Role of Lipids

in Plaque Development
Injury or infection can disrupt normal
endothelial function and initiate forma-
Pathophysiology of Coronary Heart tion of atherosclerotic lesions known as
Disease: A Brief Review fatty streaks. Fatty streaks typically con-
sist of macrophages and T cells em-
Robert J. Chilton, DO bedded in a thin layer of lipids on the
arterial wall.2-5 Macrophages engulf
lipids, becoming activated foam cells that
release an array of chemoattractant
molecules, cytokines, and growth fac-
tors. More lymphocytes are attracted to
the lesion and, in turn, add to the pool of
effector molecules that expand and per-
petuate the inflammatory response. As
Coronary heart disease (CHD) remains a persistent public health burden in the
this cycle is repeated, the plaque develops
United States, and it is the cause of one of every five deaths each year. The link
a fatty core covered by a fibrous matrix
between lipids and CHD has been firmly established, first by epidemiologic
that stabilizes the structure.3
studies and, more recently, by long-term outcomes trials that demonstrated that
The frequent presence of fatty
lowering low-density lipoprotein cholesterol (LDL-C) levels significantly
streaks in young children is consistent
reduced the risk of major coronary events. Based on this evidence, the National
with the chronic nature of atherosclerotic
Cholesterol Education Program recommends lowering the LDL-C level to
progression. Although the possible
reduce CHD risk, particularly for patients at highest risk. Recently, evidence
events that can initiate fatty streak for-
has emerged that suggests that C-reactive protein may be a mediator of
mation remain controversial, LDL-C,
atherosclerosis and its presence may be indicative of increased risk of CHD.
modified by oxidation, glycation, and
Although these data are intriguing, their relevance has yet to be established in
association with proteoglycans and
prospective outcomes trials. Until then, lipid lowering through lifestyle mod-
immune complexes, can become trapped
ification and the use of safe and effective modes of therapy should be the
in the arterial wall, injuring the endothe-
emphasis of CHD risk reduction strategies.
lium and vascular smooth muscle.6-10
Once trapped, LDL-C particles become
progressively more oxidized, form lipid
plasma cholesterol levels have long been
E merging evidence strongly suggests
that coronary heart disease (CHD),
once considered the result of vessel-
established as risk factors for CHD, and
lowering cholesterol levels, particularly
peroxides, and facilitate accumulation of
cholesterol esters.3 Also, modified LDL-
C is chemotactic for circulating mono-
occluding deposition of lipids, is a man- low-density lipoprotein cholesterol cytes and stimulates the proliferation of
ifestation of a chronic inflammatory (LDL-C), has been the focus of the pre- macrophages already in the lesion.3
response to injury or infection. Elevated vention of CHD and its sequelae for Inflammatory mediators increase the
almost 25 years. However, the complex binding of LDL-C to endothelial cells
mechanisms by which these molecules and vascular smooth muscle cells that
Address correspondence to Robert J. Chilton, DO,
FACC, FACOI, Associate Professor, Department of act are only beginning to be appreci- have migrated into the lesion.11 As the
Medicine, Division of Cardiology, The University of ated. Evidence suggests that lipid-low- plaque becomes thicker, the arterial wall
Texas Health Science Center at San Antonio, 7703 ering modes of therapy also reduce responds by “remodeling,” that is, grad-
Floyd Curl Dr, San Antonio, TX 78284-6200.
Dr Chilton has received research support from inflammation, which may reduce the ually dilating to maintain the diameter of
the National Heart, Lung,and Blood Institute; risk of cardiovascular events, even for the vessel lumen. Eventually,
Pfizer Inc; Takada Pharmaceuticals America, Inc; individuals with LDL-C levels in the macrophages may be stimulated to
Johnson & Johnson; Boston Scientific; Aventis
Pharmaceuticals Inc; Bristol-Myers Squibb Com- normal range (
130 mg/dL) based on release metalloproteinases that degrade
pany; and Merck Sharpe & Dohme Research Lab- the National Cholesterol Education Pro- the fibrous cap and render the plaque
oratories. gram (NCEP) Adult Treatment Panel vulnerable to rupture.12,13
E-mail: chilton@uthscsa.edu
III (ATP III) guidelines.1 This article Although several types of plaque
reviews the role of lipids in plaque can result in serious coronary events, ret-
development, the data supporting rospective analyses have demonstrated
Supported by an unrestricted educational atherosclerosis as an inflammatory dis- that 70% of all fatal acute myocardial
grant from Merck/ ease, and the impact of these data on infarctions and sudden coronary deaths
Schering–Plough Pharmaceuticals clinical practice. are attributable to plaque rupture14 or

