Current Perspective
Current Concepts of the Pathogenesis of the Acute
Coronary Syndromes
Peter Libby, MD
T he last decade has witnessed a major reassessment of our
perceptions about the acute coronary syndromes. Today,
we recognize that thrombosis underlies most acute complica-
tions of atherosclerosis, notably unstable angina and acute
myocardial infarction. A consensus has emerged that inflam-
mation plays a decisive role in the pathophysiology of these
acute thrombotic events (Figure 1). Knowledge of the under-
lying mechanisms has increased substantially since this topic
was last reviewed in these pages 6 years ago. The present
article provides an update of this rapidly moving field.
Most coronary thromboses result from a fracture in the
protective fibrous cap of the plaque (Figure 1, cross section
5). Ample evidence now supports the concept that the
protective fibrous cap, far from being fixed and static,
actually can undergo continuous and dynamic remodeling
and displays considerable metabolic activity.1 Fibrils of
interstitial collagen confer biomechanical strength on the
fibrous cap. The balance between synthetic and degradative
processes closely controlled by inflammatory mediators reg-
ulates the level of collagen in this structure. For example, the
lymphokine gamma interferon (IFN-␥) can inhibit de novo
synthesis of interstitial collagen by smooth muscle cells, the
major source of this extracellular matrix protein in the artery
wall.2 Proinflammatory cytokines induce the expression of
enzymes capable of breaking down constituents of the arterial
extracellular matrix. In particular, matrix metalloproteinases,
including interstitial collagenases and gelatinases, can de-
grade the collagen fibrils that lend strength to the plaque’s
fibrous cap.3– 6 Recent work has established that certain
elastolytic cathepsins, also regulated by inflammatory medi-
ators and expressed in atheroma, can weaken elastin, another
important component of the arterial extracellular matrix.
Examples include the sulfhydryl-dependent proteinases
cathepsins S and K.7,8
The plaque’s smooth muscle cell population also influ-
ences the level of extracellular matrix. Sites of fatal throm-
bosis where plaques fail mechanically and rupture typically
have few smooth muscle cells.9,10 Death of these cells, a
critical source of extracellular matrix macromolecules in the
artery wall, can occur in atherosclerotic lesions. Inflamma-
tory stimuli such as cytokines and fas ligand, factors overex-
From Leducq Center for Cardiovascular Research, Cardiovascular Division, Department of Medicine, Brigham and Women’s Hospital and Harvard
Medical School, Boston, Mass.
Correspondence to Peter Libby, MD, Cardiovascular Division, Department of Medicine, 221 Longwood Ave, LMRC 307, Boston, MA 02115. E-mail
plibby@rics.bwh.harvard.edu
(Circulation. 2001;104:365-372.)
© 2001 American Heart Association, Inc.
Circulation is available at http://www.circulationaha.org
365
pressed in atherosclerotic plaques, can trigger the complex
mechanisms of apoptosis.11 Absence of smooth muscle cells
jeopardizes the integrity of the fibrous cap because these cells
repair and maintain the all-important collagenous matrix of
the fibrous cap. Indeed, plaques that rupture have thin and
friable fibrous caps because of the lack of collagen.12,13
In a minority of cases, fatal thrombosis in coronary arteries
results from a superficial erosion of the intima without a frank
rupture through the plaque fibrous cap (Figure 1, cross
section 7).10,14 Inflammation may also contribute to this
mechanism of coronary thrombosis. Endothelial cells, like
smooth muscle cells, may undergo apoptosis in response to
inflammatory mediators.15 Loss of endothelial cells can
uncover the thrombogenic subendothelial matrix. Endothelial
cells can also express proteinases regulated by inflammatory
cytokines and oxidized lipoproteins.16 –18 One of these pro-
teinases, membrane type 1 matrix metalloproteinase, can
activate matrix metalloproteinase-2, a type IV collagenase.
Type IV collagen, a key constituent of the subendothelial
matrix, provides an important substrate for adherence of
endothelial cells to the intimal surface. Thus, activation of
proteases in response to inflammatory stimuli can sever the
tethers that hold the endothelial cell to its underlying matrix,
promoting desquamative injury to the intima, a possible
prelude to local thrombosis resulting from superficial erosion.
