1β and IL-18. Large crystals might also cause mechanical disruption of the fibrous cap.

Crea and Libby
Local changes in the equilibrium between esterified
and free cholesterol might promote plaque rupture47
(Fig-
ure 3). Cholesterol crystal formation in the lipid core could
heighten the risk of plaque rupture and thrombosis and
can coactivate the inflammasome, an intracellular multi-
meric complex that generates active IL-1β and IL-18.48
OCT has colocalized cholesterol crystals in human
coronary arteries with thin-capped plaques.49
The devel-
opment of micro-OCT with a 2-μm resolution may shed
new light on this potential mechanism of instability by
assessing its occurrence in vivo.50
Cholesterol crystals
might also theoretically resist plaque rupture by increas-
ing the stiffness of the lipid pool, although this mecha-
nism probably contributes little to plaque stability.51
The
role of calcium mineral as a causal factor in ACS remains
controversial. Large collections of calcified tissue do not
augment the biomechanical instability of plaques or as-
sociate with lesions that provoke ACS.52,53
Small foci of
calcification within the atherosclerotic intima, some caus-
ing spotty calcification visible on computed tomography,
can also introduce biomechanical inhomogeneities that
can favor plaque destabilization.3,54,55
Because it is difficult to limit environmental, physical,
or emotional triggers, the altered plaque characteristics
produced by intensive lipid-lowering treatment might
protect against this form of plaque destabilization.56
In
particular, statins and ezetimibe may interfere with cho-
lesterol crystal formation.57,58
Cyclodextrin can solubilize
cholesterol, limits experimental atherogenesis, and thus
might provide a pharmacological approach to combat-
ting cholesterol crystal accumulation in plaques.59
Enhancement of cholesterol efflux might promote
plaque stabilization, but strategies to enhance this process
by manipulation of high-density lipoprotein concentra-
tions or by administration of apolipoprotein A-1 have gen-
erally failed to confer clinical benefit.60
A large outcome
trial with anacetrapib produced a modest event reduction,
but since this agent not only raises high-density lipopro-
tein but also lowers low-density lipoprotein renders it dif-
ficult to attribute event reduction to raising high-density
lipoprotein.61
In addition, the inhibition of cholesteryl ester
hydrolase, an enzyme that converts cholesteryl esters to
free cholesterol, might prevent cholesterol crystallization.
Inhibition of acetyl-CoA acetyltransferase-1, which in con-
trast promotes cholesterol crystallization, increased ath-
eroma volume and major cardiovascular events.62
PLAQUE EROSION
Mechanisms
Current evidence suggests that mechanisms of plaque
disruption distinct from macrophage-driven rupture of
the fibrous cap of plaque can commonly cause ACS.63
The mechanism of plaque thrombosis described by pa-
thologists as superficial erosion appears not to involve
inflammation mediated by macrophages, as in the case
of fibrous cap fracture (Figure 1C). Superficial erosion
complicates lesions with a distinct epidemiology and
morphology and involves pathophysiological mecha-
nisms that differ from rupture of the fibrous cap. In-
deed, neutrophil activation seems to play a pivotal role
in thrombosis due to plaque erosion.4
Patients who
presented with ACS associated with plaque erosion
defined by OCT had higher systemic myeloperoxidase
levels compared with patients with plaque rupture.
Moreover, in postmortem coronary artery specimens,
luminal thrombi superimposed on eroded plaques con-
tain many more myeloperoxidase-positive cells than
thrombi associated with ruptured plaques64
(Figure 4).
Autopsy studies suggest that fatal plaque erosion as-
sociates more commonly with hypertriglyceridemia, dia-
betes mellitus, female sex, and old age.65
The morphology
of lesions that produce thrombosis caused by superficial
erosion differs radically from the features associated with
fibrous cap rupture. Superficially eroded lesions contain
few macrophages or T lymphocytes, inflammatory cells
considered pathogenic in plaque rupture. Rather than
depleted collagen, the lesions associated with superficial
erosion contain abundant proteoglycan and glycosami-
noglycans. Instead of a paucity of SMCs, eroded lesions
can contain abundant arterial SMCs. Plaques complicat-
ed by fibrous cap fracture typically harbor large necrotic,
lipid-rich cores. In contrast, the more fibrous lesions asso-
ciated with superficial erosion generally lack prominent
central lipid cores.66
A loss of intimal endothelial cells de-
fines lesions that provoke thrombosis by the mechanism
denoted as superficial erosion.