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 Figure 1. Underlying pathologic processes
of coronary lesions determined to be respon-
sible for coronary occlusion and death.
(Source: Naghavi M, et al. Circulation.
2003;108:1664-1672.)

plaque erosion15 (Figure 1). This obser-

vation is not surprising because plaque
destabilization is often accompanied by
release of prothrombotic factors.3 How-
ever, a recently developed consensus
document emphasizes that all types of
atherosclerotic plaques can result in coro-
nary events and sudden death.14 Vul-
nerable plaques are defined as throm-
bosis-prone or at risk of rapid progression
and exhibit some combination of the fol- levels of CRP and cardiovascular risk infarction or died of CHD during the
lowing: active inflammation, thinning has been the object of extensive research study and from up to 3969 control sub-
cap with a large lipid core, endothelial and is the topic of much current debate. jects without CHD. Results of the study
denudation with superficial platelet Some evidence suggests that CRP is an suggested that CRP was not as strong a
aggregation, fissures, or greater than 90% independent predictor of risk of cardio- predictor for CHD as more traditional
stenosis. The authors further conclude vascular events. In a study that followed risk factors such as total cholesterol level
that the thrombotic status of the blood nearly 28,000 apparently healthy women or cigarette smoking. Therefore, the
and the electrical instability of the for 8 years, Ridker and colleagues19 found authors concluded that recommenda-
myocardium are important to the ulti- that the CRP level was a stronger pre- tions regarding the use of the CRP level
mate outcome for the patient.16 dictor than the LDL-C level for myocar- in predicting the likelihood of CHD may
Although some of these criteria can dial infarction, ischemic stroke, coronary need to be reviewed.20
be visualized with noninvasive proce- revasculature, or death due to cardio- Newer information reveals that CRP
dures such as magnetic resonance vascular causes. However, because CRP is a modulator of inflammation and may
imaging or computer-enhanced tomog- and LDL-C levels appeared to identify have both proinflammatory and anti-
raphy, none is easily used for routine somewhat different risk groups, the com- inflammatory actions, which may
screening purposes. Thus, the ATP III bined risk assessment was superior to directly contribute to endothelial dys-
risk factor assessment based on a 10-year that of either marker alone.19 function by inducing cytokine release
cardiovascular risk remains the best tool In this same study, multivariate and surface expression of adhesion
to identify patients at high risk.1 analysis indicated that increasing CRP molecules. Through a conformational
levels were associated with increased rearrangement in CRP from a pentameric
Inflammation and Atherosclerosis risk of cardiovascular events at all levels to a monomeric structure, the athero-
An accumulating body of evidence sug- of estimated risk based on the Fram- genic effects of CRP are noted on human
gests that atherosclerotic progression ingham risk score and NCEP ATP III risk endothelial cells. C-reactive protein now
results from microinflammation medi- categories.19 Although the women in this appears to be more than a marker of car-
ated by proinflammatory cytokines. The study who had high CRP and low LDL- diovascular events.18
observation that monocytes and T lym- C levels were at higher absolute risk than
phocytes are present at all stages of those with low CRP and high LDL-C The Emerging Concept of the
plaque development is consistent with levels, only the latter group would be Vulnerable Patient
active inflammation. Chronic low-level considered eligible for aggressive Vulnerable plaques are not the only cul-
inflammation increases atherosclerotic therapy.19 prit factors for the development of acute
plaque deposition in animal models. In Danesh et al20 recently reported data coronary syndromes, myocardial infarc-
addition, heightened levels of the acute- from a study of circulating inflamma- tion, and sudden cardiac death. Vulner-
phase reactant C-reactive protein (CRP) tory markers that evaluated the relevance able blood (prone to thrombosis) and
is believed to be a marker of inflamma- of CRP to the prediction of CHD. These vulnerable myocardium (prone to fatal
tory processes and may also be of value investigators prospectively observed arrhythmia) play an important role in
in the prediction of coronary events.3,16,17 18,569 individuals enrolled in the Reyk- the outcome. Therefore, the term vulner-
A recently published report suggests that javik Heart Study and measured inflam- able patient may be more appropriate and
CRP is more than a marker and may be matory markers in blood samples is proposed now for the identification of
a mediator of atherosclerosis.18 obtained at baseline from up to 2459 subjects with high likelihood of having
The association between elevated patients who had a nonfatal myocardial cardiac events develop in the near future

