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Review article

Mechanisms of Disease

Mechanisms of Acute Coronary Syndromes


and Their Implications for Therapy
Peter Libby, M.D.

A 
From the Division of Cardiovascular Medi- therosclerotic lesions in humans typically form over the
cine, Department of Medicine, Brigham course of years to decades, one of the longest incubation periods among
and Women’s Hospital, Harvard Medical
School, Boston. Address reprint requests human diseases. Despite the chronicity of atherosclerosis, thrombotic com-
to Dr. Libby at the Division of Cardiovas- plications — the most dreaded clinical consequences of this disease — occur sud-
cular Medicine, Department of Medicine, denly, and often without warning. Our familiarity with the disease has generally led
Brigham and Women’s Hospital, Harvard
Medical School, 77 Ave. Louis Pasteur, us to accept this apparent paradox without wonder. What mechanisms explain the
Boston, MA 02115, or at plibby@rics.bwh abrupt transition from stable ischemic heart disease or asymptomatic atherosclero-
.harvard.edu. sis to acute coronary syndromes? This review examines our current understanding
N Engl J Med 2013;368:2004-13. of the mechanisms underlying these syndromes. According to the traditional view,
DOI: 10.1056/NEJMra1216063 progressive stenosis narrows the lumen of an atherosclerotic coronary artery to
Copyright © 2013 Massachusetts Medical Society.
such an extent that a small platelet thrombus could occlude the vessel completely.
Thus, an occlusive thrombus complicating a high-grade stenosis would arrest flow
and cause ST-segment elevation myocardial infarction. Acute coronary syndromes
without ST-segment elevation would result from an incomplete or transient ob-
struction of flow in the culprit coronary artery at a site of critical stenosis.
These concepts have governed our traditional approaches to atherosclerosis
therapy. Our diagnostic tools generally evaluate the ischemia that results from
established, fixed stenosis (e.g., stress testing and perfusion scanning) or visualize
the stenosis itself by means of arteriography. Our treatments have targeted the
stenosis with the use of percutaneous intervention or bypass surgery.

Pathogenesis of Acute Coronary Syndromes


Findings from clinical and pathological studies have challenged these commonly
held notions of the pathophysiological features of coronary atherosclerosis and its
treatment.1-4 Surprisingly, serial angiographic studies have revealed that the plaque
at the site of the culprit lesion of a future acute myocardial infarction often does not
cause stenosis that, as seen on the antecedent angiogram, is sufficiently severe to
limit flow. Angiographic monitoring of responses to thrombolytic therapy has
shown that after lysis of the offending thrombus, the underlying stenosis is often
not the cause of the critical stenosis of the artery. In a prospective angiographic
study involving patients undergoing percutaneous intervention for coronary artery
disease, only half the subsequent events arose from lesions with sufficient stenosis
to have warranted intervention at the time of revascularization.5 Computed tomo-
graphic (CT) angiography, which permits evaluation of the arterial wall (not just the
lumen), has shown that the characteristics of plaque associated with acute coronary
syndromes include low attenuation (i.e., little or no calcification) and outward ex-
pansion of the artery wall, a process that tends to accommodate the growth of
plaque while minimizing luminal encroachment.6-8 Intravascular ultrasonography
has shown that in acute coronary syndromes, the culprits often lie proximal to the
sites of maximal stenosis — the traditional targets of revascularization therapies.9

