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J Am Coll Cardiol. 2009 December 1; 54(23): 2129–2138. doi:10.1016/j.jacc.2009.09.009.

Inflammation in Atherosclerosis: From Pathophysiology to

Practice

Peter Libby, MD1, Paul M Ridker, MD, MPH1,2, and Göran K. Hansson, MD, PhD3
1Division of Cardiovascular Medicine, Department of Medicine, Brigham and Women's Hospital,

Harvard Medical School, Boston, MA

2Division
of Cardiovascular Medicine, Division of Preventive Medicine, Department of Medicine,
Brigham and Women's Hospital, Harvard Medical School, Boston, MA
3Center for Molecular Medicine, Department of Medicine, Karolinska University Hospital, Karolinska

Institutet, Stockholm, Sweden

Abstract
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Just three decades ago the prevailing viewpoint envisaged atherosclerosis as a bland proliferative
process. (1) According to that concept, endothelial denuding injury led to platelet aggregation and
release of platelet-derived growth factor which would trigger the proliferation of smooth muscle cells
in the arterial intima, and form the nidus of the atherosclerotic plaque. This cellular model of
atherosclerosis updated Virchow's concepts of atherosclerosis as a response to injury formulated in
the mid-nineteenth century. The advent of the cell biological era of atherosclerosis supplanted the
simplistic concept of the atheroma as a passive deposition of lipid debris on the artery wall. Beyond
the vascular smooth muscle cells long recognized in atherosclerotic lesions, subsequent work
identified immune cells and mediators at work in atheromata, implicating inflammatory mechanisms
in disease development. (2) The advent of gene-targeting technology enabled the testing of the roles
of specific molecules in the development of experimental atherosclerosis in mice. Such data
demonstrated a critical role for hypercholesterolemia and also supported the participation of immune
mechanisms in the pathogenesis of atherosclerosis. (3)
Multiple independent pathways of evidence now pinpoint inflammation as a key regulatory process
that links multiple risk factors for atherosclerosis and its complications with altered arterial biology.
This revolution in our thinking about the pathophysiology of atherosclerosis has begun to provide
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clinical insight and practical tools that may aid patient management. This review provides an update

Corresponding Author: Peter Libby, Division of Cardiovascular Medicine, Department of Medicine, Brigham and Women's Hospital,
Harvard Medical School, 77 Avenue Louis Pasteur, Boston, MA 02115; Phone: (617) 525-4383; Fax: (617) 525-4999;
plibby@rics.bwh.harvard.edu.
From the Leducq Transatlantic Network on Atherothrombosis
Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers
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Dr. Libby is an unpaid consultant to AstraZeneca. Dr. Ridker reports having received research funding support from multiple not-for-
profit entities including the National Heart, Lung, and Blood Institute, the National Cancer Institute, the American Heart Association,
the Doris Duke Charitable Foundation, the Leducq Foundation, the Donald W. Reynolds Foundation, and the James and Polly Annenberg
La Vea Charitable Trusts. Dr. Ridker also reports having received investigatore-initiated research support from multiple for-profit entities
including AstraZeneca, Novartis, Pharmacia, Roche, Sanofi-Aventis, and Abbott, as well as non-financial research support from Amgen.
Dr. Ridker is listed as a co-inventor on patents held by the Brigham and Women's Hospital that relate to the use of inflammatory biomarkers
in cardiovascular disease that have been licensed to Siemens and AstraZeneca, and has served as a research consultant to Schering-
Plough, Sanofi-Aventis, AstraZeneca, Isis, Dade, Merck, Novartis, and Vascular Biogenics. Dr. Hansson has no disclosures to report.
 Libby et al. Page 2

of the role of inflammation in atherogenesis and highlights how translation of these advances in basic
science promises to change clinical practice.
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Keywords
Atherosclerosis; Inflammation; Heart Disease

