Journal of the American College of Cardiology Vol. 61, No.

1, 2013
2013 by the American College of Cardiology Foundation ISSN 0735-1097/$36.00
Published by Elsevier Inc. http://dx.doi.org/10.1016/j.jacc.2012.07.064

STATE-OF-THE-PAPERS

Pathogenesis of Acute Coronary Syndromes

Filippo Crea, MD, Giovanna Liuzzo, MD, PHD
Rome, Italy

Experimental models of atherogenesis have provided a growing body of information about molecular mecha-
nisms of plaque growth; however, transition from coronary stability to instability is less well understood due to
the lack of animal models reflective of human disease. The abrupt clinical presentation of acute coronary syn-
dromes gives a strong signal of discontinuity in the natural history of atherothrombosis. The causes of such dis-
continuity are complex, probably multiple, and still largely unknown. A better knowledge of the causes of coro-
nary instability might allow identification of new therapeutic targets aimed at the preservation of plaque stability
in those subjects in whom primary prevention fails to prevent plaque growth. The goal of this review was to
propose a pathogenetic classification of acute coronary syndromes that might help in the search of new
diagnostic algorithms and therapeutic targets. (J Am Coll Cardiol 2013;61:111) 2013 by the American
College of Cardiology Foundation

Experimental models of atherogenesis have provided a
growing body of information about molecular mechanisms
of plaque growth; however, transition from coronary stabil-
ity to instability is less well understood due to the lack of
animal models reflective of human disease (1). The abrupt
clinical presentation of acute coronary syndromes (ACS)
gives a strong signal of discontinuity in the natural history of
atherothrombosis. When primary prevention of atheroscle-
rosis fails, the progression of coronary atherosclerosis can
remain clinically silent for years, decades, or even for life, as
indicated by the high prevalence of coronary atherosclerosis
in subjects dying of noncardiac causes. In contrast, some
patients, at a certain point in their life, exhibit ACS,
followed by a period of stability that can be short or last for
years or decades. These simple clinical observations suggest
that the mechanisms responsible for plaque growth and for
plaque instability are different and that the causes and
mechanisms of plaque instability are multiple. Accordingly,
the paradigm that implies a single type of culprit coronary
plaque as a cause for instability does not adequately fit the
findings of postmortem studies (2,3). Indeed, on the one
hand, plaque fissure is frequently asymptomatic and con-
tributes to stepwise, clinically silent plaque growth rather
than precipitating an abrupt coronary occlusion; conversely,
it is not observed in 30% to 50% of patients who have ACS.
Furthermore, the notion that inflammatory cell activation
plays a key role in the pathogenesis of ACS was promptly
accepted by the scientific community, and it is now com-
From the Institute of Cardiology, Catholic University, Rome, Italy. Both authors
have reported that they have no relationships relevant to the contents of this paper to
disclose.
Manuscript received January 26, 2012; revised manuscript received July 5, 2012,
accepted July 10, 2012.
monly believed that activation of inflammatory cells in the
culprit stenosis is the cause of coronary instability in all
patients (4,5). However, this notion is in sharp contrast with
the observation that about 40% of patients with ACS have
low or very low levels of C-reactive protein (CRP), a very
sensitive marker of inflammation (6,7). Finally, coronary
angiography fails to demonstrate obstructive atherosclerosis
in up to one-third of patients with symptoms suggestive of
ACS and raised troponin levels and/or ischemic-like ST-
segment changes, thus suggesting that functional alterations
of epicardial arteries and/or of coronary microcirculation
play an important pathogenetic role (8).
Pathogenetic Classification of ACS
The complexity of postmortem and clinical observations
suggests that it is unlikely to identify a common cause for
the phenotype of ACS. To better understand the multiple
causes of coronary instability, it would be desirable to
construct a pathogenetic classification of ACS based on
simple clinical descriptors.
In this review, the multiple causes of coronary instability
are discussed in 3 homogeneous groups of patients with a
similar clinical presentation: 1) patients who have obstruc-
tive atherosclerosis and systemic inflammation; 2) patients
who have obstructive atherosclerosis without systemic in-
flammation; and 3) patients without obstructive atheroscle-
rosis (Fig. 1).
We are not proposing here an alternative to the recent
universal definition of myocardial infarction (MI) (9). In-
deed, our classification of ACS provides a framework for
understanding basic mechanisms responsible for coronary
instability rather than a classification for immediate clinical
use such as that provided by the universal definition of MI.
2 Crea et al. JACC Vol. 61, No. 1, 2013
Pathogenesis of Acute Coronary Syndromes January 8, 2013:111

