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ABSTRACT: Well into the 21st century, we still triage acute myocardial Filippo Crea, MD
infarction on the basis of the presence or absence of ST-segment Peter Libby, MD
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
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Key Words: erosion
◼ inflammation ◼ microvessels
◼ myocardial infarction ◼ plaque
◼ plaque, atherosclerotic
◼ thrombosis
© 2017 American Heart
Association, Inc.
W
illem Einthoven introduced electrocardiogra- Moreover, although we have witnessed wide accep-
phy at the dawn of the 20th century. Well into tance of the formerly controversial concept that inflam-
the 21st century, we still triage acute myocar- mation contributes to atherogenesis,13 inflammation
dial infarction on the basis of this venerable technology: may not drive all transitions from stable atherosclerosis
ST segments up or not. Although this approach remains to acute thrombotic events. In a large study, about half
the appropriate evidence-based strategy today, aiming of ACS occurred in the presence of normal levels of
toward the future goal of more individualized therapy, C-reactive protein (CRP), a marker of inflammation.14
can we apply a more pathophysiologically based cat- Another recent study using optical coherence tomog-
egorization of the acute coronary syndromes (ACS)? In- raphy (OCT) demonstrated that among patients with
deed, we have learned much about the mechanisms of ACS and plaque rupture, two thirds of patients had im-
ACS since we last reviewed this topic in these pages.1,2 aging evidence of inflammatory cell infiltration in the
Moreover, the human disease of atherosclerosis has region of the ruptured fibrous cap but one third did
evolved considerably in the interim.3–5 This review aims not and the latter had lower levels of CRP.15 In addition,
to work toward a categorization of the ACS that reach- plaque erosion causes up to a third of ACS in the cur-
es beyond equating all ACS with plaque rupture or fis- rent era.16,17 Finally, about one fifth of ACS occur in the
sure, guided by the latest insights into the underlying apparent absence of coronary thrombosis, suggesting
mechanisms of ACS, and points a way forward toward that functional alterations beyond thrombus formation
the eventual clinical application of these considerations. can contribute to ACS pathogenesis.18,19
Postmortem studies carried out in the 1980s pro- The ensemble of postmortem studies and in vivo
posed that plaque rupture (also sometimes referred to studies using intravascular imaging point to 4 patho-
as fissure) caused most fatal myocardial infarctions.6 logical pathways to ACS. Although these mechanisms
These findings led to the notion of the vulnerable or may overlap and coexist in some patients, we present
high-risk plaque characterized by a large central lipid them separately for heuristic simplicity: plaque rupture
core, an abundance of inflammatory cells, a paucity of with systemic inflammation, plaque rupture without
systemic inflammation, plaque erosion, and plaque
smooth muscle cells (SMCs), and a thin fibrous cap.7
without thrombus (Figure 1).20
These observations spawned the widely accepted con-
This review considers the causes of these 4 predomi-
cept that instability of coronary atheromata resulted
nant pathways to ACS. To strive for a more precision
from fissuring of a thin-capped fibroatheroma caused
approach, we explore the therapeutic implications of
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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.
lation, activation of zymogen precursors, and balance thick collagen fibers, which might increase plaque sta-
with endogenous inhibitors such as the tissue inhibitors bility.25,26 Tregs normally help to maintain homeostasis of
of matrix metalloproteinases or the cystatins. Thus, in- cells involved in adaptive immunity, including antigen-
creased amounts of activated proteinases or reduced lev- presenting cells and effector T cells. Tregs mediate these
els of their corresponding inhibitors can enhance break- modulatory effects by contact-dependent suppression
down of the extracellular matrix of plaque.22 or by releasing anti-inflammatory cytokines such IL-
Adaptive immunity also appears altered in coronary 10 or transforming growth factor-β1.27 Patients with
plaque instability.23 Patients with ACS have an increased ACS have a reduced number and suppressive function
population of particularly proinflammatory CD4+ T cells of circulating Tregs compared with patients with stable
characterized by low cell surface expression of CD28, a angina and healthy control subjects.28 The molecular
costimulatory molecule critically involved in determin- mechanisms responsible for the T-cell dysregulation in
ing the outcome of antigen recognition by T cells.24 ACS ACS remain largely unknown. Recent work highlights
also profoundly perturb the numbers of 2 other circulat- the importance of the strength of the stimulation of
ing T-cell subsets: type 17 helper T cells and CD4+CD25+ the T-cell receptor for antigen in the differentiation of
regulatory T cells (Tregs). The net role of interleukin (IL)-17 helper T-cell subsets. The altered activity observed in
in atherosclerosis remains controversial, however; some ACS of proteins involved in the regulation of upstream
experimental studies in mice support a predominantly T-cell receptor for antigen signaling such as CD31 and
proatherogenic function for IL-17, yet type 17 helper protein tyrosine phosphatase N22 may modulate T-cell
T cells activated in plaques promote the formation of functions.29,30
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
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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.