Even in the absence of actual sloughing of endothelial
cells, an altered balance between prothrombotic and fi-
brinolytic properties of the endothelium may underlie
thrombosis in situ. Endothelial cells express tissue factor
procoagulant in response to inflammatory mediators and
bacterial products such as endotoxin.19 The fibrinolytic
pathway in endothelial cells also fluctuates, depending on
the inflammatory milieu.20 For example, the expression of
plasminogen activator inhibitor-1 (PAI-1) can vary in the
presence of inflammatory mediators.21
Vasospasm may also contribute to impaired arterial flow
in the presence of inflammation. Endothelial cells in
atherosclerotic arteries show impaired vasodilator func-
tion. This may result in part from decreased production of
nitric oxide. Also, augmented release of superoxide anion
(O2⫺) may annihilate nitric oxide radical, neutralizing its
366 Circulation July 17, 2001

Figure 1. Initiation, progression, and complication of human coronary atherosclerotic plaque. Top, Longitudinal section of artery depicting
“timeline” of human atherogenesis from normal artery (1) to atheroma that caused clinical manifestations by thrombosis or stenosis (5, 6, 7).
Bottom, Cross sections of artery during various stages of atheroma evolution. 1, Normal artery. Note that in human arteries, the intimal layer
is much better developed than in most other species. The intima of human arteries contains resident smooth muscle cells often as early as
first year of life. 2, Lesion initiation occurs when endothelial cells, activated by risk factors such as hyperlipoproteinemia, express adhesion
and chemoattractant molecules that recruit inflammatory leukocytes such as monocytes and T lymphocytes. Extracellular lipid begins to
accumulate in intima at this stage. 3, Evolution to fibrofatty stage. Monocytes recruited to artery wall become macrophages and express
scavenger receptors that bind modified lipoproteins. Macrophages become lipid-laden foam cells by engulfing modified lipoproteins. Leuko-
cytes and resident vascular wall cells can secrete inflammatory cytokines and growth factors that amplify leukocyte recruitment and cause
smooth muscle cell migration and proliferation. 4, As lesion progresses, inflammatory mediators cause expression of tissue factor, a potent
procoagulant, and of matrix-degrading proteinases that weaken fibrous cap of plaque. 5, If fibrous cap ruptures at point of weakening, coag-
ulation factors in blood can gain access to thrombogenic, tissue factor– containing lipid core, causing thrombosis on nonocclusive athero-
sclerotic plaque. If balance between prothrombotic and fibrinolytic mechanisms prevailing at that particular region and at that particular time
is unfavorable, occlusive thrombus causing acute coronary syndromes may result. 6, When thrombus resorbs, products associated with
thrombosis such as thrombin and mediators released from degranulating platelets, including platelet-derived growth factor and transforming
growth factor-␤, can cause healing response, leading to increased collagen accumulation and smooth muscle cell growth. In this manner, the
fibrofatty lesion can evolve into advanced fibrous and often calcified plaque, one that may cause significant stenosis, and produce symptoms
of stable angina pectoris. 7, In some cases, occlusive thrombi arise not from fracture of fibrous cap but from superficial erosion of endothelial
layer. Resulting mural thrombus, again dependent on local prothrombotic and fibrinolytic balance, can cause acute myocardial infarction.
Superficial erosions often complicate advanced and stenotic lesions, as shown here. However, superficial erosions do not necessarily occur
after fibrous cap rupture, as depicted in this idealized diagram.

vasodilator capacity.22 In addition to producing vasodila-
tation, nitric oxide can impair platelet aggregation. Nitric
oxide also has a direct anti-inflammatory effect, augment-
ing production of the inhibitor of nuclear factor kappa B
(NF-␬B), a transcription factor involved in the expression
of the genes encoding many proinflammatory functions of
vascular wall cells and infiltrating leukocytes.23–25 These
various findings all highlight the central role of inflamma-
tion as a determinant of the biology underlying the acute
thrombotic complications of atherosclerosis.
