ATHEROSCLEROSIS

Affan
INTRODUCTION

Accumulation of large amounts of cholesterol ester in the arterial wall and formation of complex advanced plaque are
common to all these lesions. Although their formation insidiously spans decades, atherosclerotic lesions can reach a
clinical horizon within minutes and manifest as catastrophic myocardial infarction (MI), stroke, or limb ischemia.

Inflammatory changes within the fibrous cap may render them vulnerable to rupture or erosion and ulceration. An
understanding of each of these processes helps the vascular surgeon in developing evidence based treatment strategies
for each of the clinical syndromes of atherosclerosis, which together constitute a massive public health problem.

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INTRODUCTION

During the last two decades, CHD age-specific death rates fell by greater than 40% in high-income countries. The
prolonged survival has translated into growing disease prevalence and a staggering financial burden. It is estimated
that 80,700,000 Americans have CVD with an estimated annual cost of treatment of $448.5 billion. Globally, 202
million people have peripheral arterial disease (PAD), which disproportionately affects blacks and individuals living
in low to middle-income countries.

Particularly troubling is the high prevalence of cardiovascular risk factors in children and young adults. A sedentary
lifestyle, abdominal obesity, and poor diets contribute to dyslipidemia and high blood pressure. Autopsy studies in
children and young adults demonstrate a link between these risk factors and early lesions.

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ARTERY STRUCTURE

• endothelium
Intima • subendothelial space

• smooth muscle cells (SMCs)

Media

• vasa vasorum
Adventitia • connective tissue elements

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INTIMA

 The endothelium is an organ with autocrine, paracrine, and endocrine functions that serve to regulate blood vessel tone and

thrombogenicity.

 The endothelium synthesizes an array of factors that regulate vascular tone (e.g., nitric oxide [NO], hyperpolarizing factors,

prostaglandins, endothelin, angiotensin II) and interactions with blood elements (e.g., adhesion molecules, thrombomodulin,
plasminogen activators), which all work in balance to maintain vascular homeostasis.

 Endothelial dysfunction is regarded as the earliest manifestation of vessel injury and is present before histologic evidence of

atherosclerosis.

 The subendothelial space is particularly relevant in atherosclerosis because it is the location where atherogenic particles are retained

and modified so that they can be taken up by macrophages and SMCs

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MEDIA

 In children, very few SMCs or macrophages are present in the subendothelial space; however, with age and lesion

formation, their concentration increases.

 Human medial SMCs predominantly express proteins involved in the contractile function of the cell, those found

in the intima express lower levels of these proteins, have a higher proliferative index, and exhibit greater synthetic
capacity for extracellular matrix, proteases, and inflammatory cytokines.

 These “synthetic” SMCs migrate more readily and can produce up to 25 to 46 times more collagen than

“contractile” SMCs can. Thus SMCs directly contribute to intimal thickening as a result of increased proteoglycan
production, inflammatory cell recruitment, and retention of atherogenic particles within the subendothelial space.

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ADVENTITIA

 The vasa vasorum may contribute to atherosclerosis as well. First-order vasa vasorum run longitudinally to the

lumen of the host vessel, whereas second-order vasa vasorum are arranged circumferentially. As plaque volume
increases, there is an increase in the vasa vasorum visible on histologic section.

 Whether this is a response to plaque growth or contributes to plaque growth is unknown. Although the

development of vasa vasorum in plaque involves angiogenesis, it is unclear what signals this process.

 Atherosclerotic vasa vasorum can proliferate and thereby lead to extensive neovascularization directed toward
lipid-rich atheroma. The neovessels of plaque may provide an additional portal for trafficking leukocytes to
promote the inflammatory process or become friable and contribute to intraplaque hemorrhage.

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ATHEROSCLEROTIC LESIONS

 Autopsy studies from the Bogalusa Heart Study and the Pathobiological Determinants of Atherosclerosis in Youth
study demonstrate that atherosclerotic lesions form in early childhood and increase with age and that a significant
percentage of them are raised.
 In an intravascular ultra- sound (IVUS) study of heart donors, 17% of individuals younger than 20 years had
evidence of atherosclerosis. Notably, both the Bogalusa Heart Study and the Pathobiological Determinants of
Atherosclerosis in Youth study emphasize that the number and severity of early lesions are directly related to
known cardiovascular risk factors, thus suggesting that a paradigm shift is needed to address risk factors in
childhood rather than pharmacologic therapy later in the disease process.
 Diffuse intimal thickening has been identified in the atherosclerotic-prone areas of coronary arteries as early as 36
weeks of gestation.