Recent work has implicated engagement of the innate
immune receptor Toll-like receptor 2 in promoting the
susceptibility of endothelial cells to apoptotic stimuli. Hy-
aluronic acid, a prominent constituent of the extracellular
matrix of eroded lesions, could serve as an endogenous
ligand of Toll-like receptor 2, implicated in promoting
endothelial cell apoptosis.67
Experiments that have evalu-
ated gain and loss of Toll-like receptor 2 function in mice
support these observations.68
Indeed, hyaluronan and its
receptor, CD44, colocalize along the plaque/thrombus
interface in eroded plaque but not in ruptured or stable
plaque.69
Accumulation of hyaluronan and expression
of CD44 along the plaque/thrombus interface of erod-
ed plaques may promote de-endothelization, resulting
in CD44-dependent platelet adhesion and subsequent
thrombus formation, mediated in part by a direct action
of hyaluronan on fibrin polymerization.70,71
We have hypothesized that thrombosis caused by su-
perficial erosion occurs in 2 phases. The first hit, mediat-
ed, for example, by Toll-like receptor 2, would jeopardize
endothelial viability or adherence, leading to a breach in

STATEOFTHEART
the integrity of the endothelial monolayer overlying the
atherosclerotic plaque. The denuded patch on the intimal
surface would then attract platelets that could undergo
activation by contact with collagen and other compo-
nents of the arterial extracellular matrix usually protected
from the blood compartment by the endothelial lining of
the intima. The second hit, mediated by the release of
granular contents from activated platelets and the local
production of chemoattractants for polymorphonuclear
leukocytes, would beckon these granulocytes to join the
platelets at local sites of endothelial denudation. In turn,
the activation of polymorphonuclear leukocytes could
generate structures known as neutrophil extracellular
traps, made up of strands of unwound DNA released by
the dying granulocytes.72
This uncoiled DNA becomes
decorated with proteases, tissue factor, and pro-oxidant
enzymes that could propagate local amplification of an
innate immune response, thrombin activation, and fibrin
generation and entrap further platelets and fibrin strands
in an evolving thrombus.51
This hypothetical scenario posits a mechanism of
thrombosis that is independent of the chronic inflam-
matory cells typically implicated in fibrous cap rupture:
macrophages and T lymphocytes. Rather, this schema
implicates different arms of innate immunity in throm-
bus initiation, propagation, and stabilization. These
mechanistic differences with fibrous cap fracture have
potential therapeutic implications.
Because statins alter the lipid profile primarily by low-
ering low-density lipoprotein rather than triglycerides,
therapies that address triglyceride-rich lipoproteins may
address the residual risk of events resulting from erosion
that persists in the statin era more effectively than more
intense low-density lipoprotein–lowering therapies.73
Moreover, therapies that destabilize neutrophil extra-
cellular traps such as deoxyribonuclease administration
might limit the propagation of thrombi resulting from
superficial erosion.74
Receptors such as CD44 expressed
by neutrophils may bind hyaluronan and glycosamino-
glycan enriched in plaques complicated by erosion and
furnish a potential therapeutic target.75
Jia et al76
recently reported a series of patients with
ACS with OCT-defined erosion and treated with anti-
coagulant/antiplatelet therapy rather that mechanical
revascularization. About 80% of the patients showed
a 50% reduction of thrombus volume after 1 month.
More than a third of patients lacked detectable thrombus
after 1 month. This study suggests that pharmacological
rather than interventional treatment can effectively man-
age ACS caused by superficial erosion, a proposition that
merits and requires rigorous testing in outcome trials.77
PLAQUE WITHOUT THROMBUS
Mechanisms
In patients with ACS without plaque thrombus, a func-
tional alteration of coronary circulation likely causes
Figure 4. Pathways implicated in arterial thrombosis
caused by superficial erosion.
Stimuli such as disturbed flow or engagement of innate im-
mune receptors such as Toll-like receptor-2 (TLR2) can activate
the endothelial cells that line the arterial intima. These cells can
undergo cell death, eg, by apoptosis, depicted by the cell with
the interrupted membrane and pyknotic nucleus. Injured or dy-
ing endothelial cells can desquamate, uncovering the basement
membrane. Neutrophils attracted by chemokines produced
by activated endothelial cells can congregate on the denuded
intima and can in turn degranulate and die, releasing neutro-
phil extracellular traps (NETs). These strands of extruded DNA
can bind the contents of the neutrophil granules and other
proteins, eg, myeloperoxidase or tissue factor. The NETs can
constitute a solid-state reactor that generates oxidants such as
hypochlorous acid and stimulates coagulation locally. Platelets
interacting with the basement membrane can activate, release
their granular contents, including chemokines that can recruit
further leukocytes, and form the nidus of a white thrombus.