Mechanisms by Which Lipid Lowering
May Mitigate Thrombotic Complications
of Atherosclerosis
A consistent body of evidence from large clinical trials has
established beyond doubt that lipid lowering can reduce the
 Libby
Lipid Lowering Improves Features of Experimental Atheroma
Associated With Plaque Stability
Reduces Increases
Macrophage number Interstitial collagen content
Matrix metalloproteinase expression Smooth muscle maturation
Tissue factor gene expression
Proinflammatory cytokine expression
Leukocyte adhesion molecule expression
Production of reactive oxygen species
incidence of coronary events and stroke in a broad spectrum
of individuals. Curiously, lipid lowering produces rather
modest improvements in the luminal caliber of fixed athero-
sclerotic lesions. This finding suggests that qualitative
changes in plaques, rather than improvements in the degree of
stenosis, must contribute importantly to the striking reduction
in clinical events produced by lipid lowering. In view of the
central role of inflammation in the pathophysiology of these
events, we have advanced the hypothesis that lipid lowering
acts as an anti-inflammatory intervention, modifying the
biology of plaque instability. A considerable corpus of
experimental data now support this contention (the Table). In
animals with experimental atherosclerosis, lipid lowering
reduces the number of inflammatory cells and various inflam-
matory mediators.26,27 Concomitant with the decrease in
macrophage number, the levels of collagenolytic enzymes
such as matrix metalloproteinase-1 decrease. In addition,
levels of tissue factor decline.28 Tissue factor owes its
procoagulant effect to the ability to bind factor VIIa and
augment its enzymatic activity many fold. Along with de-
creased levels of tissue factor antigen, lipid lowering de-
creases factor VIIa and X binding activity in rabbit arteries.
Thus, lipid lowering not only yields an increased level of
interstitial collagen in the atherosclerotic intima but also
decreases the thrombotic potential of the lesion. Such im-
provements in features of plaques associated with stability or
reduced thrombogenicity occur both with dietary and statin-
induced lipid lowering and with lesions resulting from either
dietary or endogenous hypercholesterolemia.29 No studies yet
available address directly the possible contributions of non–
lipid-lowering effects of statins on these variables. These
qualitative changes in the atheroma should yield a more
stable plaque, one less likely to cause thrombosis if it were to
rupture.
More recent work has demonstrated a reduction in markers
of endothelial activation, such as expression of the leukocyte
adhesion molecule, vascular cell adhesion molecule-1
(VCAM-1), as a consequence of lipid lowering (M. Aikawa,
2001, submitted). Moreover, animals subjected to lipid low-
ering show a less abundant plexus of microvessels in the
intima. Plaque microvessels serve as a portal for leukocyte
trafficking. The neovessels in the plaque, like those in the
diabetic retina, may be fragile and prone to leakage or
hemorrhage. Thrombosis in situ caused by microvascular
disruption may provide one pathway of plaque growth.
Mediators released or generated during clot formation, such
as platelet-derived growth factor and thrombin, may promote
Pathogenesis of the Acute Coronary Syndromes 367
smooth muscle cell migration and proliferation. Additionally,
intraplaque hemorrhage resulting from microvascular disrup-
tion could cause sudden expansion of lesions. In this manner,
reduced neovascularization during lipid lowering may further
stabilize atherosclerotic plaques. Moreover, as the microves-
sels in plaques may contribute to plaque growth, reduced
neovasculature resulting from lipid lowering may, like other
antiangiogenic strategies, limit plaque progression.30
The foregoing experimental studies support the view that lipid
lowering can reduce inflammation. Emerging clinical data sup-
port the validity of this concept in humans. For example, lipid
lowering with pravastatin in the Cholesterol and Recurrent
Events (CARE) study showed a significant decline in the levels
of C-reactive protein (CRP).31 Multiple studies have validated
CRP as an index of inflammation that correlates closely with
prospective cardiovascular risk (see below).
Possible “Pleiotropic” Effects of Statins
At high concentrations, inhibitors of HMG CoA reductase
(statins) can restrict many cellular processes. This enzyme
catalyzes the rate-limiting step in the synthesis of cholesterol.