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.
Local changes in the equilibrium between esterified the fibrous cap of plaque can commonly cause ACS.63
and free cholesterol might promote plaque rupture47 (Fig- The mechanism of plaque thrombosis described by pa-
ure 3). Cholesterol crystal formation in the lipid core could thologists as superficial erosion appears not to involve
heighten the risk of plaque rupture and thrombosis and inflammation mediated by macrophages, as in the case
can coactivate the inflammasome, an intracellular multi- of fibrous cap fracture (Figure 1C). Superficial erosion
meric complex that generates active IL-1β and IL-18.48 complicates lesions with a distinct epidemiology and
OCT has colocalized cholesterol crystals in human morphology and involves pathophysiological mecha-
coronary arteries with thin-capped plaques.49 The devel- nisms that differ from rupture of the fibrous cap. In-
opment of micro-OCT with a 2-μm resolution may shed deed, neutrophil activation seems to play a pivotal role
new light on this potential mechanism of instability by in thrombosis due to plaque erosion.4 Patients who
assessing its occurrence in vivo.50 Cholesterol crystals presented with ACS associated with plaque erosion
might also theoretically resist plaque rupture by increas- defined by OCT had higher systemic myeloperoxidase
ing the stiffness of the lipid pool, although this mecha- levels compared with patients with plaque rupture.
nism probably contributes little to plaque stability.51 The Moreover, in postmortem coronary artery specimens,
role of calcium mineral as a causal factor in ACS remains luminal thrombi superimposed on eroded plaques con-
controversial. Large collections of calcified tissue do not tain many more myeloperoxidase-positive cells than
augment the biomechanical instability of plaques or as- thrombi associated with ruptured plaques64 (Figure 4).
sociate with lesions that provoke ACS.52,53 Small foci of Autopsy studies suggest that fatal plaque erosion as-
calcification within the atherosclerotic intima, some caus- sociates more commonly with hypertriglyceridemia, dia-
ing spotty calcification visible on computed tomography, betes mellitus, female sex, and old age.65 The morphology
can also introduce biomechanical inhomogeneities that of lesions that produce thrombosis caused by superficial
can favor plaque destabilization.3,54,55 erosion differs radically from the features associated with
fibrous cap rupture. Superficially eroded lesions contain
few macrophages or T lymphocytes, inflammatory cells
Therapeutic Implications considered pathogenic in plaque rupture. Rather than
Because it is difficult to limit environmental, physical, depleted collagen, the lesions associated with superficial
or emotional triggers, the altered plaque characteristics erosion contain abundant proteoglycan and glycosami-
produced by intensive lipid-lowering treatment might noglycans. Instead of a paucity of SMCs, eroded lesions
can contain abundant arterial SMCs. Plaques complicat-
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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
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the integrity of the endothelial monolayer overlying the PLAQUE WITHOUT THROMBUS
atherosclerotic plaque. The denuded patch on the intimal
surface would then attract platelets that could undergo Mechanisms
activation by contact with collagen and other compo- In patients with ACS without plaque thrombus, a func-
nents of the arterial extracellular matrix usually protected tional alteration of coronary circulation likely causes
acute ischemia involving large epicardial coronary higher prevalence of coronary spasm than whites for
arteries or the coronary microcirculation (Figure 1D). unknown reasons.