Abbreviations Our pathogenetic classification as the thrombogenic potential of the plaque. The main
and Acronyms of ACS based on simple clinical mediators of inflammation-induced activation of coagula-
descriptors, however, might help tion are proinflammatory cytokines. Several studies have
ACS acute coronary
syndrome(s) in the search for new diagnos- shown, in particular, the importance of interleukin (IL)-6 in
CRP C-reactive protein
tic algorithms and therapeutic the initiation of coagulation activation and the role of tumor
targets. necrosis factor (TNF)-alpha and IL-1 in the modulation of
hs-CRP high-sensitivity
C-reactive protein
ACS with obstructive athero- anticoagulant pathways (12,13).
IL interleukin
sclerosis and systemic inflam- This clinical presentation of ACS has been carefully
mation. Although the presence investigated over the past few years. Experimental observa-
INF interferon
of obstructive atherosclerosis can tions and clinical studies have clarified key molecular path-
MI myocardial infarction
be promptly ascertained with ways, some of which will probably become important
PMN polymorphonuclear coronary angiography, the evi-
neutrophil
therapeutic targets in the near future. The 3 main features of
dence of systemic inflammation inflammation associated with ACS are: 1) widespread in-
Th17 type 17 helper
is less easy to define. Among the volvement of epicardial arteries, coronary microcirculation,
T cells
several inflammatory biomarkers and even myocardium; 2) activation of innate immunity;
TLR Toll-like receptor
tested in ACS, levels of C-reactive and 3) activation of adaptive immunity.
TNF tumor necrosis protein (CRP) assessed by using
factor
high-sensitivity CRP (hs-CRP) as- WIDESPREAD CORONARY INFLAMMATION. In patients with
Treg regulatory T cells ACS and systemic evidence of inflammation, widespread
says represent an obvious candidate
because CRP is a prototypic marker coronary inflammation is suggested by transcardiac neutro-
of inflammation characterized by high sensitivity and a wide phil activation in the effluent of myocardial regions not
dynamic range (10). However, it is difficult to establish a perfused by the culprit artery. This event seems unrelated to
cutoff at the present time. In primary prevention, hs-CRP coronary atherosclerosis or recurrent ischemia, as it is not
levels 2 mg/l (and even 1 mg/l) might be helpful in observed in patients with chronic stable angina and multi-
guiding therapy (11); however, in patients with ACS, 2 vessel coronary disease or in patients with vasospastic angina
different cutoffs have been suggested as clinically useful on (14). Widespread acute coronary inflammation is, therefore,
the basis of our initial observations: an admission value 10 the likely cause of multiple complex stenoses, multiple
mg/l and a discharge value 3 mg/l. These cutoffs, although thrombi, and multiple fissured plaques involving different
confirmed in larger studies (4), have not yet obtained coronary artery branches observed in clinical studies in
general consensus. ACS, based on angiography and intravascular imaging
Experimental studies have clarified the molecular mech- (1518). Of note, the number of disrupted coronary plaques
anisms through which activation of inflammatory cells in correlates with systemic hs-CRP levels (17,18). The notion
the plaque can trigger thrombus formation. Notably, in- of widespread coronary inflammation has been confirmed by
flammation regulates the fragility of the fibrous cap, as well postmortem studies (19).

Figure 1 Classification of Acute Coronary Syndromes

The pathogenetic classification of acute coronary syndrome (ACS) based on simple clinical descriptors provides a framework for understanding basic mechanisms
responsible for coronary instability in homogeneous groups of patients: 1) patients with obstructive atherosclerosis and systemic inflammation; 2) patients with obstruc-
tive atherosclerosis without systemic inflammation; 3) patients without obstructive atherosclerosis. This pathogenetic classification of ACS might help in the search of
new diagnostic algorithms and therapeutic targets. ATS atherosclerosis.
JACC Vol. 61, No. 1, 2013 Crea et al. 3
January 8, 2013:111 Pathogenesis of Acute Coronary Syndromes

Figure 2 Role of Innate and Adaptive Immunity in Plaque Instability in Patients With Systemic Evidence of Inflammation