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Mechanisms of Disease

This dissociation between the degree of stenosis sis has diverted attention from autopsy studies
and the propensity to provoke an acute coronary conducted by generations of pathologists that
syndrome helps to explain why myocardial infarc- have ascribed most fatal coronary events to a
tion often occurs without being heralded by the physical disruption of coronary arterial plaques
demand-induced symptoms of angina that would (Fig. 1). Frank rupture of the plaque’s fibrous cap
result from a high-grade stenosis. causes the majority of these deaths; superficial
Technologies that permit cross-sectional im- erosion of a coronary artery accounts for most of
aging of the coronary arteries, such as intravas- the balance of fatal events. Autopsy studies have
cular ultrasonography or CT angiography, un- shown that erosion through the intima of a calci-
derscore the pathological observation that the fied nodule and intraplaque hemorrhage each
outward expansion of atherosclerotic arteries ac- trigger only a small percentage of acute coronary
commodates the growth of plaque for much of syndromes.2,14
its life history.2 Luminal stenosis occurs relatively Much of the work addressing the mechanisms
late in the process of atherogenesis, when plaque of coronary thrombosis has focused on plaque
growth outstrips the ability of the artery to com- rupture, the most common cause of fatal acute
pensate by expanding outward.10,11 These find- coronary syndromes. A fibrous cap typically over-
ings support the distinction between the degree lies the lipid-rich center — also known as the ne-
of stenosis and the size of a plaque. Compensa- crotic core — of an atheromatous plaque (Fig. 1).
tory enlargement (outward expansion) of the ar- This fibrous cap stands between the blood com-
tery during plaque growth can conceal a consid- partment, with its latent coagulation factors, and
erable burden of atheroma by preventing stenosis the lipid core, a portion of the plaque filled with
and thereby obscuring signs and symptoms of thrombogenic material. Quantitative morphomet-
ischemia. Sizable plaques can reside in the walls ric studies have identified the characteristics of
of affected arteries without being detected on plaques that have ruptured and caused a fatal
arteriograms and without issuing any warning myocardial infarction. Such plaques often, but
to the patient or physician. not always, have thin fibrous caps (50 to 65 μm
Clinical data acquired during the current era thick).2,15 Ruptured plaques also tend to have
of medical management of atherosclerosis have large lipid cores and abundant inflammatory
affirmed that invasive procedures for the treat- cells, as well as punctate or spotty calcifica-
ment of stenoses generally do not prevent future tion.7,16 In a recent autopsy study,17 a fibrous-cap
thrombotic events more effectively than nonin- thickness of less than 55 μm was identified as
vasive treatments. The Occluded Artery Trial the best morphologic indicator of plaques that
concluded that restoring coronary flow in the had caused fatal ruptures. More than 30% of these
subacute phase of an acute coronary syndrome plaques were associated with a luminal stenosis
did not improve outcomes.12 Similarly, the Clin- of less than 75%, even when studied post mor-
ical Outcomes Utilizing Revascularization and tem at pressures below physiological levels.
Aggressive Drug Evaluation (COURAGE) trial Typically, the sites where plaques rupture and
showed overall that medical therapy provided as provoke fatal coronary events have few smooth-
much protection from future acute coronary syn- muscle cells.18
dromes as did mechanical revascularization.13
This assemblage of clinical data challenges the Inflammation, Collagen Metabolism,
traditional view of the pathogenesis of acute coro- and Plaque Rupture and Thrombosis
nary syndromes, which ascribes a leading role to Extensive research has focused on the fibrous
critically stenotic lesions. cap of the plaque because of its importance in
the majority of fatal acute myocardial infarc-
Thrombotic Complications tions. This structure, which protects the plaque
of Atherosclerosis from rupture, owes its tensile strength to inter-
If the progression of luminal stenosis to a critical stitial forms of collagen synthesized primarily by
narrowing does not cause many acute coronary arterial smooth-muscle cells. The association be-
syndromes, what mechanism produces these dra- tween thinning of the fibrous cap and fatal plaque
matic and sudden manifestations of chronic ath- rupture led to the hypothesis that a defect in
erosclerosis? The long-standing focus on steno- plaque collagen metabolism contributes to the

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depletion of this extracellular matrix protein, collagen metabolism that may operate during
which has a critical role in strengthening the fi- atherogenesis. Since inflammatory cells accumu-
brous cap.1 These considerations have engen- late at the site of ruptured plaques, and since bio-
dered much interest in molecular mediators of markers of inflammation predict acute coronary