The pathway leading to cholesterol also produces other less
well-known compounds such as the polyisoprenoids farnesyl
phosphate and geranylgeranyl phosphate. These polyisopre-
noids can link to proteins (prenylation), altering their func-
tions in important ways. Inhibition by statins of prenylation of
a family of intracellular signaling molecules known as small
G proteins, among others, may have direct effects on cells
independent of systemic lipid lowering. In vitro studies
showing such so-called “pleiotropic effects” of statins
abound. Yet there is uncertainty that the concentrations used
in most such cell culture studies can apply to humans treated
with clinically relevant doses of these drugs. Various statins
currently marketed vary widely in their direct effects on cells.
However, in humans, no consistent evidence available estab-
lishes differences between various statins in regard to such
putative pleiotropic effects. Various clinical trials currently
underway may illuminate this issue. To date, appropriately
powered studies have shown benefits on clinical end points of
all statins tested. Hence, effects on lipid levels likely account
for much of the clinical benefits of this class of drugs.
One potentially relevant pleiotropic effect of statins is atten-
uation of proliferation of cultured smooth muscle cells, an action
caused part to by interference with G protein–mediated cell
cycle regulation.32 With respect to plaque progression and
evolution, limitation of smooth muscle proliferation might slow
lesion growth. However, in the context of atheroma stability, a
reduction in the population of smooth muscle cells might favor
plaque disruption. As noted above, the smooth muscle cell
synthesizes virtually all of the interstitial collagen responsible for
the strength of the plaque’s fibrous cap. Plaques that clinically
rupture and cause fatal thrombosis have relatively few smooth
muscle cells.9,10 For this reason, a direct inhibitory effect of
statins on smooth muscle growth could conceivably render
lesions less stable. However, this concern probably does not
apply clinically, because concentrations of statins required to
inhibit smooth muscle proliferation in vitro are rarely, if ever,
achieved in vivo.
368 Circulation July 17, 2001
Statins can also increase vascular cell functions related to
thrombus formation and stability. For example, these agents
can increase the expression of plasminogen activator and
decrease the expression of its inhibitor, PAI-1.21 In addition
to the effects on smooth muscle cell and endothelial functions
alluded to earlier, statins can alter macrophage metabolism.
Indeed, statins can inhibit tissue factor expression.33 Once
again, however, these direct effects of statins on cellular
function require concentrations of the drugs beyond those
likely to have clinical relevance. However, some of the
so-called pleiotropic effects of statins clearly do pertain in
vivo. For example, treatment of mice with statins can im-
prove cerebral blood flow and reduce stroke size by increas-
ing endothelial nitric oxide synthase activity. Animals lacking
nitric oxide synthase because of targeted gene manipulation
do not have increased cerebral flow or decreased stroke size
after treatment with statins.34
Plaque Stabilization by Lipid Lowering:
Beyond LDL
Over the last several years, a remarkably consistent body of
controlled clinical trials has established the efficacy of
lowering LDL in improving clinical outcomes. However,
most adverse events still occur in patients at risk despite
substantial lowering of LDL by statin treatment. Thus, our
goals for the coming decade should include further reductions
in cardiovascular risk by addressing other risk factors. Certain
recent studies provide guides in this regard. In the Veterans
Affairs HDL Intervention Trial (VA-HIT), treatment of
individuals with established atherosclerosis with gemfibrozil
significantly reduced cardiovascular events in the absence of
a change in LDL level.35 The Lyon Heart Study showed that
a Mediterranean diet could likewise reduce coronary risk
without substantially altering levels of LDL.36 Both of these
interventions may alter a more recently recognized mecha-
nism for controlling vascular gene expression. The drug
gemfibrozil, a member of the fibrate class, acts by binding the
nuclear receptor peroxisomal proliferation activating
receptor-␣ (PPAR-␣).37 Polyunsaturated fatty acids, in-
creased in the Mediterranean diet, may also activate PPAR-␣.
Figure 2. PPAR pathways. Originally recog-
nized as instigator of peroxisomal proliferation
unique to rodents, PPARs are nuclear receptors
for small lipophilic molecules that freely parti-
tion into cells. When these receptors bind their
small ligand partner, they pair with another
member of nuclear receptor family, retinoid X
receptor (RXR). This heterodimeric transcription
factor complex then binds to cognate
sequences in promoter regions of target genes,
altering their transcription. PPAR-␣ regulates
cassette of genes involved in lipoprotein me-
tabolism, raising levels of apolipoprotein A-1,
major apolipoprotein of HDL. PPAR-␥ regulates
expression of genes involved in adipogenesis
and insulin sensitivity. Kindreds with mutations
that affect function of PPAR-␥ develop an insu-
lin resistance syndrome, including hypertension.