Innate and Adaptive Immunity: Twin Arms of the Immune Response Involved
in Atherosclerosis
Through evolution, the inflammatory response has grown in complexity and has provided host
defenses against infection and injury. Moreover, inflammatory mechanisms also participate in
the repair of injured tissues. The primitive arm of inflammation, known as innate immunity,
echoes in mammals pathways extant in early eukaryotes. (4) Primitive phagocytic cells,
evolutionary precursors of the mammalian monocyte/macrophage (Figure 1), exist in marine
invertebrates as recognized by Metchnikoff in the 19th century. (5) The innate immune response
mounts rapidly and combats perceived foreign invaders, often with preformed mediators.
“Natural antibodies”, certain complement proteins, and families of cell surface receptors
recognize microbial products that can elicit an immediate response without requiring
“education” of the immune system. The receptors involved in these primordial host defense
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responses include several families of macrophage scavenger receptors, also implicated in

uptake of modified lipoproteins, and a family of Toll-like receptors (TLR) (Figure 2). The
TLRs, named after Drosophila genes, belong to the family of pattern recognition receptors that
recognize microbial structures and products. These receptors trigger a complex intracellular
signaling cascade that stimulates the production of pro-inflammatory cytokines and other
inflammatory mediators. The innate immune response, characterized as “fast and blunt”,
recognizes a limited diversity of structures on the order of hundreds.

The adaptive immune response has arisen more recently in evolution (Figure 3). This arm of
host defenses, in contrast to the innate immune response, requires “education” of the immune
system. Common clinical experience illustrates the lag time in developing an adaptive immune
response. For example, an antibody response, or a cellular immune response requires weeks
to months following vaccination with an antigen. Also in contrast with the innate immune
response, the adaptive arm displays exquisite specificity. Instead of recognizing mere hundreds
of molecular patterns, the repertoire of antibodies and T cell receptors can recognize many
millions of specific structures.

The inflammatory response in atherosclerosis involves elements of both the innate and adaptive
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limbs of immunity.

Innate immunity in atherosclerosis

Considerable evidence supports the early involvement of the monocyte/macrophage, the most
prominent cellular component of the innate immune response, during atherogenesis.
Observations in human arterial specimens and many experimental models of atherosclerosis
have identified monocyte recruitment as an early event in atherogenesis. The recruitment of
mononuclear phagocytes involves attachment to activated endothelial cells by leukocyte
adhesion molecules. Several protein mediators, specialized cytokines known as chemokines,
direct cell migration of monocytes into the intima. Maturation of monocytes into macrophages,
their multiplication, and production of many mediators ensues. Previous reviews recount the
details of these now well-understood molecular mechanisms that we will not repeat here. (6,
7)

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Since last reviewed, several new findings regarding monocyte recruitment to atherosclerosis
have come to light. First, examination of the kinetics of monocyte recruitment to mouse
atherosclerotic lesions suggests that monocyte entry occurs not just during the initial stages of
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lesion formation, but continues even in established lesions. (8) This observation has
implications for targeting monocyte recruitment for atherosclerosis treatment.

Another recent recognition revolves around monocyte heterogeneity in atherosclerosis. (9)

Evidence from mouse experiments and in humans suggests a disease-relevant dimorphism of
monocytes. (10,11) (12) Hyperlipidemia elicits a profound enrichment of a pro-inflammatory
subset of monocytes in the mouse. These pro-inflammatory monocytes, recognized by high
levels of a marker known as Ly-6c, or Gr-1, may correspond to a human monocyte subset
marked by the presence of P-selectin glycoprotein ligand (PSGL). (13) These pro-
inflammatory monocytes home to atherosclerotic lesions, where they propagate the innate
immune response by expressing high levels of pro-inflammatory cytokines and other
macrophage mediators including matrix metalloproteinases (Figure 1, left).

Recent evidence has also highlighted the potential participation of mast cells in atherosclerosis.
Long identified as a minority leukocyte population in the arterial adventitia and atherosclerotic
intima, mast cells exhibit numerous functions implicated in atherogenesis. (14) (15) For
example, mast cells release vasoactive small molecules such as histamine and leukotrienes, as
well as serine proteinases and heparin, a co-factor in growth factor action and angiogenesis.
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Recent pharmacologic and genetic studies have provided firm evidence for mast cell
participation in atherogenesis in mice. (16) (17) As established pharmacologic agents can
modulate mast cell functions in humans, these recent observations also have therapeutic
implications. The extension of these mouse experiments to the human situation requires further
research.