Epicardial coronary vasospasm may occur in patients Microvascular spasm also can cause myocardial isch-
in whom coronary angiography does not demonstrate emia.83 This mechanism likely operates in patients with
an obstructive atherosclerotic plaque.78 In the CASPAR Takotsubo cardiomyopathy,84 which frequently occurs
study (Coronary Artery Spasm in Patients With Acute in the absence of obstructive atherosclerosis, although
Coronary Syndrome), coronary angiography failed to ≈15% of these patients exhibit concomitant obstructive
show culprit lesions in ≈30% of patients with sus- atherosclerosis.85 Microvascular spasm can also contrib-
pected ACS.79 Intracoronary acetylcholine administra- ute to ischemia in the face of angiographically normal-
tion elicited coronary spasm in nearly 50% of these appearing epicardial coronary arteries. Microvascular
patients. Similar findings pertained to a Japanese ischemia often manifests as angina pectoris but can
population.80 Coronary artery spasm also may cause also cause non–ST-segment–elevation ACS as defined
coronary instability in patients with obstructive ath- by electrocardiographic alterations and biomarker evi-
erosclerosis. Indeed, a classic study by Bertrand et al81 dence of myocyte injury.86 Coronary spasm can also
found that ergonovine induced spasm in 20% of pa- contribute to plaque instability by causing endothelial
tients with recent myocardial infarction and in 40% of damage, as shown in an infarction-prone strain of the
patients with unstable angina. In a more recent study, Watanabe heritable hyperlipidemic rabbit.44
acetylcholine induced spasm in 20% of white patients Either macrovascular or microvascular spasm can
and in 60% of patients with myocardial infarction result from impaired vasodilatation or from vasocon-
within the previous 14 days.82 Japanese people have a strictor stimuli acting on hyperreactive vascular SMCs
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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.
greater mechanistic understanding of the diverse un- D, Maseri A; FAMI Study Investigators. High-sensitivity C-reactive protein
is within normal levels at the very onset of first ST-segment elevation acute
derlying causes of acute myocardial ischemia. myocardial infarction in 41% of cases: a multiethnic case-control study.
J Am Coll Cardiol. 2011;58:2654–2661. doi: 10.1016/j.jacc.2011.08.055.
15. Scalone G, Niccoli G, Refaat H, Vergallo R, Porto I, Leone AM, Burzotta F,
DISCLOSURES D’Amario D, Liuzzo G, Fracassi F, Trani C, Crea F. Not all plaque ruptures
are born equal: an optical coherence tomography study [published online
Dr Libby reports receiving grants from Novartis and holding ahead of print December 24, 2016]. Eur Heart J Cardiovasc Imaging. doi:
scientific advisory board positions for Olatec and Interleukin 10.1093/ehjci/jew208.
16. Arbustini E, Dal Bello B, Morbini P, Burke AP, Bocciarelli M, Specchia G,
Genetics (company no longer operating). Dr Crea reports no
Virmani R. Plaque erosion is a major substrate for coronary thrombosis in
conflicts. acute myocardial infarction. Heart. 1999;82:269–272.
17. Bentzon JF, Otsuka F, Virmani R, Falk E. Mechanisms of plaque forma-
tion and rupture. Circ Res. 2014;114:1852–1866. doi: 10.1161/CIRCRE-
AFFILIATIONS SAHA.114.302721.
18. Niccoli G, Montone RA, Cataneo L, Cosentino N, Gramegna M, Refaat
From Department of Cardiovascular and Thoracic Sciences, H, Porto I, Burzotta F, Trani C, Leone AM, Severino A, Crea F. Morpho-
Catholic University, Rome, Italy (F.C.); and Division of logical-biohumoral correlations in acute coronary syndromes: patho-
genetic implications. Int J Cardiol. 2014;171:463–466. doi: 10.1016/j.