Both (A) innate immunity and (B) adaptive immunity play a key role in the pathogenesis of coronary plaque instability. (A) All types of inflammatory cells are present in athero-
sclerotic plaques. Macrophages and mast cells infiltrate the lesion and are particularly abundant in the shoulder region where the atheroma grows and where the risk of plaque
rupture is higher. (B) T-cell infiltrates are always present in atherosclerotic lesions, and their activation may play a primary role in the transition from stable to unstable plaques.
Such infiltrates are predominantly CD4 T cells, which recognize protein antigens (such as oxidized low-density lipoprotein, human heat shock protein 60, and chlamydial pro-
teins) processed and presented by activated antigen-presenting cells (APCs). Recently, attention has been focused on the possible role of type 17 helper T cells (Th17), known
to play critical roles in the development of autoimmunity and allergic reactions by producing interleukin (IL)-17 and, to a lesser extent, tumor necrosis factor (TNF)-beta and IL-6.
Another subset of Th1 cells in the plaque has the CD4CD28null phenotype. These T cells have important plaque-destabilizing properties. Regulatory T cells (Treg) maintain the
homeostasis of cell subsets involved in adaptive immunity. In human atherosclerotic lesions, Treg colocalize with IL-10 and transforming growth factor (TGF)-1 expression.
Ang angiotensin I; CCR chemokine receptors; CRP C-reactive protein; EC endothelial cell; EDRF endothelium-derived relaxing factor; ET1 endothelin 1; IFN
interferon; IL12R IL-12 receptor; KIR killer immunoglobulin-like receptor; LTB-4 leukotriene B-4; M-CSF macrophage colonystimulating factor; MMPs metalloprotei-
nases; M macrophage; MPO myeloperoxidase; MP-TF tissue factor bearing microparticles; PAF platelet-activated factor; PAI plasminogen activator inhibitor;
PLT platelet; PMN polymorphonuclear neutrophil; ROS reactive oxygen species; sCD40L soluble CD40 ligand; SMC smooth muscle cell; TF tissue factor; TLR
Toll-like receptor; TRAIL TNF-related apoptosis-induced ligand.
4 Crea et al.
Pathogenesis of Acute Coronary Syndromes
ACTIVATION OF INNATE IMMUNITY. The notion that innate
immunity plays an important role in ACS is supported by
the demonstration of activated monocytes, polymorphonu-
clear neutrophils (PMNs), eosinophils, and mast cells not
only at the site of plaque rupture but also in the whole
coronary circulation of patients with ACS (Fig. 2A) (4,5).
Recently, we demonstrated high telomerase activity in
PMN coming from the culprit coronary plaque of patients
with ACS but not from the plaque of patients with stable
angina or in the PMN from the peripheral blood. Telom-
erase activity is normally absent in differentiated cells such as
PMN, but it can be reactivated under mitogenic stimulation
and it might represent a way to overcome replicative
senescence; the result would be a prolonged survival and
toxic potential of these inflammatory cells (20). The only
predictor of telomerase reactivation in coronary plaques of
ACS patients was a short time interval from symptom onset
to PMN sampling, supporting a possible role of telomerase
reactivation in PMN persistence in the plaque in the very
early phases of coronary instability. This mechanism is likely
to maintain active the inflammatory process, as neutrophil
apoptosis has been identified as 1 of the key mechanisms
needed to switch off inflammation. Accordingly, we have
recently reported on the delayed apoptosis of peripheral
PMNs in patients with ACS (21).
Macrophages account for the majority of leukocytes in
plaques. Plaque resident macrophages differentiate from
monocytes recruited from circulating blood. However,
monocytes represent a heterogeneous circulating population
of cells, according to their differential expression of CD14
and CD16 (22,23). Human coronary artery lesions contain
macrophage subpopulations with different gene expression
patterns, which indicate heterogeneity (22). Patients with
coronary atherosclerosis have higher numbers of circulating
CD14CD16 monocytes than healthy subjects. Further-
more, CD14CD16 count correlates negatively with the
concentration of high-density lipoprotein and positively
with levels of atherogenic lipids (23). Finally, peak levels of
CD14hiCD16lo monocytes after acute MI correlate nega-
tively with the recovery of left ventricular ejection fraction 6
months after MI (24). Of note, in exploiting the functional
differences in phagocytic activity between monocyte subsets,
noninvasive imaging technologies have been developed to
observe and quantify subpopulations of monocytes in pa-
tients (25).
Monocytes accumulated within thrombi, obtained during
primary percutaneous coronary interventions, specifically
overexpress Toll-like receptor (TLR)-4, together with spe-
cific patterns of locally expressed chemokines and cytokines
compared with circulating monocytes (26,27). TLRs are key