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 Although the fatty streak dominated by lipid-filled macrophagesis itself benign, it is the precursor of the more
clinically relevant late lesion. The fatty streak is the first lesion visible to the naked eye. Its yellow color is
attributed to lipid in the form of cholesterol and cholesterol esters within macrophages and SMCs.
 From the aforementioned studies, it is clear that atherosclerosis begins early in life in all races, is associated with
risk factors, and occurs in anatomic locales susceptible to the formation of more advanced fibrous plaque.
 Advanced lesions, or fibrous plaque, are characterized histologically by the amount of extracellular lipid and
fibrous connective tissue seen. They are whitish in gross appearance and are elevated so that they protrude into the
lumen. These fibroatheromas are prone to produce clinical sequelae by erosion of the surface endothelial cells,
rupture of the fibrous cap, erosion of a calcium nodule, or intraplaque hemorrhage

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FIGURE
INTRAVASCULAR
PLAQUE

Thrombotic complication of a Trhombus

fibroatheroma seen on a trichrome-
stained (thrombus and intraplaque
hemorrhage stain red; collagen
stains blue) cross-section of a
human coronary artery. The fibrous
cap has ruptured (area between the Ruptured cap
arrows), and the highly thrombotic
lipid core is exposed to circulating
blood with the subsequent Lipid-rich core
production of acute occlusive
thrombosis.

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 Plaques differ in consistency and may be relatively soft and friable or densely sclerotic and calcific. Likewise,
some have well-formed fibrous caps, whereas others are covered by a narrow zone of loose connective tissue or by
endothelium alone.
 the fibrous cap of ruptured plaque is often infiltrated with foam cells, which are largely of macrophage origin and
thus indicative of active inflammation and vulnerability to rupture. A priori identification of these so-called thin-
cap fibroatheromas is an active area of cardiovascular imaging research.

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THEORIES OF PATHOGENESIS

Lipid Hypothesis

Response-to-Injury Hypothesis

Monoclonal Hypothesis

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LIPID HYPOTHESIS

 Cholesterol is transported in the aqueous environment by esterification of the sterol of long-chain fatty acids and

packaging of these esters with the hydrophobic cores of plasma lipoproteins. With its polar hydroxyl group
esterified, cholesterol remains sequestered within this core, which is essentially an oil droplet composed of
cholesteryl esters and triglycerides, solubilized by a surface monolayer of phospho- lipid and unesterified
cholesterol and stabilized by protein. In persons who are fasting, lipids circulate in plasma as lipoprotein particles
that are defined on the basis of their density as very-low-density lipoprotein (VLDL), intermediate-density
lipoprotein (IDL), LDL, and high-density lipoprotein (HDL). The protein of the VLDL, IDL, and LDL molecule is
apoB- 100, which has β-electrophoretic mobility.

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 The major milestone in the lipoprotein field was discovery of the defective gene associated with familial

hypercholesterolemia. In fibroblasts cultured from normal human subjects, the activity of 3-hydroxy- 3-
methylglutaryl coenzyme A (HMG-CoA) reductase, the rate-controlling enzyme in cholesterol biosynthesis, is
regulated by the content of LDL (but not HDL) in the culture medium. Researcher found that 3-hydroxy- 3-
methylglutaryl coenzyme A reductase was not sensitive to normal feedback regulation by LDL in cultured
skin fibroblasts from homozygous familial hypercholesterolemia patients. They then determined that the
defect was related to deficient binding of LDL to the cells of patients with familial hypercholesterolemia and
that suppression of 3-hydroxy-3-methylglutaryl coenzyme A reductase activity was related to the amount of
LDL bound. Therefore these patients had overproduction of cholesterol because they lacked the appropriate
receptor.
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RESPONSE-TO-INJURY HYPOTHESIS