Cardiovascular Medicine, Department of Medicine, Brigham
ijcard.2013.12.238.
and Women’s Hospital, Harvard Medical School, Boston, 19. Jia H, Abtahian F, Aguirre AD, Lee S, Chia S, Lowe H, Kato K, Yo-
MA (P.L.). netsu T, Vergallo R, Hu S, Tian J, Lee H, Park SJ, Jang YS, Raffel OC,
Mizuno K, Uemura S, Itoh T, Kakuta T, Choi SY, Dauerman HL, Prasad
A, Toma C, McNulty I, Zhang S, Yu B, Fuster V, Narula J, Virmani R,
Jang IK. In vivo diagnosis of plaque erosion and calcified nodule in
FOOTNOTES patients with acute coronary syndrome by intravascular optical coherence
Circulation is available at http://circ.ahajournals.org. tomography. J Am Coll Cardiol. 2013;62:1748–1758. doi: 10.1016/j.
jacc.2013.05.071.
20. Crea F, Liuzzo G. Pathogenesis of acute coronary syndromes. J Am Coll
Cardiol. 2013;61:1–11. doi: 10.1016/j.jacc.2012.07.064.
REFERENCES 21. Liuzzo G, Biasucci LM, Gallimore JR, Grillo RL, Rebuzzi AG, Pepys MB,
Maseri A. The prognostic value of C-reactive protein and serum amyloid A
1. Libby P. Molecular bases of the acute coronary syndromes. Circulation.
protein in severe unstable angina. N Engl J Med. 1994;331:417–424. doi:
1995;91:2844–2850.
10.1056/NEJM199408183310701.
2. Libby P. Current concepts of the pathogenesis of the acute coronary syn-
22. Schönbeck U, Mach F, Sukhova GK, Murphy C, Bonnefoy JY, Fabunmi
dromes. Circulation. 2001;104:365–372.
RP, Libby P. Regulation of matrix metalloproteinase expression in human
3. Libby P. Mechanisms of acute coronary syndromes and their implications
vascular smooth muscle cells by T lymphocytes: a role for CD40 signaling
for therapy. N Engl J Med. 2013;368:2004–2013. doi: 10.1056/NEJM-
Downloaded from http://ahajournals.org by on November 2, 2020
63. Lüscher TF. Substrates of acute coronary syndromes: new insights into 81. Bertrand ME, LaBlanche JM, Tilmant PY, Thieuleux FA, Delforge MR, Carre
plaque rupture and erosion. Eur Heart J. 2015;36:1347–1349. doi: AG, Asseman P, Berzin B, Libersa C, Laurent JM. Frequency of provoked
10.1093/eurheartj/ehv149. coronary arterial spasm in 1089 consecutive patients undergoing coronary
64. Ferrante G, Nakano M, Prati F, Niccoli G, Mallus MT, Ramazzotti V, Mon- arteriography. Circulation. 1982;65:1299–1306.
tone RA, Kolodgie FD, Virmani R, Crea F. High levels of systemic my- 82. Pristipino C, Beltrame JF, Finocchiaro ML, Hattori R, Fujita M, Mongiardo
eloperoxidase are associated with coronary plaque erosion in patients R, Cianflone D, Sanna T, Sasayama S, Maseri A. Major racial differences
with acute coronary syndromes: a clinicopathological study. Circulation. in coronary constrictor response between Japanese and Caucasians with
2010;122:2505–2513. doi: 10.1161/CIRCULATIONAHA.110.955302. recent myocardial infarction. Circulation. 2000;101:1102–1108.
65. Yahagi K, Kolodgie FD, Lutter C, Mori H, Romero ME, Finn AV, Virmani 83. Camici PG, Crea F. Coronary microvascular dysfunction. N Engl J Med.
R. Pathology of human coronary and carotid artery atherosclerosis and 2007;356:830–840. doi: 10.1056/NEJMra061889.
vascular calcification in diabetes mellitus. Arterioscler Thromb Vasc Biol. 84. Galiuto L, De Caterina AR, Porfidia A, Paraggio L, Barchetta S, Locorotondo
2017;37:191–204. doi: 10.1161/ATVBAHA.116.306256. G, Rebuzzi AG, Crea F. Reversible coronary microvascular dysfunction: a
66. Hansson GK, Libby P, Tabas I. Inflammation and plaque vulnerability. J In- common pathogenetic mechanism in apical ballooning or tako-tsubo syn-
tern Med. 2015;278:483–493. doi: 10.1111/joim.12406. drome. Eur Heart J. 2010;31:1319–1327. doi: 10.1093/eurheartj/ehq039.