Many links exist between lipoproteins and innate immunity. Modified lipoproteins interact
with scavenger receptors (Figure 2), and may thus send proinflammatory signals. Oxidized
phospholipids derived from modified lipoproteins may also drive inflammation. A lipoprotein-
associated phospholipase (LP-PLA2) currently targeted in clinical trials may generate pro-
inflammatory derivatives of oxidatively modified lipoproteins. (18) Recent data show that
apolipoprotein CIII, a constituent of certain triglyceride-rich lipoproteins associated with poor
clinical outcomes, incite inflammation by binding to TLR2 (Figure 2). (19)

Another area of recent advance in relation to innate immunity in atherosclerosis regards the
links between thrombosis and inflammation. Previously considered independent pathways in
host defense, current evidence supports considerable crosstalk. (20) For example,
prostaglandins produced through the cyclooxygenase pathway control inflammation as well
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as thrombosis. Therefore, anti-inflammatory cyclooxygenase-2 inhibitors may heighten

thrombotic risk. A major protein mediator of coagulation, thrombin, can elicit the expression
of pro-inflammatory cytokines from vascular endothelial and smooth muscle cells. Platelets,
when activated, can secrete preformed pro-inflammatory cytokines and exteriorize and shed a
multipotent pro-inflammatory stimulus, CD40-ligand (CD154). Platelets can also release a pro-
inflammatory mediator known as myeloid-related protein 8/14 (MRP-8/14). (21) This
heterodimeric molecule serves as a biomarker for adverse cardiovascular events in both
apparently well populations, and in survivors of acute coronary syndromes. (22) Current
investigations are expanding our knowledge of the inflammatory actions of MRP-8/14. For
example MRP-8/14 can bind TLR-4, activating innate immunity through this pattern
recognition receptor.(23)(Figure 2) This ligand can also promote endothelial cell apoptosis, a
process implicated in plaque thrombosis. (24) These recent observations tighten the link
between inflammation and thrombosis, suggesting an intimate interlacing of these two
convergent pathways in atherosclerosis.

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Adaptive immunity in atherosclerosis

Accumulating evidence supports a key regulatory role for adaptive immunity in atherosclerosis
and its complications. The subject of several recent reviews, this section will highlight recent
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advances in this area.(3) (25) (26) Interacting with a special subset of mononuclear phagocytes
specialized in antigen presentation known as dendritic cells (Figure 1), T lymphocytes
encounter antigens and mount a cellular immune response (Figure 3). The dendritic cells
populate atherosclerotic plaques and regional draining lymph nodes where they can present
antigens to T cells with co-stimulatory molecules that incite this key afferent limb of adaptive
immunity. Putative antigens that stimulate T cells in the context of atherosclerosis include
certain heat shock proteins, components of plasma lipoproteins, and potentially microbial
structures as well. The clone of T cells that recognizes antigen in this context will proliferate
to amplify the immune response. Upon renewed exposure to the specific antigen, these T cells
produce cytokines, trigger inflammation, and some T cells have mechanisms specialized for
killing cells. (Figure 3) This amplification accounts for the delay in the typical adaptive immune
response that is slower and much more structurally specific than the “fast and blunt” innate
immune response described above.

Various functionally distinct classes of T cells exist. Helper T cells spearhead antigen
recognition, and fall into two major functional subtypes known as Th1 and Th2 (Figure 3, left).
Th1 responses generally amplify pro-inflammatory pathways by secretion of cytokines such
as interferon-gamma. The Th1 response appears to aggravate atherosclerosis. A more recently
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recognized T cell subset, Th17 cells, may also exert particularly pro-inflammatory actions. Th2
cells elaborate cytokines that may modulate inflammation such as interleukin-4 that can
promote humoral immunity (see below). Whereas the role of Th2 in atherosclerosis is
controversial,(27-30) some, but not all, evidence suggests that Th2-slanted responses may drive
aneurysm formation. (31,32) (33) Humans may have less accentuated polarization of Th1 vs.
Th2 cells than inbred mice.