pattern-recognition receptors expressed by innate immunity
cells, and they can recognize a large number of molecules
named pathogen-associated molecular patterns; they are
usually expressed by pathogens but are absent in normal
mammal tissues. Interestingly, Niessner et al. (28) demon-
strated that IFN-alpha produced by plasmacytoid dendritic
JACC Vol. 61, No. 1, 2013
January 8, 2013:111
cells in atherosclerotic plaques could enhance TLR-4 sig-
naling by sensitizing these cells to lipopolysaccharide and
other microbial molecules but also to (modified) endoge-
nous molecules, all abundantly present in the atherosclerotic
lesion microenvironment. These sensitized antigen-presenting
cells strongly up-regulate the production of cytokines such as
TNF-alpha, IL-12, IL-23, and metalloproteinase-9, thus en-
hancing plaque instability.
Recently, it has been demonstrated that human platelets
express functional TLRs capable of recognizing bacterial
components (29). TLR activation directly induces platelet
aggregation and increased platelet adhesion to collagen
under flow conditions. Moreover, TLR stimulation, in
particular TLR2, induces a significant increase in platelet
leukocyte interactions and the amplification of platelet-
derived inflammatory signals. These findings highlight the
role of platelets as immunologic cells, critically participating
in both inflammatory and thrombotic processes (29). In-
deed, platelet TLR2 and related innate immune transcripts
have been associated with cardiovascular disease and its risk
factors (30). More recently, Beaulieu et al. (31) have shown
expression of TLR2 in megakaryocytes and suggested that
inflammatory processes, through TLR2 stimulation, can
increase megakaryocyte maturation and modulate mega-
karyocyte phenotype, potentially influencing platelet func-
tion and thrombosis.
ACTIVATION OF ADAPTIVE IMMUNITY. The higher systemic
frequency of activated T cells in patients with ACS com-
pared with those with stable angina (3235), and the higher
prevalence of oligoclonal T-cell expansion in unstable cor-
onary plaques compared with stable plaques (33,36), suggest
that the sudden change leading to coronary instability might be
related to mechanisms involving adaptive immunity (Fig. 2B).
In particular, the more recent acquisitions regarding the
role of adaptive immunity suggest that T-cell repertoire
perturbation might play a pivotal role in coronary instability.
Indeed, we have consistently observed that patients with
ACS have an increased frequency of autoaggressive CD4
T cells characterized by defective cell surface expression of
CD28, a major costimulatory molecule critically involved in
determining the outcome of antigen recognition by T cells
(32,33). In ACS, CD4CD28null T cells are increased in
the peripheral blood and infiltrate unstable coronary plaques
where they undergo clonal expansion, probably triggered by
specific antigens (37). They release large amounts of proin-
flammatory cytokines, in particular IFN-gamma (thus acti-
vating monocytes and macrophages), and have direct cyto-
lytic effects on endothelial cells, amplified by hs-CRP (38),
and on vascular smooth muscle cells (39). Apoptosis of
vascular smooth muscle cells has been implicated in destruc-
tion of the plaque surface (40). By directly stimulating
apoptosis of vascular smooth muscle or by coordinating and
activating macrophages to kill these cells through the
elevated production of IFN-gamma, CD4CD28null T cells
could weaken the fibrous cap and destabilize angiogenic
JACC Vol. 61, No. 1, 2013
January 8, 2013:111
vessels, precipitating atherosclerotic plaque rupture (41).
Moreover, CD4CD28null T cells, either isolated from
plaque tissue or from peripheral blood of patients with
ACS, spontaneously express IL-12 receptor and respond to
IL-12 released by innate immunity cells with the up-
regulation of chemokine receptors; thus, IL-12 can favor
their tissue homing even in the absence of antigenic stim-
ulation (42). Alternative costimulatory molecules regulate
CD4CD28null T cells and their inflammatory and cyto-
toxic function can be inhibited by blocking these costimu-
latory receptors (43). We have recently shown that high
frequencies of CD4CD28null T cells increase the risk of
ACS, particularly in patients with diabetes (44,45).
Two other T cell subsets, type 17 helper T cells (Th17)
and CD4CD25 regulatory T cells (Treg), are profoundly
perturbed in ACS. Th17 cells expressing retinoic acid
related orphan receptor gamma t play critical roles in the
development of autoimmunity and allergic reactions by
producing IL-17 and, to a lesser extent, TNF-beta and IL-6
(46,47). Although the precise role of IL-17 in atheroscle-
rosis remains controversial, recent experimental studies in
mouse models have provided direct evidence that IL-17 is
predominantly proatherogenic.
Treg expressing the forkhead/winged helix transcription
factor (Foxp3) have been found to prevent atherosclerosis in
mouse models (48). The normal function of Treg may be