See text for references.
PPAR-␣ acts as part of a transcription factor complex that
regulates the expression of a number of genes implicated in
atherogenesis and plaque stability (Figure 2). Notably,
PPAR-␣ agonism can limit cytokine-induced activation of
inflammatory functions of vascular endothelial cells, eg,
expression of VCAM-1 in response to tumor necrosis
factor-␣ and tissue factor gene expression in these cells.38 – 40
Thus, the results of the VA-HIT and Lyon Heart Study might
derive in part from an anti-inflammatory action. Because
these interventions act by a mechanism distinct from LDL
lowering, combining statin therapy with the Mediterranean
diet or PPAR-␣ agonists might have additive effects on
reducing cardiovascular risk. Because oxidized phospholipids
may augment certain cytokines via PPAR-␣ activation, under
some circumstances, this nuclear receptor may play a proin-
flammatory role.41
PPAR-␥, a close relative of PPAR-␣, binds a distinct series
of ligands and controls a separate set of genes involved in
cardiovascular and metabolic diseases.37 Notably, mutations
that alter the function of PPAR-␥ cause a syndrome of insulin
resistance, hypertension, and dyslipidemia characteristic of
the cardiovascular dysmetabolic syndrome.42 PPAR-␥ ago-
nists include the insulin-sensitizing thiazolidinedione family
of antidiabetic drugs (the glitazones). In vitro, PPAR-␥
agonists can decrease proinflammatory functions of macro-
phages and smooth muscle cells.41,43– 47 However, PPAR-␥
agonism can also augment endothelial PAI-1 production48
and expression of the scavenger receptor for modified li-
poprotein CD36 on mononuclear phagocytes.49 These in vitro
observations cannot predict the net effects of PPAR-␥ ago-
nism in the intact organism. However, they certainly under-
score the importance of careful consideration of cardiovas-
cular risk as an outcome in future clinical studies of this new
class of pharmacological agents.
ACE Inhibition as Anti-Inflammatory
Therapy: An Additional Avenue for Reducing
Atherosclerotic Events
Multiple clinical studies have substantiated an initially unex-
pected reduction in acute coronary events in patients treated
 Libby
with ACE inhibitors. Emerging evidence suggests that ACE
inhibitor therapy may possess benefits beyond blood pressure
lowering (Figure 3). For example, in the recent Heart Out-
comes Prevention Evaluation (HOPE) trial, ACE inhibitor
therapy produced little reduction in blood pressure but strik-
ingly diminished cardiovascular events.50 How can one fit
these unanticipated clinical findings with ACE inhibition into
the current concepts of the role of inflammation in plaque
biology? Indeed, angiotensin II activates inflammatory func-
tions of vascular wall cells. For example, angiotensin II can
augment interleukin-6, macrophage chemoattractant
protein-1 elaboration by human smooth muscle cells in
culture.51–54 Administration of ACE inhibitors can reduce
cytokine levels and indexes of activation of NF-␬B in rabbits
with experimentally induced atherosclerosis.55,56 Angiotensin
II also alters fibrinolytic balance by augmenting PAI-1
expression, a function it shares with more classically recog-
nized proinflammatory cytokines.57 Activation of the renin-
angiotensin system also spurs the production of reactive
oxygen species from vascular cells, a property increasingly
well understood at the molecular level.58
These various data suggest that inhibition of angiotensin II
signaling by ACE inhibitors or angiotensin II receptor block-
ers might actually act as anti-inflammatory therapy. Angio-
tensin II increases levels of the peptide mediator bradykinin
and interrupts angiotensin II production. Bradykinin, an
endothelial-dependent vasodilator, augments local production
of nitric oxide. As noted earlier, in addition to its vasodilatory
properties, nitric oxide may mitigate atherogenesis because of
anti-inflammatory properties mediated by interference with
the NF-␬B transcriptional control pathway.24,59 Bradykinin
also elevates intracellular levels of the second messenger
cGMP. The increased cGMP may contribute to some of the
beneficial actions of ACE inhibitors, eg, by promoting
vasodilatation resulting from smooth muscle relaxation. In
this regard, bifunctional inhibitors of ACE and the neutral
endopeptidase that catabolizes certain other peptide hor-
mones, including atrial and brain natriuretic peptides, should
also augment intracellular cGMP levels. Future studies
should evaluate the effect of angiotensin receptor blockers
and the bifunctional peptidase inhibitors on cardiovascular
outcomes as well.