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Mechanisms of Disease

only on its rate of synthesis but also on the rate


Figure 1 (facing page). Characteristics of Atherosclerotic
Plaques Associated with Various Presentations at which it breaks down. Interstitial collagen is
of Coronary Artery Disease. usually very stable and resists degradation by
Characteristic morphologic features of coronary athero- most proteolytic enzymes. Only a handful of hu-
sclerotic plaques are depicted in association with three man proteinases have interstitial collagenase ac-
clinical presentations. The anterior surface of the heart tivity capable of catalyzing the initial attack on
(left) shows a representative atherosclerotic plaque at
fibrillar collagen. These enzymes belong to the
a typical location in the proximal left anterior descend-
ing coronary artery. The cross-sectional and longitudi- matrix-metalloproteinase (MMP) family. The
nal views of the artery depict details of the lesion types, macrophage, a cell type that abounds in lesions
shown at the level of the plaque. The pair of images at that have caused fatal thrombi, overproduces all
the top shows an eccentric, positively remodeled ather- three human MMP interstitial collagenases —
omatous plaque with a thin fibrous cap that has rup-
MMP-1, MMP-8, and MMP-13 — in plaques.21-25
tured and provoked the formation of a thrombus. The
healing of such disrupted atheromatous plaques can Moreover, plaques with features similar to those
promote evolution to a more fibrous plaque (shown in that have caused thrombotic complications dis-
the middle pair of images). Such a stenotic, fibrous plaque play biochemical signatures of collagen cleavage
can cause stable ischemic syndromes (e.g., demand in situ in macrophage-rich regions.24 Studies of
angina pectoris) as a result of narrowing of the arterial
the regulation of MMP production by human
lumen. In this situation, plaques can contain strata that
show “buried caps,” which result from a prior disrup- macrophages have shown that the T-cell–derived
tion of the fibrous cap that provoked the formation of cytokine CD40 ligand (CD154) boosts the pro-
thrombus, followed by healing, fibrosis, and often con- duction of interstitial collagenase by human
strictive (inward) remodeling. This process can promote macrophages.26 Thus, cross-talk between adap-
the progression of a nonocclusive, atheromatous, lipid-
tive immune cells (T cells) and the more numer-
rich plaque to a stenotic, more fibrous, calcified plaque.
The bottom pair of images shows a proteoglycan-rich ous innate immune effector cells (macrophages)
plaque that has caused an occlusive thrombus as a re- inhibits the synthesis and augments the degra-
sult of superficial erosion of the intimal surface. dation of interstitial collagen. These observa-
tions in human tissues and in isolated human
cells provide a cellular and molecular mecha-
syndromes, studies (discussed below) have fo- nism linking inflammation to the thinning and
cused on the hypothesis that macrophages — and weakening of the fibrous cap, which can pre-
the mediators that they produce and that regu- cipitate plaque rupture, thrombosis, and acute
late their function — disrupt the collagen in the coronary syndromes. Recent experiments show
plaque in a manner that may jeopardize the in- that the systemic inflammatory reaction to acute
tegrity of the fibrous cap, thus precipitating an myocardial infarction can aggravate inflamma-
acute coronary syndrome. tion in the plaque, including increased protease
A study of the control of collagen biosynthesis activity.27 This finding helps explain why recur-
by human vascular smooth-muscle cells in culture rent thrombotic events tend to cluster in the after-
revealed that exposure to interferon-γ, a product math of an acute coronary syndrome and often
of activated T cells, strongly inhibited the ability involve lesions not deemed responsible for the
of smooth-muscle cells to make the new collagen initial presentation.5 It also clarifies why imme-
required to repair and maintain the integrity of diate revascularization, by limiting myocardial
the fibrous cap.19 Even in smooth-muscle cells injury and consequent systemic inflammation,
maximally stimulated with transforming growth may reduce the risk of recurrent events, whereas
factor β to produce interstitial collagen, inter­ revascularization after completion of an infarct
feron-γ reduced collagen synthesis to baseline does not generally confer such a benefit.
levels or lower. Another study showed an inverse Another recently recognized regulator of plaque
correlation between T-cell accumulation in human proteinase expression, local endothelial shear
atherosclerotic plaques and the messenger RNA stress, also has clinical relevance to the forma-
that encodes the precursor of interstitial collagen, tion of lesions prone to rupture. In pigs, regions
an observation that supports the relevance in vivo of the coronary vasculature with low endothelial
of the profound inhibition of new collagen syn- shear stress colocalize with coronary atheroma-
thesis by a T-cell–derived mediator.20 ta with thin fibrous caps and exhibit enhanced
The level of any macromolecule depends not expression of matrix-degrading proteinases, in-

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of the fibrous cap in established atherosclerotic