essential to maintain the homeostasis of cell subsets involved
in adaptive immunity, including antigen-presenting cells
and effector T cells, by contact-dependent suppression or by
releasing anti-inflammatory cytokines, such IL-10 and
transforming growth factor beta1 (49). Consistently, a crit-
ical role for the anti-inflammatory cytokine IL-10 has been
assumed in Treg-mediated atheroprotection, both in exper-
imental models and in human atherosclerotic lesions, for
which the expression of Treg colocalized with IL-10 ex-
pression. The balance between Th17 and Treg may be
important in the development and prevention of inflamma-
tory and autoimmune diseases (50).
Recently published data provide evidence of a defective
Treg compartment in ACS. The number and the suppres-
sion efficiency of Treg were reduced in patients with ACS
compared with patients with stable angina and healthy
controls (51,52). A parallel increase in the circulating levels
of Th17 has also been observed (53,54). Furthermore, in
autoimmune diseases, such as rheumatoid arthritis and
multiple sclerosis characterized by CD4CD28null T-cell
expansion, CD4CD28null T cells are only partially suscep-
tible to the regulatory capacities of Treg.
Taken together, these findings support the notion that, at
least in a subset of patients with ACS, the failure to mount
a counter-regulatory response to the activation of aggressive
effector T cells might play a key pathogenetic role and may
represent an attractive therapeutic target.
The presence of activated T cells in ACS implies anti-
genic stimulation. Indeed, T cells specific for antigens such
as Chlamydia pneumonia, heath shock proteins, or oxidized
Crea et al. 5
Pathogenesis of Acute Coronary Syndromes
low-density lipoproteins have been isolated from atheroscle-
rotic plaques of patients with ACS (5).
ACS with obstructive atherosclerosis without systemic
inflammation. In patients in whom coronary instability
occurs in the absence of systemic evidence of inflammation,
other mechanisms are likely to play a key pathogenetic role.
These mechanisms include extreme emotional disturbance-
ranging from external events of short duration, such as
earthquakes and a beloved teams loss of a football match, to
acute manifestations of more long-lasting internal emo-
tional dispositions-intense physical exertion, and local me-
chanical stress at the level of the artery wall, that is, both
circumferential stress and shear stress. In addition, subclin-
ical inflammation in the microenvironment of the culprit
stenosis might play a role in the chain of events leading to
coronary instability, although trigger and mechanisms of
inflammation are probably different from those operating in
patients with systemic evidence of inflammation. It is worth
noting that while in the latter, a large number of studies
have clarified the molecular mechanisms leading to coronary
instability (4,5), patients without systemic evidence of in-
flammation have been investigated less extensively; conse-
quently, the precise causes of instability are still poorly
known, thus providing a strong stimulus for further research
in this fascinating setting.
ENVIRONMENTAL, PHYSICAL, AND EMOTIONAL STRESSORS.
The ability of environmental, physical, or emotional stres-
sors to trigger MI has been attributed to the surge in
sympathetic nervous system activation and catecholamine
release that lead to increases in heart rate, blood pressure,
and cardiac work as well as to local vasoconstriction at the
site of vulnerable plaques, thereby precipitating plaque
rupture (55). Activation of the sympathetic nervous system
also leads to platelet activation, hypercoagulability, and
intense coronary microvascular constriction (56). Obviously,
environmental, physical, or emotional stressors per se are
insufficient to cause coronary instability, but they might
trigger instability in the presence of a vulnerable plaque, in
particular if causing a severe stenosis (57). Indeed, under
these circumstances, the direct hemodynamic effects on the
vulnerable atherosclerotic plaque can cause mechanical rup-
ture of the thin cap while thrombus formation is favored by
prothrombotic effects as well as by the increased shear stress
at the level of the vulnerable plaque (58).
Accordingly, a higher prevalence of plaque fissure has
been found among patients dying of sudden coronary death
during intense physical exercise compared with patients in
whom death occurred at rest. Furthermore, plaque fissure
triggered by environmental, physical, and emotional stres-
sors exhibited a thinner cap compared with plaque fissure
occurring at rest and was noted in the central region of the
plaque. This finding suggests greater susceptibility to bio-
mechanical forces rather than in the shoulder region of the
plaque where inflammatory cells are more abundant (2).
6 Crea et al. JACC Vol. 61, No. 1, 2013
Pathogenesis of Acute Coronary Syndromes January 8, 2013:111