 Endothelial injury may result from mechanical disruption, exposure to toxic or infectious
agents, or endogenous inflammatory signals. Injury to the endothelium allows adhesion of
platelets and an influx of LDL and other serum factors into the subendothelial space.
Platelets release their alpha granules and stimulate migration of SMCs into the intima,
where they proliferate and form a thickened neointima responsible for narrowing of the
arterial lumen. Restoration of a healthy endothelial cell layer abates the process.
 LDL accumulates in the intima within 2 hours after a bolus infusion and that the accumulation occurs
before the formation of fatty streaks, they concluded that retention of LDL is the initiating event of
atherosclerosis. The so-called response-to-retention theory purports that retained apoB–containing
lipoproteins stimulate a macrophage and T cell–dominated inflammatory response in the arterial wall

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MONOCLONAL HYPOTHESIS

 The hypothesis put forth by Benditt and Benditt uses the concept that in every female cell there is only one active
X chromosome and the progeny of that cell will express the same X chromosome as the parent cell. Glucose- 6-
phosphate dehydrogenase (G6PD) has two isoforms that can be separated by electrophoresis. Its gene is located on
the X chromosome and can therefore be used to identify the progeny of a parent cell. This approach was used to
determine that uterine leiomyomas are composed of cells with the same active X chromosome, whereas adjacent
normal myometrium was composed of a mixture of cells containing both G6PD isoforms and, therefore, that both
X chromosomes were active.
 They determined that SMCs from the plaque contained only one G6PD isoform, whereas adjacent control areas
contained a mixture of isoforms. This allowed them to conclude that each lesion is a clonal outgrowth derived
from a single precursor SMC located in the intima. It is noteworthy that SMCs within individual human neonatal
intimal thickenings are monoclonal in origin, whereas cells from the subjacent media are polyclonal.

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ATHEROSCLEROSIS AS A CHRONIC INFLAMMATORY DISEASE

 Atherosclerosis is now recognized as an inflammatory disease, and components of the innate and adaptive immune

system are involved in every step of the atherosclerotic process. Much of our modern understanding comes from
examination of human pathology specimens and transgenic animals. Genetic deletion of apolipoprotein E (ApoE−/−)
or the LDL receptor (Ldlr−/−), which produce mice with severe hypercholesterolemia and atherosclerotic lesions with
features of mature human atheroma, have become cornerstones in atherosclerosis research laboratories. The
importance of the LDL receptor in cholesterol regulation was noted by Goldstein and Brown when studying patients
with familial hypercholesterolemia. Apolipoprotein E suppresses atherosclerosis, and ApoE−/− mice have very low
levels of pre-β HDL and their plasma is poor at promoting the efflux of cholesterol from lipid-laden macrophages.
 Crossbreeding these mice with other strains carrying null mutations in immunologically relevant genes produces a

robust research tool to dissect out the contribution of individual components of immune pathways in
atherosclerosis. For example, some of the earliest approaches using compound mutant mice involved the global
loss of the entire adaptive immune system. Rag1−/− and Rag2−/− mice lack the V(D)J recombinase required to
form lymphocyte antigen receptor genes and hence have a complete loss of B and T cells. ApoE−/− mice fed a
regular chow diet developed plasma cholesterol levels between 390 and 470 mg/dL. Double knockout
ApoE−/−/Rag1−/− mice had a 40% reduction in aortic atherosclerotic lesions compared with immunocompetent
animals, thus demonstrating the role cellular immunity plays in the pathogenesis of atherosclerosis.

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 INITIATION AND PROGRESSION OF
ATHEROSCLEROTIC PLAQUE.

Cardiovascular risk factors, hemodynamic forces, toxins, and infectious agents interact with the vessel at the level of the
endothelium to produce injury, resulting in decreased nitric oxide production and increased permeability. Once injured, the
endothelium increases the expression of leukocyte adhesion molecules, which increases the adherence of macrophages and
other leukocytes. Permeability of the endothelium also permits entry of leukocytes and lipoproteins into the subendothelial
space. Chemokines and cytokines such as monocyte chemotactic protein-1 and interleukin-8 further enhance the recruitment
of leukocytes and smooth muscle cells (SMC) into the subendothelial space. Lipoproteins retained in the subendothelial space
are biochemically modified such that they can be taken up by macrophages and SMC to form foam cells. Foam cells at the
central-most position of the developing atheroma become necrotic and form the central lipid core, whereas the shoulder
regions contain SMC, macrophages, and other leukocytes. Platelet- derived growth factor and transforming growth factor-β
LOW-DENSITY LIPOPROTEIN RETENTION