67. Quillard T, Araújo HA, Franck G, Shvartz E, Sukhova G, Libby P. TLR2 and 85. Templin C, Ghadri JR, Diekmann J, Napp LC, Bataiosu DR, Jaguszewski M,
neutrophils potentiate endothelial stress, apoptosis and detachment: im- Cammann VL, Sarcon A, Geyer V, Neumann CA, Seifert B, Hellermann J,
plications for superficial erosion. Eur Heart J. 2015;36:1394–1404. doi: Schwyzer M, Eisenhardt K, Jenewein J, Franke J, Katus HA, Burgdorf C,
10.1093/eurheartj/ehv044. Schunkert H, Moeller C, Thiele H, Bauersachs J, Tschöpe C, Schultheiss HP,
68. Franck G, Mawson T, Sausen G, Salinas M, Masson GS, Cole A, Beltrami- Laney CA, Rajan L, Michels G, Pfister R, Ukena C, Böhm M, Erbel R, Cuneo
Moreira M, Chatzizisis Y, Quillard T, Tesmenitsky Y, Shvartz E, Sukhova GK, A, Kuck KH, Jacobshagen C, Hasenfuss G, Karakas M, Koenig W, Rott-
Swirski FK, Nahrendorf M, Aikawa E, Croce KJ, Libby P. Flow perturbation bauer W, Said SM, Braun-Dullaeus RC, Cuculi F, Banning A, Fischer TA, Va-
mediates neutrophil recruitment and potentiates endothelial injury via sankari T, Airaksinen KE, Fijalkowski M, Rynkiewicz A, Pawlak M, Opolski
TLR2 in mice: implications for superficial erosion. Circ Res. 2017;121:31– G, Dworakowski R, MacCarthy P, Kaiser C, Osswald S, Galiuto L, Crea F,
42. doi: 10.1161/CIRCRESAHA.117.310694. Dichtl W, Franz WM, Empen K, Felix SB, Delmas C, Lairez O, Erne P, Bax JJ,
69. Kolodgie FD, Burke AP, Wight TN, Virmani R. The accumulation of specific Ford I, Ruschitzka F, Prasad A, Lüscher TF. Clinical features and outcomes
types of proteoglycans in eroded plaques: a role in coronary thrombosis in of takotsubo (stress) cardiomyopathy. N Engl J Med. 2015;373:929–938.
the absence of rupture. Curr Opin Lipidol. 2004;15:575–582. doi: 10.1056/NEJMoa1406761.
70. Day AJ. The structure and regulation of hyaluronan-binding proteins. Bio- 86. Arrebola-Moreno AL, Arrebola JP, Moral-Ruiz A, Ramirez-Hernandez JA,
Melgares-Moreno R, Kaski JC. Coronary microvascular spasm triggers
chem Soc Trans. 1999;27:115–121.
transient ischemic left ventricular diastolic abnormalities in patients with
71. Butler LM, Rainger GE, Nash GB. A role for the endothelial glycosami-
chest pain and angiographically normal coronary arteries. Atherosclerosis.
noglycan hyaluronan in neutrophil recruitment by endothelial cells cul-
2014;236:207–214. doi: 10.1016/j.atherosclerosis.2014.07.009.
tured for prolonged periods. Exp Cell Res. 2009;315:3433–3441. doi:
87. Kaski JC, Maseri A, Vejar M, Crea F, Hackett D. Spontaneous coronary
10.1016/j.yexcr.2009.08.012.
artery spasm in variant angina is caused by a local hyperreactivity to a
72. Döring Y, Soehnlein O, Weber C. Neutrophil extracellular traps in ath-
generalized constrictor stimulus. J Am Coll Cardiol. 1989;14:1456–1463.
erosclerosis and atherothrombosis. Circ Res. 2017;120:736–743. doi:
88. Lanza GA, Pedrotti P, Pasceri V, Lucente M, Crea F, Maseri A. Autonomic
10.1161/CIRCRESAHA.116.309692.
changes associated with spontaneous coronary spasm in patients with
73. Libby P. Triglycerides on the rise: should we swap seats on the seesaw? Eur
variant angina. J Am Coll Cardiol. 1996;28:1249–1256. doi: 10.1016/
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