PhysicalChemical Alterations of Plaque Composition May Cause ACS in Patients Without

Figure 3
Systemic Evidence of Inflammation

Effects of cholesterol crystals on plaque integrity in coronary arteries of patients who died of acute coronary syndrome (ACS) assessed by using light and scanning elec-
tron microscopy. A and B show scanning electron microscopy results of the culprit stenosis from the left anterior descending artery of a 57-year-old woman who died of
ACS. (A) Example of cholesterol crystals perforating the intimal surface at the plaque shoulder (bar 10 m). (B) A color-coded image defines thrombus (red), fissured
plaque (blue), and the site of a cholesterol crystal perforating the intima (green-yellow). Modified, with permission, from Abela et al. (59).

ACUTE CHANGES OF PHYSICALCHEMICAL CHARACTERISTICS IL-1-beta, a potent proinflammatory cytokine, through an

OF THE PLAQUE. Among patients who do not exhibit sys-
temic evidence of inflammation or ACS triggered by envi-
ronmental, physical, or emotional stressors, physical
chemical alterations of plaque composition might be a cause
of instability. Abela et al. (59) proposed the intriguing
working hypothesis that shifts in environmental factors,
including local saturation of cholesterol, temperature, pH,
and hydration status, could alone or in various combinations
lead to cholesterol crystallization with sudden and forceful
volume expansion causing plaque fissure and thrombosis
(Fig. 3). Intraplaque hemorrhage can enhance this mecha-
nism by triggering the crystallization of free cholesterol
from erythrocyte membranes and causing abrupt enlarge-
ment of the necrotic core (60 62). Although postmortem
images, obtained by vacuum dehydration to preserve cho-
lesterol crystals, seem to suggest that needle-shaped choles-
terol crystals might be able to perforate a thin fibrous cap
(59), these observations are anecdotal and need to be
confirmed in larger studies. The development of micro
optical coherence tomography with a 2 micron resolution
will probably shed new light on this potential mechanism of
instability by allowing assessment of its occurrence in vivo (63).
Interestingly, it has recently been shown that human
monocytes and macrophages avidly phagocytose cholesterol
crystals, resulting in a dose-dependent secretion of mature
inflammasome-mediated pathway (64,65). This mecha-
nism may represent an important link between choles-
terol metabolism and local inflammation in the microen-
vironment of atherosclerotic lesions. In this setting,
however, the causes of inflammation are likely to be
different from those operating in patients with systemic
evidence of inflammation.
ACS without obstructive atherosclerosis. Among pa-
tients who present with ACS in the absence of obstructive
atherosclerosis, functional alterations of epicardial coronary
arteries or of coronary microcirculation are the likely cause
of instability in the majority of patients. Plaque fissure has
recently been observed in women with ACS and without
obstructive atherosclerosis, potentially causing transient
thrombus formation (66). However, its pathogenic role is
difficult to establish because plaque fissure is frequently
asymptomatic and is observed in a sizeable proportion of
patients with stable ischemic heart disease (67).
FUNCTIONAL ALTERATIONS OF EPICARDIAL CORONARY
ARTERIES. In some of these patients, instability is due to
coronary spasm. In the CASPAR (Coronary Artery Spasm
in Patients with Acute Coronary Syndrome) study, coronary
angiography failed to show obstructive atherosclerosis in
about 30% of patients with suspected ACS. More impor-
JACC Vol. 61, No. 1, 2013 Crea et al. 7
January 8, 2013:111 Pathogenesis of Acute Coronary Syndromes

Functional Alterations of Coronary Microcirculation May Cause ACS in Patients Without

Figure 4
Obstructive Coronary Atherosclerosis

Reversible intense coronary microvascular dysfunction has been demonstrated in Takotsubo or apical ballooning syndrome. A series of patients with apical ballooning
syndrome underwent myocardial contrast echocardiography at baseline (Bsl); during infusion of adenosine (Adn) (140 g/kg/min), a potent coronary microvascular vaso-
dilator; and at 1-month follow-up (FUP). During Adn challenge, all patients exhibited a significant improvement of myocardial perfusion and of left ventricular (LV) function,
which further improved at 1-month follow-up. (A) A clear perfusion defect is present at baseline within LV apical myocardium (arrows). (B) A striking decrease in the
extent of the perfusion defect is evident during Adn infusion. Values of contrast score index and of LV ejection fraction in individual patients are shown at Bsl, at peak of
Adn infusion, and at 1-month FUP in C and D, respectively. #p 0.05 and *p 0.001 versus baseline. ACS acute coronary syndrome. Modified, with permission,
from Galiuto et al. (72).