Pathogenesis of the Acute Coronary Syndromes 369
Figure 3. Angiotensin II (A II) is inflammatory
mediator. Angiotensin II can be considered an
“honorary” proinflammatory cytokine, in addi-
tion to its well-known vasoconstrictor proper-
ties. Angiotensin II augments expression of leu-
kocyte adhesion molecules such as VCAM-1. It
can also stimulate expression of leukocyte che-
moattractants such as monocyte chemoattrac-
tant protein-1 (MCP-1). Angiotensin II stimu-
lates expression of interleukin-6 (IL-6), instigator
of acute-phase response, provoking elaboration
of CRP, serum amyloid A, and fibrinogen from
hepatocyte. Angiotensin II also augments pro-
duction of reactive oxygen species by vascular
cells augmenting oxidative stress, which is
potent proinflammatory stimulus.
Infections and Atheroma: Will Antibiotics
Prevent Acute Coronary Syndromes?
Recent results have rekindled interest in the possible role of
infectious agents in atheroma. Mechanisms by which infec-
tions such as Chlamydia pneumonia or cytomegalovirus may
aggravate or initiate atherosclerosis have been previously
reviewed in these pages.60 Indeed, this complex topic merits
a separate discussion but warrants here a brief summary of the
current state of this association. Prospective and well-
controlled seroepidemiological studies have failed to support
a consistent link between infections and coronary events.61
However, almost half of the human plaques studied show
evidence of the presence of C pneumonia. Chlamydial prod-
ucts, including its heat shock protein 60, and endotoxin can
promote inflammation of vascular cells and the activation of
atherogenic functions of macrophages.62– 65 These findings
render it plausible that Chlamydia might potentiate the
complication of existing atheroma. Various pilot studies of
antibiotic treatment for secondary prevention of coronary
events lack power to provide a definitive answer. Large
randomized trials now in progress should reveal whether
antibiotic treatment can forestall recurrent coronary events.
Markers and Surrogates of Atherosclerotic Risk
Recent clinical trials with statins have vindicated the choles-
terol hypothesis, establishing beyond doubt the efficacy of
LDL lowering in reducing cardiovascular risk in a broad
swath of the population. The foregoing discussion has high-
lighted other interventions on the horizon that may further
limit the risk of acute complications of atherosclerosis. Our
ability to modify the natural history of atherosclerosis may
well have outstripped our ability to predict who might benefit
from therapy. Contemporary clinical trials show that benefits
of lipid lowering can accrue to patients not currently eligible
for treatment on the basis of current guidelines. For example,
the Air Force/Texas Coronary Atherosclerosis Prevention
Study (AFCAPS/TexCAPS) showed reductions in cardiovas-
cular events in individuals with average LDL levels not
eligible for treatment on the basis of the National Cholesterol
Education Adult Treatment Panel II Guidelines.66,67 This
finding illustrates the urgent need to identify approaches to
risk stratification that add to the utility of the lipoprotein
profile.68
370 Circulation July 17, 2001
Help in this regard should come from two directions. First,
the clinical application of the surge in understanding of the
role of inflammation in atherosclerotic events has led to
multiple studies that have validated inflammatory markers
such as CRP as a marker for risk of future cardiovascular
events.69 –71 Other inflammatory markers, including soluble
intercellular adhesion molecule-172 and soluble E-selectin,73
for example, may also predict risk of atherosclerotic compli-
cations. However, the high sensitivity assay of CRP is well
standardized, widely available, and reproducible and adds to
the predictive value of traditional risk factors, including the
lipoprotein profile. Addition of a small panel of such serum
markers of risk, including those linked to inflammation,
should hone our ability to target therapy in the future.