Another T cell subtype, known as regulatory T cells or Treg for short, appears to pay an
intriguing modulatory role in atherosclerosis. Treg can dampen inflammatory responses.
Genetic manipulations that interfere with Treg functions mediated by transforming growth
factor beta (TGF-β) augment atherogenesis in mice, yield lesions with signs of heightened
inflammation, and even trigger thrombosis. (34,35) Thus, Treg cells and Th2 vs. Th1 and Th17
cells can counterbalance the pro-atherogenic effects of Th1 cells indicating the yin and yang
complexity of cellular immunity.

The types of T cells just described express the surface marker CD4 and recognize antigen
presented by dendritic cells and macrophages.(Figure 3) One third of all T cells in human
lesions are of a different type that carries the CD8 marker and recognizes antigens bound to
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HLA molecules on many different cell types, typically viral antigens on infected cells. (Figure
3) When activated, CD8 T cells kill neighbor cells via cell/cell contact. Several mediators
produced in lesions can recruit CD8 T cells capable of killing smooth muscle cells and
macrophages, processes linked to lesion growth and complication. (36)

All these T cells share the capacity to recognize protein antigens bound to HLA molecules on
cell surfaces. The NKT cell, in contrast, reacts towards lipid antigens presented by CD1
molecules on antigen-presenting cells. Once activated, the NKT cell produces proinflammatory
cytokines that promotes atherosclerosis. (37)

Humoral immunity in atherosclerosis

B lymphocytes secrete antibodies that like T cells, can recognize many millions if not billions
of diverse structures. Convergent lines of experimental evidence suggest that humoral

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 Libby et al. Page 5

immunity can attenuate rather than promote atherogenesis. For example, splenectomy, ablating
an important B cell compartment, aggravates atherosclerosis. (38) Hypercholesterolemic mice
develop a strong humoral response directed against epitopes characteristic of oxidatively
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modified low-density lipoprotein (LDL). (39,40) Immunization of rabbits or mice with

oxidized LDL attenuates atherosclerosis. Interestingly, the antibodies elicited in mice in
response to oxidized LDL also recognize a pneumococcal antigen. (41) This finding
underscores the view that host defenses against infectious agents can overlap with
inflammatory pathways involved in atherogenesis. The observation that humoral immunity
against oxidized LDL might protect against atherosclerosis has inspired therapeutic
explorations of vaccination against oxidized LDL to mitigate this disease.

Clinical Translation of Inflammation Biology: The Role of Biomarkers

Following on the ferment in the basic science laboratory regarding inflammation in
atherosclerosis, we have now entered an era of clinical translation of inflammation biology to
the clinic. The description of inflammatory pathways above identified several new potential
therapeutic avenues. Many existing systemic anti-inflammatory strategies such as
glucocorticoids, non-steroidal anti-inflammatory drugs, or anti-cytokine agents exert unwanted
actions that render them less than ideal candidates for evaluation as long-term therapeutics for
modulation of atherosclerosis. Of many promising more specific anti-inflammatory agents in
development for atherosclerosis, none appear sufficiently validated for clinical use at present.
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In contrast, the use of inflammatory biomarkers to predict risk, to monitor treatments, and to
guide therapy has shown substantial potential for clinical applicability.

Biomarkers of inflammation in risk prediction

The contemporary literature now contains numerous reports of the relationship between various
biomarkers of inflammation and prospective cardiovascular risk, in apparently well individuals
as well as in patients with coronary heart disease or heart failure. The clinical utility of a
biomarker for risk prediction depends on practicability, ease, cost, and reproducibility of the
measurement, and the ability to add to the predictability of existing biomarkers such as those
incorporated in the Framingham algorithm. Many reviews have highlighted this fast moving
field. (42) Among the many biomarkers of inflammation proposed for diagnostic use,
myeloperoxidase, lipoprotein-associated phospholipase A2 (Lp-PLA2), pentraxin-3, cytokines
such as IL-6, proteases such as matrix metalloproteinase 9, and C-reactive protein (CRP)
measured by a highly sensitive assay (hs-CRP) have generated considerable attention. For a
variety of reasons, CRP has emerged as a leading biomarker of inflammation for clinical
application. In well individuals without acute infections or inflammatory diseases (e.g.,
rheumatoid arthritis), levels of hsCRP remain stable over long periods of time with a year-to-
year and decade-to-decade variability comparable to that of cholesterol (43) (44) CRP has
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considerable chemical stability, requires no special precautions for sampling, and has a
relatively long half-life without the diurnal variation that plagues certain other biomarkers.