tantly, intracoronary acetylcholine administration elicited
coronary spasm in nearly 50% of these patients (8).
Spasm is caused by vasoconstrictor stimuli acting on
hyperreactive smooth muscle cells (68). It can occur at the
site of an angiographically normal coronary segment or in
the presence of a nonobstructive atherosclerotic plaque. The
molecular causes of smooth muscle cell hyperreactivity are
still not understood. Because several vasoconstrictor stimuli
acting on different unrelated receptors are able to precipitate
coronary spasm in the same patient, smooth muscle cell
hyperreactivity, rather than by an abnormality of a single
receptor, might be caused by an alteration of ionic pumps,
such as an enhanced activity of the sodium ion/hydrogen ion
exchanger; this eventually leads to intracellular calcium
overload. More recently, several experimental and clinical
studies have shown that enhanced light myosin chain
phosphorylation by rho-kinase, making myosin more sen-
sitive to intracellular calcium, might play a key role in the
pathogenesis of coronary spasm (69).
FUNCTIONAL ALTERATIONS OF CORONARY MICRO-
CIRCULATION. Intense constriction of coronary micro-
circulation is a second mechanism that may cause ACS in
patients who exhibit nonobstructive coronary atheroscle-
rosis (70,71). This is the likely mechanism of instability
in patients with Takotsubo syndrome, which is charac-
terized by ischemic pain at rest, ST-segment elevation,
cardiac enzyme release, and a characteristic regional
akinesia more frequently affecting distal myocardial re-
gions associated with hypercontractility of the remaining
regions. Indeed, in these patients, using echocontrastog-
raphy, we have recently found regional apical hypoperfu-
sion that transiently improves during administration of
adenosine, a potent arteriolar vasodilator; this transient
improvement is associated with a transient improvement
of regional wall motion abnormalities and of ejection
fraction (Fig. 4) (72). Thus, reversible coronary micro-
vascular dysfunction seems to be the common pathophys-
iological determinant of this syndrome. The causes of
this intense microvascular constriction and the reasons
for its peculiar locations are still largely unknown. Sym-
pathetic hyperreactivity and myocarditis are potential, yet
unproved, causes.
Parvovirus B19 genome has been found in myocardial
biopsies of patients with angiographically normal coronary
arteries who present with typical ischemic pain, ischemic
ST-segment changes, cardiac necrosis enzyme increase, and
various degrees of regional wall motion abnormalities (73).
Its presence in the myocardium was associated with coro-
nary vasoconstriction in response to acetylcholine, thus
suggesting severe endothelial dysfunction (74).
8 Crea et al.
Pathogenesis of Acute Coronary Syndromes
Finally, microvascular constriction of lesser intensity oc-
curring in the absence of regional wall motion abnormalities
and associated with an unstable pattern of angina, ischemic
ST-segment changes, and/or a cardiac necrosis enzyme
increase has recently been proposed as the unstable coun-
terpart of stable microvascular angina, which is more prev-
alent in women than in men (71). Accordingly, the preva-
lence of women who present with ACS in the absence of
obstructive atherosclerosis is 2-fold higher than that of
men (75). The mechanisms of this poorly defined pre-
sentation of coronary instability are unknown. Functional
alterations of coronary microcirculation, similar to mech-
anisms described in women with stable microvascular
angina, might be involved (76). There are a number of likely
causes for impairment of coronary flow reserve in patients
with nonobstructive atherosclerosis. Coronary flow is regu-
lated by several endothelium-dependent and endothelium-
independent factors influencing microvascular tone.
Endothelium-independent factors include aortic pressure,
myocardial compressive forces, neurohumoral substances, and
myocardial metabolism. The endothelium regulates vasomotor
tone by stimulating release of vasoactive factors. A major
vasodilator substance is nitric oxide, originally identified as an
endothelium-derived relaxing factor. In the WISE (Womens
Ischemia Syndrome Evaluation) study, coronary microvascular
reactivity to adenosine predicted an adverse outcome in women
evaluated for suspected ischemia (77,78).
Finally, it has recently been proposed that epicardial or
microvascular spasm might promote coronary thrombosis at
the site of a susceptible plaque, thus potentially also repre-
senting the primary cause of instability in some of the
patients exhibiting obstructive atherosclerosis (79) (Fig. 1).
Clinical Perspectives
The large body of knowledge we have gained in the past 50
years in the field of cardiovascular diseases clearly indicates
that our main goal is primary prevention. Indeed, more than
90% of acute vascular events are explained by environmental
causes, which can theoretically be eradicated and thus
prevent plaque growth (80). It is extremely important,
therefore, to reduce the burden of cardiovascular risk factors.
It is equally important, however, to improve our knowledge
of the complex mechanisms responsible for sudden transi-
tion from coronary stability to instability. Indeed, when we
fail with prevention of plaque growth, a subordinate goal is
the preservation of plaque stability.
Coronary thrombosis is the final common pathway lead-
ing to coronary instability, and it is our current main
therapeutic target. This goal has allowed us to considerably
improve the outcome of ACS. However, more potent
antithrombotic regimens have recently been found to in-
crease the risk of major bleedings that are associated, in
turn, with a higher risk of mortality (81). To identify new
therapeutic targets, we need to know more about the
different causes of coronary thrombosis.
JACC Vol. 61, No. 1, 2013
January 8, 2013:111
The pathogenetic classification we propose is mainly
conceived to stimulate innovative research on the causes of
coronary instability, but it may also help in the management
of patients presenting with ACS.
Several studies have shown that patients with ACS in
whom obstructive atherosclerosis is associated with in-
creased levels of CRP or other markers of inflammation
have a worse outcome than patients with a similar severity of
coronary atherosclerosis but normal levels of inflammatory