Crea and Libby
acute ischemia involving large epicardial coronary
arteries or the coronary microcirculation (Figure 1D).
Epicardial coronary vasospasm may occur in patients
in whom coronary angiography does not demonstrate
an obstructive atherosclerotic plaque.78
In the CASPAR
study (Coronary Artery Spasm in Patients With Acute
Coronary Syndrome), coronary angiography failed to
show culprit lesions in ≈30% of patients with sus-
pected ACS.79
Intracoronary acetylcholine administra-
tion elicited coronary spasm in nearly 50% of these
patients. Similar findings pertained to a Japanese
population.80
Coronary artery spasm also may cause
coronary instability in patients with obstructive ath-
erosclerosis. Indeed, a classic study by Bertrand et al81
found that ergonovine induced spasm in 20% of pa-
tients with recent myocardial infarction and in 40% of
patients with unstable angina. In a more recent study,
acetylcholine induced spasm in 20% of white patients
and in 60% of patients with myocardial infarction
within the previous 14 days.82
Japanese people have a
higher prevalence of coronary spasm than whites for
unknown reasons.
Microvascular spasm also can cause myocardial isch-
emia.83
This mechanism likely operates in patients with
Takotsubo cardiomyopathy,84
which frequently occurs
in the absence of obstructive atherosclerosis, although
≈15% of these patients exhibit concomitant obstructive
atherosclerosis.85
Microvascular spasm can also contrib-
ute to ischemia in the face of angiographically normal-
appearing epicardial coronary arteries. Microvascular
ischemia often manifests as angina pectoris but can
also cause non–ST-segment–elevation ACS as defined
by electrocardiographic alterations and biomarker evi-
dence of myocyte injury.86
Coronary spasm can also
contribute to plaque instability by causing endothelial
damage, as shown in an infarction-prone strain of the
Watanabe heritable hyperlipidemic rabbit.44
Either macrovascular or microvascular spasm can
result from impaired vasodilatation or from vasocon-
strictor stimuli acting on hyperreactive vascular SMCs
Figure 5. Cellular mechanisms of arterial epicardial spasm relevant to acute coronary syndrome pathogenesis.
Smooth muscle cells in the media layer of coronary arterial vessels can contract in response to stimuli from the autonomic ner-
vous system (eg, acetylcholine), local responses to autacoids (eg, histamine), and pharmacological stimuli. Local hyperreactivity
of smooth muscle cells mediated mainly by enhanced Rho kinase activity results in spasm in response to constrictor stimuli.
Normal endothelial cells produce endogenous vasodilator substances, including nitric oxide (NO). A large body of literature
supports the contribution of dysfunctional endothelium to inappropriate constriction of coronary and other arteries.

STATEOFTHEART
(Figure 5).87,88
Shimokawa et al89
demonstrated SMC
hyperreactivity in a coronary segment in pigs after
adventitial exposure of a coronary segment to an in-
flammatory stimulus (IL-1β). Subsequent experimental
and clinical data suggested that an increase in Rho-
kinase activity was a major mechanism of SMC hy-
perreactivity.90–92
Perivascular fibrosis in the coronary
microvasculature can contribute to myocardial isch-
emia.93
This observation highlights the potential contri-
bution of fixed structural changes in coronary arterioles
beyond impaired endothelial vasodilator function as a
contributor to myocardial ischemia in the absence of
obstructive disease of the epicardial coronary arteries.
Several vasoconstrictor substances implicated as trig-
gers of epicardial coronary spasm may cause ischemia in
the same patient under different conditions.94
Accord-
ingly, the vasoactive substances themselves may not re-
spond to therapeutic targeting. The current treatment
of epicardial spasm uses nonspecific vasodilators such
as long-acting nitrates and calcium channel blockers.95
Nitrates and calcium channel antagonists may alleviate
ischemia caused by vasospasm. However, we need to
identify the molecular alterations responsible for SMC
hyperreactivity because many patients do not respond
satisfactorily to standard doses of vasodilators.96
Knowl-
edge of the postreceptor mechanisms responsible for
SMC hyperreactivity and epicardial coronary spasm
might enable the development of new therapeutic op-
tions for patients who present poor clinical response to
nonspecific vasodilator therapy. Fasudil, a Rho kinase
inhibitor, reduces the rate of coronary spasm episodes
in patients with vasospastic angina.97
Similarly, further
efforts are warranted to unravel the molecular mecha-
nisms responsible for coronary microvascular dysfunc-
tion in Takotsubo cardiomyopathy and in ischemia with
normal coronary arteries.20
The observation that Tako
tsubo cardiomyopathy may have worse outcomes than
previously considered and the challenges of managing
patients with episodic ischemia caused by microvascu-
lar dysfunction render this quest urgent.85
Preventing
or reversing perivascular fibrosis in the coronary arterial
microvasculature represents another novel target be-
yond traditional antiatherosclerotic therapies.