More than a dozen large-scale prospective cohort studies indicate that hsCRP predicts incident
myocardial infarction, stroke, and cardiovascular death even after full adjustment for the
traditional Framingham covariates (45). Unbiased computational approaches have identified
hsCRP as a marker that, along with parental history, sharpens the predictive ability of the
traditional Framingham algorithm in women and in men. (46,47) As demonstrated in the
Reynolds Risk Scores (www.reynoldsriskscore.org), consideration of hsCRP along with
parental history can correctly reclassify many individuals categorized as having intermediate
risk according to the traditional Framingham criteria, a risk stratum that accounts for the
majority of cardiovascular events. hsCRP may thus serve as a useful adjunct to the Framingham
index as a tool to identify individuals at heightened risk for cardiovascular events.

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hsCRP as a potential therapeutic goal

Practitioners routinely follow certain biomarkers as a way of monitoring the dosing of
cardiovascular therapeutics. We measure LDLC serially when prescribing lipid-lowering
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agents, blood pressure in anti-hypertensive therapy, and heart rate when titrating beta-
adrenergic blocking agents. Given the body of evidence implicating inflammation in
atherosclerosis, could an inflammatory biomarker such as hsCRP be used to monitor therapy
in a way that would improve clinical effectiveness? A pre-specified analysis of the PROVE-
IT (TIMI-22) study, previously discussed in these pages, suggested dual mechanisms of benefit
of statin therapy, LDL-lowering, and a direct anti-inflammatory effect independent of LDL-
lowering, reflected by reduction of hsCRP. (48) (49) Specifically, within the PROVE IT
TIMI-22 trial, clinical outcomes were best among statin-treated participants who not only
achieved LDLC levels below 70 mg/dL, but who also achieved hsCRP levels below 2 mg/L.
(50) A post hoc analysis of the A to Z trial affirmed this “dual target” concept in survivors of
acute coronary syndromes by showing greater benefit following statin initiation among those
who achieved lower levels of both LDLC and hsCRP.(51) While these two data sets support
the concept of monitoring hsCRP to gauge the intensity of statin therapy, this concept has not
undergone prospective testing in outcomes trials, and existing guidelines do not currently
recommend this practice.

Targeting therapy using hsCRP

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Can the application of biomarkers of inflammation identify individuals that don't meet
established treatment criteria who might nonetheless benefit from therapeutic intervention? A
post-hoc analysis of the AFCAPS/TexCAPS proved hypothesis-generating in this regard.
(52) Stratification of this population of individuals with no established cardiovascular disease
into four cells defined by above and below median LDLC, and above and below median hsCRP
showed that both groups with high LDLC benefited from therapy as indicated by a number
needed to treat below 60. Individuals with LDLC and hs-CRP below median did not benefit
from therapy, yielding a number needed to treat of approximately 1,000 to prevent 1
cardiovascular event. The provocative cell in this analysis, the 25% of the individuals in this
cohort with below median LDLC but above median hsCRP, yielded clinical benefit
indistinguishable from the two high LDL groups. This observation suggested that well
individuals with average levels of LDLC, currently below treatment thresholds, might
nonetheless benefit from statin therapy if they had concomitant elevations of hsCRP.

The recently reported JUPITER trial tested this hypothesis prospectively. JUPITER enrolled
17,802 individuals without manifest cardiovascular disease, with LDLC levels below 130 mg/
dL, but with hsCRP levels greater than 2 mg/dL; all study participants were randomly allocated
to rosuvastatin 20 mg daily or to placebo and were then followed for incident vascular events.
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On the advice of its Independent Data Monitoring Board, JUPITER was stopped early due to
a 44 percent reduction in the trial primary endpoint of all vascular events (P<0.00001), a 54
percent reduction in myocardial infarction (P=0.0002), a 48 percent reduction in stroke
(P=0.002), a 46 percent reduction in the need for arterial revascularization (P<0.0001), and a
20 percent reduction in all-cause mortality (Figure 4). All pre-specified subgroups within the
trial significantly benefitted from rosuvastatin including those traditionally considered to be at
low risk such as those with Framingham Risk Scores less than 10 percent, those without
metabolic syndrome, women, and those with elevated levels of hsCRP but no other major ATP-
III risk factor (figure 5).