 Trafficking of circulating LDL into and out of the subendothelial space is probably a function of concentration

gradients and endothelial permeability. Normal intima does not retain LDL particles, thus suggesting that most
particles return to plasma or are degraded in situ. However, subendothelial retention of apoB-100-containing
lipoproteins is an early event in atherosclerosis. Factors favoring net retention include a balance of uptake and
degradation of LDL by macrophages, progress of LDL-containing macrophages into the circulation, and complex
interaction with proteoglycans such that the LDL particles are sufficiently modified to maintain the gradient. Once
bound to the matrix, the lipoprotein is modified so that it becomes oxidized. Oxidized LDL, unlike native LDL, is
chemotactic to monocytes and rapidly taken up by macrophages to form foam cells by scavenger receptors.

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MONOCYTES

 Poole and Florey noted that macrophages adhere to the surface of endothelial cells overlying atheroma. In studies of

hypercholesterolemic monkeys, monocytes are seen attached to the endothelium within 12 days of initiation of an atherogenic diet. It is
now apparent that monocytes play a very early role in atheroma formation. Endothelium, which is rendered activated, expresses
adhesion molecules that interact with circulating leukocytes, principally monocytes Fibrous cap formation and lymphocytes. E- and
P-selectins slow monocytes, mediate rolling, and loosely tether them to the endothelium. More permanent fixation is due to members
of the immunoglobulin superfamily (vascular cell adhesion molecule-1 [VCAM-1] and intercellular adhesion molecule-1 [ICAM]),
which are upregulated and firmly fix the leukocytes to the wall. The importance of VCAM-1, and ICAM-1 in the pathogenesis of
atherosclerosis is evident in either ICAM-1 or VCAM-1 mutant mice exhibiting far less atherosclerosis than wild type counter-parts.
The adherent leukocytes are stimulated to migrate into the subendothelial space by a number of chemokines, including monocyte
chemoattractant protein-1 and oxidized LDL.

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MACROPHAGES

 Once within the subendothelial space, monocytes undergo a series of phenotypic modulations and become resident tissue macrophages that take up

oxidized LDL via the scavenger receptor A (SR-A), as well as CD36. One of the key signals for macrophage activation, macrophage colony-
stimulating factor, can enhance scavenger receptor expression and promote replication of macrophages and their production of proinflammatory
cytokines. Experiments in mutant mice deficient in macrophage colony-stimulating factor have shown the importance of this factor in atheroma
formation. Although most foam cells are macrophage in origin, SMC also take up lipids via scavenger receptors and CD36.

 Proinflammatory M1 macrophages, induced by hyperlipidemia, produce the inflammatory cytokines IL-1β and TNF-α. The IL-1 gene family

encodes three major proteins. The first two, IL-1α and IL-1β, exert proinflammatory effects by binding to the IL-1 receptor type 1. The third is IL-
1 receptor antagonist (IL-1Ra), an endogenous inhibitor that competitively blocks the binding of IL-1α and IL-1β to the IL- 1 receptor. Direct
evidence for the proatherogenic role of IL-1 was obtained in experiments in which ApoE−/− mice received subcutaneous injection of recombinant
IL-1 receptor antagonist.

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MACROPHAGES

 Mice injected with IL-1 receptor antagonist displayed a marked reduction in atherosclerotic lesion size. Similarly

IL- 18, previously called interferon-γ (IFN-γ)-inducing factor, is a Th1-promoting cytokine and therefore has the
capacity to promote inflammation through the innate and the adaptive immune pathways. Knockout of IL-18 in
atherosclerosis prone animals reduces aortic atherosclerotic lesion size.

 Macrophages also contribute to thrombosis in several pivotal ways. As discussed later, ruptured atherosclerotic

lesions characteristically contain abundant macrophages underlying a thin and collagen-poor fibrous cap. Matrix
metalloproteinase (MMP)-1, MMP-8, and MMP-13 specifically co-localize with macrophages in human
atheroma.

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 Rupture of the fibrous cap may be a balance between collagen synthesis by SMC and collagen breakdown by matrix

metalloproteinases generated by activated macrophages. Studies in collagenase-resistant mutant “knock-in” mice crossbred
with ApoE−/− mice demonstrated increased intimal collagen and SMC content.