Table 1. Interventions That Increase Collagen Content of Atherosclerotic
Lesions in Studies in Animals.* plaques.36
The combined studies of plaque in humans and
Intervention Species Source of Data animals support the concepts formulated in the
Reduction of dietary lipids Rabbit Aikawa et al.31 early 1990s.1 Decreased synthesis and increased
Treatment with statins Rabbit Fukumoto et al.32 breakdown of collagen, controlled by inflamma-
Introduction of a mutation that renders Mouse Fukumoto et al.33 tory signals, reduce the content of this critical
resistance to collagenase extracellular matrix macromolecule in plaques.
Induction of MMP-13 deficiency Mouse Deguchi et al.34 The resultant friable fibrous cap may render
Induction of MMP-14 deficiency Mouse Schneider et al.35 plaques susceptible to rupture and thrombosis
Treatment with MMP-13 inhibitor Mouse Quillard et al.36
(Fig. 2). Yet, a weakened fibrous cap alone does
not suffice to precipitate plaque rupture, and not
* MMP denotes matrix metalloproteinase. all plaques that rupture have thin fibrous caps.37
Additional contributors to the triggering of plaque
rupture may include coronary vasospasm and
cluding interstitial collagenases.28,29 In humans, punctate calcifications. Recent computational
regions of low shear stress in coronary arteries analyses indicate that microcalcifications within
are more likely to cause acute coronary events the atherosclerotic intima can result in a strik-
than regions of high shear stress.30 ing increase in circumferential stress and could
Despite their appeal, the initial data that sup- thus contribute to plaque rupture.16
ported the contribution of proteinases to the When the fibrous cap ruptures, allowing blood
pathogenesis of acute coronary syndromes de- to come into contact with thrombogenic mate-
pended primarily on association, and evidence rial in the plaque’s lipid core, thrombosis can
that altered collagen metabolism determines the ensue. When a plaque is disrupted, tissue factor,
collagen content of the fibrous cap remained a potent procoagulant produced by macrophages
speculative. Insights furnished by the study of in the plaque’s core, triggers thrombin generation
experimental preparations that permit gain-of- and platelet activation and aggregation.38,39 The
function and loss-of-function manipulation now same proinflammatory signal that augments col-
support a causal role for altered collagen metabo- lagenase production — CD154 — also induces
lism in the collagen content of plaque (Table 1). the expression of tissue factor in human mono-
In mice with a genetic susceptibility to diet- nuclear phagocytes (Fig. 2).26 Thus, inflammatory
induced atherosclerosis, further mutation of a cells and mediators not only regulate collagen
gene that encodes the precursor of interstitial synthesis and breakdown but also increase the
collagen, rendering it resistant to MMP collage- thrombogenic potential of the atherosclerotic
nases, yielded an accumulation of collagen in the plaque. These dual actions explain the strong
plaque.33 In other experiments, genetic inactiva- links between inflammation and the throm-
tion of collagenolytic enzymes or their activators botic complications of atherosclerosis.40
increased the collagen content of plaque.34,35
Although such germline manipulations permit Superficial Erosion of Plaques
exquisite selectivity, the congenital absence of an Superficial erosion of coronary atheromata causes
enzyme could confound the interpretation of the approximately 20 to 25% of cases of fatal acute
results owing to the possibility of compensatory myocardial infarctions.2 Observations made with
changes in other pathways. Moreover, the ge- the use of optical coherence tomography support
netic approach does not permit analysis of the the relevance of findings in autopsy studies to
influence of collagenolysis on aspects of plaque clinical acute coronary syndromes.41-44 This ana-
structure that relate to rupture in lesions that tomical substrate for coronary thrombosis oc-
have already formed. A recent study has there- curs more frequently in women than in men and
fore used pharmacologic inhibition of intersti- in persons with certain risk factors, such as hy-
tial collagenase to test this hypothesis. Indeed, pertriglyceridemia. Many lesions that cause coro-
oral administration of a selective inhibitor of a nary thrombosis because of superficial erosion
principal interstitial collagenase, MMP-13, in lack prominent inflammatory infiltrates; such
mice yielded an increase in the collagen content plaques exhibit proteoglycan accumulation (Fig. 1).

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Mechanisms of Disease

Figure 2. Inflammatory Pathways Predisposing Coronary Arteries to Rupture and Thrombosis.