markers (6,14,17,18,82,83). Thus, in the former, reassess-
ment of the inflammatory status after discharge may help in
the identification of patients at higher risk of recurrence of
coronary instability. Although the assessment of the inflam-
matory status is currently based on biomarkers only, recently
developed imaging techniques able to monitor inflammatory
cell activity in atherosclerotic plaques might prove to be
more predictive than biomarkers (84). In addition, an unmet
need in this patient subset is a specific anti-inflammatory
treatment based on the modulation of both innate and
adaptive immunity (1,4,85). Although nonsteroidal anti-
inflammatory drugs have been associated with a higher risk
of cardiovascular events (probably related to inhibition of
prostacyclin synthesis in endothelial cells), and steroid
utilization is hampered by its well-known adverse effects
(particularly in diabetic and hypertensive patients), disease-
modifying antirheumatic drugs have been found in obser-
vational studies to be associated with a lower cardiovascular
risk (85). Antagonism of key cytokines such as TNF-alpha
is another potential approach, particularly in high-risk
patients with high levels of CD4CD28null T cells, al-
though the high cost and the potential adverse effects make
this approach difficult to pursue. Interestingly, statins have
been found to modulate this aggressive subset of T cells,
which might help explain the early beneficial effect of
intensive statin treatment in patients with a recent ACS
(86). Antagonists of IL-1-beta, agonist of IL-1Ra, or
inhibitors of inflammasome activation are close to clinical
testing. A recent pilot study in patients with acute MI has
provided encouraging results, showing that IL-1 blockade
with anakinra, a recombinant human IL1-Ra, is safe and
favorably affects cardiac remodeling after acute MI without
modifying either final infarct size or infarct healing (87).
Recently, at least 2 additional IL-1targeted drugs, a
recombinant protein with high affinity for IL-1-beta
(known as IL-1 Trap or rilonacept) and a fully humanized
antiIL-1-beta monoclonal antibody (canakinumab), have
proven effective in several chronic inflammatory diseases,
including rheumatoid arthritis and diabetes, and might thus
be of potential interest in ACS (88). Other ways to limit
IL-1-beta activation are inhibition of caspase-1 or the
inflammasome; some of these inhibitors have been tested in
clinical trials (85). Another potential therapeutic target is
regulatory T cells in those patients in whom their number or
function is depressed. Putnam et al. (89) recently found that
these cells can be isolated and expanded ex vivo for the
treatment of autoimmune diseases. Finally, the identifica-
JACC Vol. 61, No. 1, 2013
January 8, 2013:111
tion of the antigens triggering adaptive immunity may open
the way to specific vaccinations. Of note, the demonstration
that vaccination against influenza might be associated with
reduction of cardiovascular events is the first example of this
innovative approach (90,91).
In patients with ACS in whom obstructive atherosclerosis
is not associated with systemic inflammation, anatomic
(more than functional) features of the atherosclerotic plaque
are important in determining coronary instability. Accord-
ingly, in a recent trial, plaques characterized by a large
plaque burden, small lumen diameter, and a thin cap were
associated with a greater than 10-fold risk of causing ACS
during a 3-year follow-up than plaques not exhibiting any of
these 3 features (57,92).
Because it is difficult to limit environmental, physical, or
emotional triggers, an obvious target in this patient subset is
plaque stabilization as achieved by intensive statin treatment
(86). Another class of drugs that might help in plaque
stabilization is represented by inhibitors of phospholipase
A2. Indeed, darapladib, an antagonist of lipoprotein-bound
phospholipase A2, was found to reduce the necrotic core
(assessed by using virtual histology) compared with placebo
(93). Yet, a larger trial with clinical endpoints of varespladib,
an antagonist of secretory phospholipase A2, versus placebo
was halted prematurely because of lack of efficacy (94).
Another important but still elusive target to promote plaque
stabilization is enhancement of cholesterol efflux (95).
Among patients in whom obstructive atherosclerosis is
not associated with systemic inflammation and ACS occurs
in the absence of environmental, physical, or emotional
triggers, more needs to be learned about the mechanisms
modulating cholesterol crystallization, including the inflam-
masome pathway activated by cholesterol crystals, so that
new therapeutic targets can be identified.
Finally, epicardial and microvascular vasoconstriction is
the key therapeutic target when ACS is not associated with
obstructive atherosclerosis. Recently, data from clinical trials
suggest that the outcome of these patients is, on average,
better than that of patients with obstructive atherosclerosis;
however, about 10% of patients presenting with ACS in the
absence of coronary atherosclerosis have a major cardiac
event at 1-year follow-up (96).
Although nitrates and calcium antagonists are helpful in
patients with vasospastic angina, further efforts are needed
to identify the molecular alterations responsible for smooth
muscle cell hyperreactivity because a sizeable proportion of
patients with vasospastic angina are refractory to standard
doses of vasodilators (68). It has been observed that fasudil,
a specific rho-kinase inhibitor, reduces the rate of coronary
spasm episodes in patients with vasospastic angina (69).
Similarly, further efforts are warranted to unravel the mo-
lecular mechanisms responsible for coronary microvascular
dysfunction in Takotsubo syndrome, in myocarditis, and in
unstable microvascular angina.
Crea et al. 9
Pathogenesis of Acute Coronary Syndromes
Acknowledgment
The authors thank Daniela Pedicino, MD, for her assis-
tance in the preparation of the manuscript and figures, and
for her helpful comments.
Reprint requests and correspondence to: Dr. Filippo Crea,
Institute of Cardiology, Catholic University, Largo A. Gemelli, 8,
00168 Rome, Italy. E-mail: filippo.crea@rm.unicatt.it.
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Key Words: acute coronary syndromes y inflammation y
microcirculation y pathogenesis y stress y vasospasm.