Also, the recent solution of the human genome will enable
the flowering of functional genomics. In coming years, we
will see delineation of polymorphisms in the human genome,
some of which will doubtless predict an individual’s cardio-
vascular risk. Clearly, application of this knowledge will
require careful consideration of ethical issues and confiden-
tiality. However, we already make public health recommen-
dations based on genotyping. For example, screening for
phenylketonuria at birth leads to dietary recommendations
broadcast widely on containers of diet cola and other products
sweetened with aspartame. This example illustrates the prin-
ciple of making an individualized recommendation for con-
trol of a risk factor on the basis of a genetic predisposition
tested for at birth.
I believe that in the future we will target our preventive
therapies by a combination of a panel of few serum tests,
including traditional and a few nontraditional markers. I
foresee the utility of only a small number of serum markers,
because it will become increasingly difficult to demonstrate
additive information over established markers, such as the
lipoprotein profile and CRP. These markers will provide an
integrated assessment of the interaction between genotype
and the environment, including individual behaviors (eg,
smoking and diet).68 Genotyping, probably accomplished by
high-throughput screening early in life, will identify genetic
markers (eg, single nucleotide polymorphisms and haplo-
types) that should predict individual responses to risk factors.
The combination of the serum markers and hereditary pre-
disposition revealed by genetic analysis should sharpen our
ability to make a prescription for management of risks in
individuals in a rational manner.
Conclusions
Our view of the mechanisms underlying the acute complica-
tions of atherosclerosis has shifted remarkably in the last
decade. In the past era, we relied on flow-limiting arterial
stenoses and functional indexes of end-organ ischemia to
guide our therapies. We held high-grade arterial stenoses
responsible for the bulk of acute ischemic complications of
atherosclerosis. Considerable clinical data have compelled a
reassessment of these concepts. Current findings establish the
importance of qualitative aspects of plaques as decisive
determinants of their propensity to cause acute complications.
Among these functional features of plaques associated with
vulnerability, inflammation has emerged as a leading patho-
physiologic mechanism, providing new potential therapeutic
targets and novel avenues to risk assessment.
In addition to local effects of inflammation at the level of
the atherosclerotic lesion itself, systemic aspects of the
inflammatory response may alter thrombotic risk. Inflamma-
tion upsets the prevailing homeostatic balance. Increased
fibrinogen and plasminogen activator inhibitor circulate at
higher concentrations in inflammatory states. A given plaque
disruption could have a greater chance to produce an occlu-
sive thrombus under such conditions.
Our newfound understanding of the role of inflammation in
acute complications of atherosclerosis helps us to compre-
hend the mechanisms by which a variety of interventions can
reduce clinical events. Exercise reduces cardiovascular risk.
By increasing nitric oxide production, elevating HDL, and
augmenting insulin sensitivity, exercise may act in part by
reducing inflammation. Dietary modifications such as in-
creased consumption of unsaturated fatty acids may act as an
anti-inflammatory therapy by altering the pattern of prosta-
noids produced and/or by activating PPAR-␣. Dietary inter-
ventions may also limit postprandial hyperlipemia associated
with triglyceride-rich lipoprotein particles, a recently recog-
nized activator of inflammatory functions of endothelial
cells.74 Beyond the lifestyle measures of exercise and diet,
pharmacotherapy with statins, PPAR-␣ activators, and ACE
inhibitors may owe their clinical benefits in part to an
anti-inflammatory action. Despite these advances in our
understanding and intervention in regard to cardiovascular
risk, much remains to be done. Further inroads into reduction
of cardiovascular risk may well emerge as we begin to apply
our recently acquired knowledge of the role that inflamma-
tion plays in atherosclerosis and plaque stability. In all
likelihood, future basic research, including the application of
functional genomics, will teach us new lessons about athero-
sclerosis and its complications and show the path to further
ways to limit this disease.
Acknowledgment
Supported in part by grants from the National Heart, Lung, and
Blood Institute (HL-34636 and HL-56985).
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KEY WORDS: angiotensin 䡲 myocardial infarction 䡲 atherosclerosis
䡲 inflammation 䡲 metalloproteinases 䡲 thrombosis