 Similarly, compound mutant ApoE−/− mice crossed with MMP-13/ collagenase-3−/− mice have increased fibrillar collagen

that is thicker and more aligned in aortic atherosclerosis. Hence, interstitial collagenases produced by activated macrophages
greatly influence the structure and integrity of the fibrous cap overlying atherosclerotic plaques. Macrophages and SMC
within atherosclerotic plaques also overexpress the potent pro- coagulant tissue factor in response to C-reactive protein or
CD40 ligand. Hence, inflammation links atherosclerosis and thrombosis, leading some to refer to it as “atherothrombosis.”

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LYMPHOCYTES AND ADAPTIVE IMMUNITY

 The finding macrophages expressed the major histocompatibility class II antigens needed for antigen presentation
to CD4+ T cells suggested that adaptive immunity was involved in the atherosclerotic process. T lymphocytes,
which account for as much as 10% to 20% of the leukocyte population, are found most abundantly in the shoulder
and fibrous cap region of the atheroma. In advanced lesions, these T cells display markers of chronic activation
and produce the prototypical Th1 cytokine, IFN-γ, which further stimulates expression of class II major
histocompatibility antigens in SMC and macrophages. The crossbreeding of severe combined immunodeficiency
(SCID) mice that lack T and B cells with ApoE−/− mice produces offspring that are both hypercholesterolemic
and immunodeficient. When lesions in these mice were compared with those in the immunocompetent ApoE−/−
ani- mals, a dramatic 70% reduction of lesion size was observed. However, transfer of oxidized LDL-reactive T
cells to ApoE−/−/ SCID mice is more efficient at lesion acceleration than the transfer of T cells with no specificity
to a plaque-derived antigen, demonstrating the importance of antigen presentation in the pathogenesis of
atherosclerosis.

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SMOOTH MUSCLE CELLS

 Proinflammatory mediators can stimulate the migration of SMC from the tunica media into the intima. Growth
factors produced locally provide a paracrine stimulus for SMC proliferation and activation. Activated SMC appear
capable of producing growth factors (e.g., PDGF, fibroblast growth factors) that can stimulate their own
proliferation and that of their neighbors in an autocrine and paracrine fashion. TGF-β stimulates the production of
matrix and collagen in the subendothelial space. As the plaque matures, necrotic foam cells contribute to the
central lipid core, whereas collagen contributes to the overlying fibrous cap of a mature fibroatheroma.

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CALCIFICATION

 Bone morphogenetic protein-2 (BMP-2), a member of the TGF-β family, and inorganic phosphate induce the
osteochondrogenic phenotype in SMC.BMP-2, in turn, is produced by endothelial cells exposed to hypoxia,
reactive oxygen species, turbulent flow, high pressure, or inflammation. Atherosclerotic calcification proceeds
through a process similar to chondrogenesis, whereby cartilaginous metaplasia precedes osteoblast induction. This
is distinct from medial artery calcification, which proceeds through a process similar to intramembranous bone
formation. The latter is common in patients with diabetes or chronic kidney disease. The reason that some plaques
undergo calcific changes whereas others do not is not clear.
 Thus, the inflammatory reaction stimulated by modified LDL and white blood cells in the subendothelial space
provides a nidus for the subsequent events leading to the formation of mature fibrocalcific atherosclerotic plaque.
Notably, this process, which probably begins in childhood, is silent until sufficient arterial stenosis exists or until a
catastrophic plaque-destabilizing event occurs and produces a clinical symptom.

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PUTTING IT ALL TOGETHER: THE INFLAMMASOME

 As discussed earlier, IL-1β has several layers of regulation and is synthesized as pro-IL-1β and requires activated
caspase-1 to cleave pro-IL-1β and IL-18 into their active and secreted form. Caspase-1 activation requires a
second signal mediated through a complex of intracellular proteins known as inflammasomes. The nucleotide-
binding domain leucine-rich (NLR) family pyrin domain-containing 3 (NLRP3) inflammasome has been most
extensively studied. When NLRP3 receptors are activated, they oligomerize and recruit caspase-1 through the
adapter protein ASC (apoptosis-associated speck-like protein containing a caspase recruitment domain) and
autocatalytically activate caspase-1, which cleaves pro-IL-1β into its mature forms. NLRP3 inflammasome
activation historically included pore-forming toxins, extracellular adenosine triphosphate, viral DNA, and gout-
associated uric acid crystals. However, recent evidence demonstrates that cholesterol crystals can also activate the
inflammasome and therefore increase secretion of the potent proinflammatory cytokines IL-1β and IL-18. These
data argue that cholesterol crystals are not solely an inert byproduct within the wall of the artery but an active
contributor to atherosclerosis.