CONCLUSIONS AND PERSPECTIVES
A dichotomous approach based on the ECG has tradi-
tionally dominated our clinical management of ACS:
ST-segment–myocardial infarction versus non–ST-
segment–myocardial infarction. Our thinking concern-
ing the pathophysiological bases of the ACS has also
evolved separately and, in parallel, has been dominated
by the concept of the vulnerable plaque as a substrate
for fibrous cap rupture or of a minority mechanism:
superficial erosion. We and others have championed
and explored the role of inflammation as a pathway
to the ACS.
However, we now have a greater appreciation that
not all cases of ACS fit this mold. To move forward, we
need to remain vigilant not to cling to our cherished no-
tions and to remain open to shifts in the nature of the
diseases we treat and to new vistas opened by scientific
advances. As discussed here, we need to consider more
deeply in the current era arterial spasm, rupture with-
out inflammation, and distinct aspects of innate im-
munity or dyslipidemia as instigators of plaque erosion.
The complexity of clinical ACS surpasses our traditional
categorization of this condition. We should evolve be-
yond the current constrained concepts by expanding
our understanding.
We have achieved considerable mastery of plaque
rupture with inflammation from a mechanistic and
therapeutic viewpoint. Control of traditional risk fac-
tors such as hypercholesterolemia, hypertension, and
smoking addresses the pathophysiology of this mecha-
nism of ACS. The other categories that we discuss here
may account for an increasing proportion of ACS, now
that we are addressing more effectively the traditional
risk factors.5
We should remain open to the possibility,
even likelihood, that tailored therapeutic approaches
may apply to the prevention and treatment of the less
well-recognized pathways to acute myocardial ischemia
discussed here.
We must aim to link the clinical presentation of
ACS more tightly to pathophysiological mechanisms.
More than a century after the introduction of ECG, we
still triage our patients with ACS on the basis of this
mature technology. To move forward in the manage-
ment of ACS, we should strive for a more personal-
ized approach to therapy based on criteria more tightly
linked to the diverse pathophysiological mechanisms
than ECG repolarization abnormalities. We need to
develop and validate soluble and imaging biomarkers
that reflect the underlying mechanism that yields acute
ischemia. Point-of-care assessment of such biomarkers
would help render their use clinically practical in the
triage of patients who present with ACS, with the goal
of sparing some the need for urgent invasive diagnos-
tic or therapeutic measures.18,67,98
We then need rig-
orous clinical evaluation of targeted therapies guided
by a more precise pathophysiological classification of
ACS that reaches beyond our current dichotomous ap-
proach based on the ECG. If these ventures succeed,
we may one day look back on today’s treatment of ACS
as oversimplified and rather primitive. We should strive
as a community not to be satisfied with our current ap-
proach to ACS management but reach to realize the
promise of a more personalized precision deployment
of treatment strategies, including new ones based on

Crea and Libby
greater mechanistic understanding of the diverse un-
derlying causes of acute myocardial ischemia.
DISCLOSURES
Dr Libby reports receiving grants from Novartis and holding
scientific advisory board positions for Olatec and Interleukin
Genetics (company no longer operating). Dr Crea reports no
conflicts.
AFFILIATIONS
From Department of Cardiovascular and Thoracic Sciences,
Catholic University, Rome, Italy (F.C.); and Division of
Cardiovascular Medicine, Department of Medicine, Brigham
and Women’s Hospital, Harvard Medical School, Boston,
MA (P.L.).
FOOTNOTES
Circulation is available at http://circ.ahajournals.org.
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Filippo Crea and Peter Libby
Treatment
Acute Coronary Syndromes: The Way Forward From Mechanisms to Precision
Print ISSN: 0009-7322. Online ISSN: 1524-4539
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