The treated group in JUPITER enjoyed substantive reductions in both absolute and relative
risk. Despite excluding all individuals with hyperlipidemia (LDL>130, actual median LDL at
entry was 108 mg/dL), the placebo event rate in JUPITER exceeded that of AFCAPS/
TexCAPS, indicating that those with a heightened inflammatory burden disclosed by elevated

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 Libby et al. Page 7

hsCRP have high vascular risk even when cholesterol levels lie within a range considered
acceptable by current guidelines. With regard to cost-effectiveness, the commonly accepted
metric of Number Needed to Treat at 5 years (5-yr NNT) is 25 in JUPITER for the primary
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study endpoint and 32 for the “hard endpoint” of myocardial infarction, stroke, or death. These
NNT values compare favorably to the 5-yr NNT values of 50 that have been reported in prior
primary prevention trials of statin therapy in the setting of overt hyperlipidmia. They also
compare very favorably to the treatment of hypertension (5-yr NNT 80 to 160) or to aspirin
prophylaxis (5-year NNT 250-300). Prespecified analyses within the JUPITER database affirm
that maximum treatment benefit occurs with reduction of both LDLC and hsCRP. (53) This
finding has clinical relevance since, in JUPITER, the median on-treatment LDLC was only 55
mg/dL (and 25 percent of the trial had LDLC less than 45 mg/dL), yet optimum benefits not
only when LDLC levels reached these very low targets, but when hsCRP levels also fell greatly.

The Future of Inflammation in Atherosclerosis

Targeting inflammation in atherosclerosis: Beyond statins
As described above a growing body of evidence supports the use of statins as an anti-
inflammatory intervention in atherosclerosis due to both LDL-lowering and direct anti-
inflammatory actions. Progress in understanding the basic biology of inflammation in
atherosclerosis has identified potential novel strategies for modulating inflammation in
atherosclerosis. No large-scale clinical trial has yet established that an anti-inflammatory
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intervention that does not alter lipid levels can improve cardiovascular outcomes. Although
certain established systemic anti-inflammatory therapies such as corticosteroids or non-
steroidal anti-inflammatory agents do not appear promising as anti-atherosclerotic
interventions, other agents warrant consideration in this regard. Clinical trials currently
underway are exploring the potential of inhibiting lipoprotein-associated phospholipase A2 as
an anti-inflammatory therapy, although the first hypothesis testing trial for this agent failed to
meet either of its pre-specified primary endpoints. (53,54) Various protein therapeutic
strategies such as anti-integrin or anti-cytokine therapies have received consideration for
therapeutic application. Therapeutic vaccination with lipoprotein peptides is also being
considered for clinical evaluation (55). All of these potential direct anti-inflammatory
modalities will require extensive clinical evaluation and direct testing in randomized trials
before adoption and practice.

Imaging of inflammation in atherosclerosis

Traditional cardiovascular imaging has focused on anatomy. Magnetic resonance and nuclear
imaging techniques can approach aspects of cardiac function such as perfusion and viability.
The identification of molecular mediators of inflammation that operate during atherogenesis
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has generated considerable interest in harnessing them as targets for imaging. Examples of
tempting targets in this regard include adhesion molecules such as vascular cell adhesion
molecule-1 (VCAM-1), monocyte/macrophage functions such as phagocytosis tracked with
microparticulate markers, glucose uptake as monitored by fluorodeoxyglucose, microvessels
identified by integrin-directed agents, modified LDL accumulating in lesions, and proteinases
implicated in vascular remodeling and plaque destabilization. (56-59) A growing experimental
literature has demonstrated the feasibility of many of these targeted imaging strategies. Few if
any of these modalities appear near ready for clinical application however. Even those currently
feasible in clinical practice, such as 18F-fluorodeoxyglucose imaging, will require considerable
clinical validation before adoption in clinical practice. (60,61)

Genetics of inflammation in atherosclerosis

Progress in genetics and genomics, and enormous technical strides in genotyping have
heightened interest in defining genetic biomarkers of cardiovascular risk that may open new

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perspectives in personalized medicine in the future. The computational analysis of various

biomarkers alluded to previously identified family history of cardiovascular disease in a parent
at age equal to or less than 60 (≤ 60) along with hs-CRP added to the traditional Framingham
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variables in predicting cardiovascular risk. (46,47) This observation suggests the importance
of genetic factors as contributors to cardiovascular risk prediction not completely captured by
the Framingham algorithm.