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 Moreover, hypercholesterolemic Ldlr−/− mice reconstituted with bone marrow from mice deficient in NLRP3,
ASC, or IL- 1β have significantly reduced aortic lesion sizes compared with those reconstituted with wild-type
bone marrow. These mice showed significantly lowered levels of IL-1β and IL-18. The implication of caspase-1
was evaluated recently in atherosclerosis as a pathogenic enzyme because this deficiency decreases atherosclerosis
in apoE-deficient mice. Hence, within the vascular wall, lipids and inflammation appear to be inextricably linked.
Indeed, the independent role of IL-1β mediated actions on atherosclerosis progression has been confirmed in
humans in the CANTOS trial, whereby anti-IL-1β monoclonal antibody therapy (canakinumab) was associated
with a significant reduction in morbid cardiovascular outcomes.

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C-REACTIVE PROTEIN

 Many prospective studies have established an association be- tween biomarkers of inflammation and first and
recurrent cardiovascular events. The inflammatory cytokines IL-6 and IL- 1β, as well as acute-phase reactants C-
reactive protein (CRP), fibrinogen, and serum amyloid A, have all been associated with peripheral arterial disease
and its progression. Among the many inflammatory biomarkers evaluated, high-sensitivity C- reactive protein
(hsCRP) has emerged as the leading biomarker for clinical application. This is because CRP is a very stable
analyte over time, has a relatively long half-life, has no diurnal variation, and requires no special processing for
sampling. In addition, very low (<0.5mg/L) and very high (>10mg/L) val- ues of hsCRP both provide important
prognostic information on cardiovascular risk.

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LOCALIZATION OF ATHEROSCLEROSIS

 The area well developed atherosclerosis are branch points, bifurcations, and major curvatures disrupt laminar flow
and cause boundary layer separation, flow reversal, and shifting stagnation points. Such areas are characterized by
increased particle contact time with the luminal surface, which may favor lipid deposition. Hence, fluid
mechanical forces influence endothelial gene expression through certain response elements sensitive to shear
stress. Endothelial dysfunction, characterized by decreased NO production, promotes vessel wall entry and
modification of circulating LDL. Therefore, it is possible that the differential regulation of endothelial genes by
distinct flow profiles allows certain areas of the vasculature to more effectively resist the influence of risk factors
such as hyperlipidemia and diabetes.

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PROGRESSION/REGRESSION OF PLAQUES

 Our current understanding of atherosclerotic plaque emphasizes a dynamic evolution. Serial angiographic studies
of human coronary arteries demonstrate periods of intermittent growth spurts followed by relative quiescence.
What may account for the non-uniform progression of these atherosclerotic lesions. One prevailing theory
suggests that most plaque disruptions with in situ thrombus formation do not always proceed to total occlusion and
clinical sequelae, but instead are clinically silent. Though unnoticed by the patient or clinician, they are far from
benign. The local nonocclusive platelet thrombus induces a healing response with local inflammatory cytokine and
growth factor production. TGF-β and PDGF stimulate SMC collagen production and migration.

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 Thrombin production accelerates SMC migration and proliferation, and fibrin stimulates wound contraction and
progressive luminal narrowing. Healed fibrous cap ruptures can be detected microscopically by the identification
of breaks in the fibrous cap with a surrounding repair reaction consisting of a proteoglycan-rich mass or collagen-
rich scar. Thus, in contrast to slow steady plaque growth in which compensatory enlargement of the vessel may
protect from luminal encroachment, acute plaque rupture with nonocclusive thrombosis may signal a cascade of
events leading to a fibrous atheroma and constrictive remodeling.

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 LIFE CYCLE OF HUMAN
ATHEROSCLEROTIC PLAQUE.