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 Markers and Modulators

White blood cell adhesion

CD40 ligand
Plaque Biology
C-reactive protein Systemic Biology

Interleukin

Tumor necrosis factor
 Inflammation
 Inflammation
 Blood rheology
 Matrix matters

Matrix Metalloproteinases  Coagulation
 Intraplaque
— Hemorrhage
Tissue inhibitors of matrix
metalloproteinases  Infection
— Angiogenesis

Cathepsins

Transforming growth factor–  Multiple complex
 Endothelial cells
plaques

Platelets

Tissue factor

Tissue factor pathway inhibitor

Tissue plasminogen activator
Figure 2. Factors contributing to the “vul-
Plasmnogen activator inhibitor–1
nerable patient.”
Fibrinogen

von Willebrand factor

(Figure 2). A quantitative method for Prevention and Treatment erator–activated receptor  and increase
cumulative risk assessment of vulner- of Cardiovascular Disease HDL-C.32
able patients needs to be developed that Clinical data have clearly established the In the Reversing Atherosclerosis
may include variables based on plaque, efficacy of lipid-lowering modes of with Aggressive Lipid Lowering
blood, and myocardial vulnerability. therapy in reducing cardiovascular risk. (REVERSAL) trial,30 patients receiving
According to Naghavi et al, 16 First-line lipid-lowering therapy for most aggressive statin therapy had a seven-
markers suggesting the presence of vul- individuals is the initiation of therapeutic fold greater reduction in CRP compared
nerable blood include increased levels lifestyle changes (TLC). Components of with patients receiving the more mod-
of CRP and circulating interleukin-6 TLC that have been shown to be effective erate regimen. In the Pravastatin or
levels, which are elevated in patients in lowering LDL-C levels include dietary Atorvastatin Evaluation and Infection
with acute coronary syndromes. Inves- changes, commencement of regular Therapy (PROVE-IT) trial,33 patients had
tigators have also shown that high physical activity, smoking cessation, and fourfold higher baseline CRP levels than
plasma concentrations of soluble CD40 weight loss.1 Although a number of phar- those in REVERSAL (12.3 mg/L vs 2.9
ligand may indicate an increased vas- macologic agents are available to modify mg/L). However, CRP levels still
cular risk in apparently healthy lipid levels, data from multiple prospec- decreased by more than 80% during the
women. 21 Likewise, Hwang et al 22 tive outcomes trials have demonstrated 18 to 30 months of follow-up. In the acute
reported that circulating levels of sol- that 3-hydroxy-3-methylglutaryl coen- setting, however, the decrease was not
uble intracellular adhesion molecule zyme A reductase inhibitors (statins) are significantly different between treatment
were predictive of future acute coronary the most effective agents to reduce risk of groups. The cholesterol absorption
events. Markers of systemic inflamma- CHD.26-29 An in-depth discussion of these inhibitor ezetimibe, coadministered with
tion, such as soluble adhesion molecules, agents is provided elsewhere in this sup- a statin significantly reduced markers of
circulating bacterial endotoxin, soluble plement. cardiovascular risk, including CRP.31,34,35
human heat-shock protein 60, and anti- Although the primary mechanism This result suggests that statins with or
bodies to mycobacterial heat-shock pro- by which statins reduce CHD risk is via without cholesterol absorption inhibitors
tein 65, may predict an increased risk of LDL-C reduction, the anti-inflammatory demonstrate enhanced anti-inflamma-
atherosclerosis.23 Pregnancy-associated activity associated with statins may tory effects.
plasma protein A is present in unstable explain some of their efficacy, particu-
plaques, and its circulating levels are larly in patients who do not have ele- Comment
elevated in patients with acute coronary vated cholesterol levels. The anti-inflam- Lipids, particularly cholesterol, play a
syndromes.24 Increased serum levels of matory effect of statins has been fundamental role in the development of
pregnancy-associated plasma protein A demonstrated in a number of recent CHD. A substantial volume of evidence
may reflect instability of atherosclerotic trials.30,31 Statins have been noted to indicates that reducing cholesterol levels
plaques.25 induce activation of peroxisome prolif- reduces the risk of CHD in both primary

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Territo MC, Lusis AJ, et al. The yin and yang of oxi-
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