An initial wave of enthusiasm stimulated multiple studies of individual single nucleotide

polymorphisms (SNPs) or in a more sophisticated approach haplotypes.(62) The advent of
genome-wide association screens (GWAS) has proven quite fruitful. (63) (64) The concordant
identification of a region on chromosome 9 as associated with cardiovascular disease in several
independent large genetic studies has reinforced future potential of genetics in identifying risk
predictors and potential therapeutic targets. (63) Identification by GWAS of “sentinel”
members of pathways known to participate in atherosclerosis enhances confidence in the
validity of this approach, yet many questions remain unanswered. (65) The functional genomic
work required to unravel the biological pathways revealed by GWAS will require considerable
investigative effort in years to come. Inevitably, the pursuit of genetic factors identified by
GWAS will identify participants in inflammatory pathways that will broaden our understanding
and mastery of inflammation in atherosclerosis.

Conclusion
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Since our last reviews on these topics, evidence for the involvement of the immune and
inflammatory responses in atherogenesis has only intensified. This review has focused on
recent advances in this area. We stand on the threshold of an era when clinical inflammation
of inflammation biology will prove clinically useful and transformative of clinical practice.
This example of translational medicine indicates how clinical challenges have inspired
laboratory research that revolutionized our concepts of the pathogenesis of atherosclerosis over
the last two decades. The rapid clinical application of these advances in basic science to clinical
cardiovascular medicine promises to provide important new tools for diagnosis, monitoring,
and management of patients with or at risk for cardiovascular disease in the near future.

Acknowledgments
Funding: This work was supported by grants from the Fondation Leducq (P.L., G.H., P.R.), the Swedish Research
Council (G.H.), the Swedish Heart-Lung Foundation (G.H.), and the D.W. Reynolds Foundation (P.L., P.R.).

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Figure 1. Elements involved in innate immunity

This figure summarizes some of the functions ascribed to various cellular participants in
atherosclerosis that may participate in the disease and its complication when dysregulated.
Mononuclear phagocytes represent the bulwark of the innate immune defenses in mammals.
Monocytes give rise to macrophages, which in the arterial intima form foam cells, the hallmark
of the arterial fatty streak. Recent work has focused on heterogeneity of mononuclear
phagocytes. We now recognize a pro-inflammatory subset distinct from a less inflammatory
population of monocytes. The inflammatory subset expresses high levels of the cell-surface
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marker Ly6c (also known as GR-1) in the mouse. These inflammatory monocytes express
higher levels of Toll-like receptors (TLR), and the other functions indicated, including
elaboration of high levels of the cytokines tumor necrosis factor (TNF) and interleukin-1 (IL–
1). The less inflammatory subset of monocytes express higher levels of transforming growth
factor beta (TGF-beta), the scavenger receptors CD36 and scavenger receptor – A (SR-A), and
angiogenic mediators including vascular endothelial growth factor (VEGF). Dendritic cells
express human leukocyte antigen (HLA) molecules among the other indicated structures.
Dendritic cells present antigens to T cells, linking innate to adaptive immunity. Mast cells
elaborate many mediators as shown. Recent data support a causal role for mast cells in mouse
atherosclerosis. Platelets also participate in adaptive immunity. When activated, platelets
exteriorize CD40 ligand (CD40L or CD154) and release mediators including RANTES
(regulated and T cell expressed secreted), myeloid related protein – 8/14 (MRP-8/14), platelet-
derived growth factor (PDGF), and TGF-beta.