A cross-section of an atheromatous plaque at the bottom of the figure shows the central lipid core that contains
macrophage foam cells (yellow) and T cells (blue). The intima and media also contain arterial smooth-muscle cells
(red), which are the source of arterial collagen (depicted as triple helical coiled structures). Activated T cells (of the
type-1 helper T-cell subtype) secrete cytokine interferon-γ, which inhibits the production of the new, interstitial col-
lagen that is required to repair and maintain the plaque’s protective fibrous cap (upper left). The T cells can also ac-
tivate the macrophages in the intimal lesion by expressing CD40 ligand (CD154), which engages its cognate receptor
(CD40) on the phagocyte. This inflammatory signaling causes overproduction of interstitial collagenases (matrix
metalloproteinases [MMPs] 1, 8, and 13) that catalyze the initial rate-limiting step in collagen breakdown (top right).
CD40 ligation also causes macrophages to overproduce tissue-factor procoagulant. Thus, inflammatory signaling puts
the collagen in the plaque’s ­f ibrous cap in double jeopardy — decreasing synthesis and increasing breakdown —
rendering the cap susceptible to rupture. Inflammatory activation also boosts tissue-factor production, which trig-
gers thrombus formation in the disrupted plaque. These are the mechanisms through which inflammation in the
plaque can precipitate the thrombotic complications of atherosclerosis, including acute coronary syndromes.

The mechanisms of superficial erosion have re- ed leukocytes associated with atheromata — can
ceived much less attention than those involved in initiate apoptosis of endothelial cells.46 As these
the rupture of the fibrous cap. The programmed cells undergo apoptosis, they produce the proco-
cell death (i.e., apoptosis) of endothelial cells agulant tissue factor. The oxidant hypochlorous
could contribute to their desquamation.45 Oxida- acid may thus initiate or propagate endothelial
tive stress can promote endothelial apoptosis. In cell loss and local thrombosis in coronary arteries.
particular, hypochlorous acid — the product of Endothelial cells can also express proteinases that
myeloperoxidase, an enzyme released by activat- may sever their tethers to the underlying base-

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caliber but may qualitatively limit the propensity


Table 2. Favorable Effects of Lipid Lowering in Experimentally Produced
Atherosclerotic Plaques. of plaques to rupture and their thrombogenicity.
These changes in the biologic features of plaque
Reduces inflammation (lowers levels of macrophages, cytokines, and chemo- are now considered to confer “stabilization,” a
kines and expression of leukocyte adhesion molecules)
feature that distinguishes lipid-lowering inter-
Reduces expression of interstitial collagenase (MMP-1)
ventions from those that address luminal steno-
Increases levels of interstitial collagen sis without altering the molecular and cellular
Lowers levels of oxidized low-density lipoprotein processes inculpated in the triggering of throm-
Reduces production of reactive oxygen species botic complications.49 A comprehensive series of
Increases expression of endothelial nitric oxide synthase studies in rabbits and mice tested this hypothe-
Reduces thrombotic potential (reduced tissue factor content and activity)
sis. One series of investigations in rabbits with
experimentally induced atherosclerosis lowered
Increases fibrinolytic potential (reduced level of plasminogen activator
inhibitor-1) lipid levels by means of diet alone, a “lifestyle”
intervention. A combination of arterial injury and
an atherogenic diet provoked the development of
ment membrane.45 Modified low-density lipopro- fibrofatty aortic plaques in rabbits. After a period
tein (LDL), for example, can induce the expression of lesion generation, the rabbits were switched to
of the enzyme MMP-14 by human endothelial a low-fat, low-cholesterol diet or were kept on a
cells.47 MMP-14 can activate MMP-2, an enzyme diet that maintained dyslipidemia. The lipid-low-
that degrades basement-membrane forms of ering diet reduced the content of inflammatory
nonfibrillar collagen (type IV). The mechanisms cells, augmented interstitial collagen accumula-
of superficial erosion merit attention in future in- tion, and reduced tissue factor antigen and activ-
vestigations; they are much less well understood ity in concert with other effects that contrast
than the mechanisms underlying the fracture of with the features of human plaques prone to
the plaque’s fibrous cap. rupture and thrombosis (Table 2).31,50
Other studies showed that statin treatment
Therapeutic Implications of New Mechanistic caused similar reductions in inflammatory-cell
Insights content and collagenase levels and augmented col-
Although revascularization procedures that tar- lagen accumulation in atheromata of Watanabe
get occlusive coronary stenosis relieve anginal heritable hyperlipidemic rabbits.32,51 Because rab-
symptoms, they have not consistently reduced bits of this strain — characterized by mutated
the risk of an acute coronary syndrome or death LDL receptors — have only modestly reduced LDL
from coronary artery disease. In stark contrast, cholesterol levels when treated with statins, these
contemporary medical therapy — notably, statin studies indicate that statins have a stabilizing
treatment — has prevented both first and recur- effect on plaques that extends beyond their lipid-
rent acute coronary syndromes in broad catego- lowering action.52
ries of patients. Curiously, even though these Observations in humans support the concept,
medical interventions reduce events, they have established in animals, that lipid lowering can
little effect on the degree of stenosis as assessed increase the fibrous nature of plaques — a
on angiography and result in only modest reduc- change that should confer resistance to rupture.
tions in atheroma volume as assessed on intra- Imaging studies suggest that plaques have a
vascular ultrasonography.48 Can the new insights more fibrous character in patients receiving
into the mechanisms of acute coronary syn- treatment with statins than in those not receiv-
dromes, described above, illuminate these clini- ing such treatment.53-56 Statin therapy is also
cal findings and explain how medical treatment associated with reduced lipid content and in-
reduces the thrombotic complications of athero- dexes of macrophage activity and more fibrous
sclerosis? atheromata as assessed on magnetic resonance
Event reduction that is out of proportion to imaging in both rabbits and humans.57-59 These
the shrinkage of stenoses has led to the hypoth- studies in humans affirm the clinical relevance
esis that lipid lowering alters qualitative charac- of the studies in animals described above and
teristics of atheromata — that such treatment the classic observations of Armstrong and col-
causes modest quantitative improvement in lumen leagues regarding the “regression” of atheroscle-

