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Mechanisms of Acute Coronary Syndromes NEJM
Mechanisms of Acute Coronary Syndromes NEJM
Mechanisms of Disease
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.
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
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
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-
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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