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Figure 2. Cells involved in atherosclerosis express pattern recognition receptors involved in innate
immunity
With the cooperation of CD14, TLR4 binds bacterial lipopolysaccharides (LPS) and a variety
of other potential instigators of inflammation and atherosclerosis including heat shock proteins
(hsp). TLR2 usually exists as a heterodimer with TLR1 or TLR6. TLR2 complexes can bind
microbial products as shown and, in addition, apolipoprotein CIII (Apo CIII). Scavenger
receptor A binds modified low-density lipoproteins (LDL). CD36 binds oxidatively modified
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LDL. The receptor for advanced glycation endproducts (RAGE) also decorates many cells
involved in atherosclerosis and may function in inflammatory signaling.

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Figure 3. Cells involved in adaptive immunity

The text describes the functional roles of the five classes of lymphocytes depicted in
atherosclerosis. B cells elaborate antibodies (Ab). A specialized subset of B cells (B1 cells)
elaborate primarily IgM antibodies, including natural antibodies that recognize constituents of
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oxidized LDL (oxLDL). The bottom panel of this figure portrays diagrammatically the effect
of the various cell types on lesions, based mostly on experiments in mice. Up arrows indicate
aggravation of lesion formation. Down arrows indicate reduction in lesion formation. IFN-γ
—interferon-gamma; TNF—tumor necrosis factor; IL-4— interleukin-4; TGF-β—
transforming growth factor beta; IL-10—interleukin-10; hsp60—heat shock protein 60. This
diagram summarizes the “net” effect attributed to the cell type on atherosclerosis primarily on
the basis of experiments in mice. In some cases, this figure necessarily oversimplifies the
complexity of the data. For example, not all TH2 cell functions and not all antibodies elaborated
by B cells may mitigate atherogenesis. (66,67)
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Figure 4. Cumulative incidence of cardiovascular events in the JUPITER trial, according to study
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group
Panel A shows the cumulative incidence of the primary endpoint (nonfatal myocardial
infarction, nonfatal stroke, arterial revascularization, hospitalization for unstable angina, or
confirmed death from a cardiovascular cause). Panel B shows the cumulative incidence of
nonfatal myocardial infarction, nonfatal stroke, or confirmed death from a cardiovascular
cause. Panel C shows cumulative incidence for arterial revascularization or hospitalization for
unstable angina. Panel D shows the cumulative incidence of death from any cause. [Adopted
from Ridker PM, Danielson E, Fonseca FAH, Genest J, Gottto AM, Kastelein JJP, Koenig W,
Libby P, Lorenzatti AJ, MacFadyen JG, Nordestgaard BG, Shepherd J, Willerson JT, Glynn
RJ for the JUPITER Study Group. Rosuvastatin to prevent vascular events in men and women
with elevated C-reactive protein. N Engl J Med 2008;359:2195-207.]

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Figure 5. Effects of rosuvastatin on the primary trial endpoint, according to baseline characteristics
of the JUPITER cohort
[Adopted from Ridker PM, Danielson E, Fonseca FAH, Genest J, Gottto AM, Kastelein JJP,
Koenig W, Libby P, Lorenzatti AJ, MacFadyen JG, Nordestgaard BG, Shepherd J, Willerson
JT, Glynn RJ for the JUPITER Study Group. Rosuvastatin to prevent vascular events in men
and women with elevated C-reactive protein. N Engl J Med 2008;359:2195-207.]

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Figure 6. Hazard ratios for incident cardiovascular events in the JUPITER trial according to
achieved concentrations of LDL cholesterol and high-sensitivity C-reactive protein (hsCRP) after
initiation of rosuvastatin therapy
Data were adjusted for age, baseline LDL and HDL cholesterol, baseline hsCRP, blood
pressure, gender, body mass index, smoking status, and parental history of premature coronary
heart disease. Event rates are per 100 person-years. [Adopted from Ridker PM, Danielson E,
Fonseca FAH, Genest J, Gotto AM, Kastelein JJP, Koenig W, Libby P, Lorenzatti AJ,
MacFadyen JG, Nordestgaard BG, Shepherd J, Willerson JT, Glynn RJ, on behalf of the
JUPITER Trial Study Group. Reduction in C-reactive protein and LDL cholesterol and
cardiovascular event rates after initiation of rosuvastatin: a prospective study of the JUPITER
trial. Lancet 2009;373:1175-1182.]
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