Rather than relentless progressive

enlargement, human atherosclerotic plaque
may undergo periods of progression,
regression, and growth spurts. As the plaque
extrudes into the lumen, the vessel
undergoes compensatory enlargement,
which preserves the lumen. The so-called
vulnerable plaque consists of a relatively
large lipid core and a thin (<100μm) fibrous
cap. Thrombotic complications can occur as
a result of cap rupture, superficial
endothelial erosion, intraplaque hemorrhage,
or erosion of a calcified nodule in which
circulating blood elements come in contact
with the thrombogenic lipid core. The fate
of such an event may be manifested as a
myocardial infarction, transient ischemic
attack, or in situ thrombosis of a peripheral
artery. Far more commonly, however, they
result in nonocclusive thrombus that incites
a healing response. These healed ruptures
result in a fibrous plaque with a narrowed
lumen.

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THROMBOTIC COMPLICATIONS OF ATHEROSCLEROSIS

 Significant resources in vascular surgery are expended in caring for the acute thrombotic events complicating
atherosclerosis and in situ thrombosis of the peripheral circulation. These catastrophic clinical syndromes often
occur suddenly and without warning.
 Once the plaque is fractured, blood is exposed to the underlying thrombogenic substrate and thrombosis ensues.
Tissue factor initiates the extrinsic clotting cascade and is a major regulator of coagulation and thrombosis.
Thrombus formation and platelet adhesion create further stenosis and thrombotic occlusion. As previously
mentioned, most thrombotic complications of plaque lead to progression of stenosis rather than occlusion of the
artery. Cigarette smoking, hyperglycemia, and elevated LDL cholesterol all increase blood thrombogenicity. These
same risk factors are characterized by endothelial abnormalities such as increased generation of superoxide anion
and decreased endothelium-derived NO. Thus risk factors are linked to progression of atherosclerosis and to its
thrombotic complications at susceptible areas in the vascular tree through abnormalities in blood coagulation, as
well as endothelial function.

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 Although complete fracture of the fibrous cap may be the most common cause underlying coronary thrombosis,
other mechanisms may be more important in the periphery. Intraplaque hemorrhage can transform an
asymptomatic carotid plaque into a symptomatic lesion and produce transient ischemic attacks or stroke.
Neovascularization and proliferation of the vasa vasorum, as in diabetic retinopathy, may produce a local
microvascular network that is fragile and friable. Intraplaque hemorrhage can cause rapid plaque expansion and
thinning or disruption of the cap. Superficial plaque erosion producing in situ thrombus without plaque rupture is
prevalent in patients with diabetes and in women. Apoptosis of endothelial cells may promote superficial erosion,
and various inflammatory stimuli may promote apoptosis. In particular, macrophage-derived myeloperoxidase
may be operative in that it promotes both tissue factor generation and endothelial cell apoptosis, thus linking
superficial erosion and in situ thrombosis. Finally, erosion through the intima of a calcified nodule represents
another less common form of atherosclerotic thrombosis that may be relevant in both the coronary and peripheral
circulations.

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IDENTIFICATION OF VULNERABLE LESIONS

 How does one predict a priori which patients may be more likely to progress from an atherosclerotic lesion to one

with symptoms? As discussed previously, IVUS evaluation determines the true extent of the size of the
atherosclerotic plaque and can detect the degree to which an artery has remodeled in response to a plaque. For
instance, it has been determined that excessive expansive remodeling may result in a thin vulnerable plaque.

 Impaired endothelial vasodilator function is seen in patients with CVD risk factors. Brachial artery flow-mediated

vasodilation has been used as a surrogate for the more relevant coronary circulation functional risk. Impaired
flow-mediated vasodilation is seen in patients with inflammation and in those with classic risk factors, and it is
often present before symptoms of peripheral or coronary arterial disease are evident.

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 Impaired flow-mediated vasodilation has also been demonstrated to predict adverse events in patients undergoing vascular

surgery. Hence, the classic Framingham risk factors, as well as inflammation, appear to impair endothelial function and
promote atherosclerosis.

 Finally, molecular imaging is on the immediate horizon to help identify vulnerable plaque. For example, plaque with active

inflammation may be identified by extensive accumulation of macrophages. Successful detection of plaque inflammation with
magnetic resonance imaging was possible with gadolinium-loaded micelles coupled with antibodies to the scavenger receptor.
Alternatively, computed tomography may be used with a novel iodinated nanoparticulate contrast agent to detect inflammation
in atherosclerotic plaque. Contrast-enhanced ultrasound may also be used by attaching VCAM-1 to microbubbles and
identifying areas of active adhesion molecule expression

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