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Mechanisms of Disease

rotic lesions in nonhuman primates after dietary fects of colchicine. Nevertheless, these encourag-
restriction of lipids.60 ing results should prompt a larger-scale, double-
Despite the remarkable benefits of statin ther- blind trial of this inexpensive agent, which has a
apy, patients appropriately treated with this class long history of clinical use and a well-known and
of agents are still at considerable risk for acute acceptable risk profile. Two large clinical trials are
coronary syndromes61 — hence the need to make testing the use of darapladib, a small molecular
further inroads against this residual burden of inhibitor of a lipoprotein-associated phospholi-
disease. The advent of novel strategies for lower- pase, to reduce clinical events.71,72 Although this
ing LDL cholesterol levels below those achiev- intervention has the potential for antiinflamma-
able with statins alone (e.g., inhibition of serum tory actions, in a phase 2 trial it did not reduce
proprotein convertase subtilisin/kexin 9 [PCSK9]) levels of C-reactive protein but did limit lipid core
provides considerable promise in this regard.62,63 size, a characteristic that may render plaques
Therapies that target other aspects of the lipid susceptible to rupture.73 Other interventions un-
profile have proved disappointing when put to der investigation include antibody neutralization
the test, despite extensive preclinical and clinical of the proinflammatory cytokine interleukin-1β
biomarker data. Clinical trials of interventions or the use of low-dose methotrexate on a weekly
that address levels of high-density lipoprotein basis, treatments currently used successfully for
(HDL) cholesterol have shown no benefit (e.g., other inflammatory conditions.74,75
the cholesteryl ester transfer protein [CETP] in-
hibitors tested thus far, and niacin).64-67 Simi- Sum m a r y
larly, recent large-scale trials of fibrates, agents
that substantially lower triglyceride levels and Our understanding of the pathogenesis of acute
modestly raise HDL cholesterol levels, in pa- coronary syndromes has undergone a veritable rev-
tients with type 2 diabetes mellitus have not olution in the past 20 years. We now understand
shown a reduction in cardiovascular events.68,69 in molecular and cellular terms how most serious
Given the role of inflammation in the patho- thrombotic complications of coronary atheroscle-
physiological aspects of plaque rupture, several rosis occur. In particular, inflammatory pathways
studies are assessing the use of antiinflamma- have emerged as important drivers of plaque dis-
tory therapies other than statins to reduce the ruption and thrombosis. This insight into the
risk of a recurrent acute coronary syndrome. A re- pathophysiological features of acute coronary syn-
cent clinical trial of low-dose colchicine (0.5 mg dromes expands the scope of treatment of this
per day) in patients with stable ischemic heart disease beyond the traditional focus on reducing
disease has shown a reduced incidence of acute stenoses. The laboratory and clinical data summa-
coronary syndromes.70 This trial was relatively rized here should help us both to understand how
small (532 patients, with a total of 55 events), contemporary therapies can reduce the risk of
and the investigators did not use a double-blind these events and to make further inroads against
design and did not report levels of inflammatory the residual burden of disease in the future.
biomarkers, which might have provided a glimpse Disclosure forms provided by the author are available with the
into the possible mechanisms underlying the ef- full text of this article at NEJM.org.

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