MINI-SYMPOSIUM: CARDIOVASCULAR PATHOLOGY
Pathogenesis of
atherosclerosis
Tao Wang
Jagdish Butany
Abstract
The pathogenesis of atherosclerosis involves a complex interplay of
endothelial dysfunction, lipid accumulation, inflammation, vascular
smooth muscle cell proliferation, matrix turnover, and calcification.
Genomic and epidemiological studies shed some light on the role of
genetics in cardiovascular disease. It is appreciated that atheroscle-
rotic lesions represent dynamic processes that evolve from fatty
streaks to stable or unstable plaques. The clinical consequences of
atherosclerosis, such as unstable angina, myocardial infarction or
stroke, are a significant source of morbidity and mortality throughout
the world. An understanding of the pathogenesis of atherosclerosis
is important for understanding disease progression, the development
of new therapeutics and ultimately the improvement of patient
outcomes.
Keywords atherosclerosis; cardiovascular disease; endothelium;
lipid
Introduction
Atherosclerosis is a complex, chronic disease which is tradi-
tionally thought of as the accumulation of fibrofatty deposits in
the intima of medium and large muscular arteries. For many
years, this was assumed to be a passive process and an inevitable
aspect of aging. We now appreciate that it is in fact a complex
interplay of lipid metabolism, active cellular interactions,
inflammation, and matrix remodeling.1,2 Atherosclerosis is the
pathological basis of peripheral vascular, coronary and cerebro-
vascular diseases, all major causes of mortality and morbidity
throughout the world.2 Despite the development of effective
cholesterol reducing agents and lifestyle modification initiatives,
only modest decreases in rates of atherosclerosis and its clinical
sequelae are seen.
The disease-causing lesions are believed to originate from
benign-looking, non-occlusive, lipid-laden plaques in childhood
known as fatty streaks.3,4 These coalesce to form atheromas,
which are enlarged plaques characterized by neointimal lipids,
foam cells, debris, connective tissue and an overlying fibrous
cap.1,5 The disrupted microenvironment leads to endothelial
dysfunction, which in turn encourages further lipoprotein
migration.1,6 Smooth muscle cells progressively migrate to the
Tao Wang MD MSc Department of Laboratory Medicine and
Pathobiology, University of Toronto, Toronto, Ontario, Canada.
Conflicts of interest: none.
Jagdish Butany MBBS MS FRCPC Department of Pathology, University
Health Network, Toronto, Ontario, Canada. Conflicts of interest:
none.
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plaque and deposit fibrous matrix proteins, and the lesion be-
comes a fibroatheroma.5
Atherosclerotic plaques can be described in terms of
complexity and stability. Complexity is reflected by the degree
and extent of inflammatory cell infiltration, necrosis, lipid
deposition, calcification and hemorrhage. Complex plaques are
unstable and prone to rupture, a process which is characterized
by a structural gap or fissure in the fibrous cap.1 Localized me-
chanical shear stress forces can trigger plaque rupture, but so can
the same mechanisms that lead to plaque complexity, such as
inflammation or hemorrhage. Once a plaque ruptures, the
exposed pro-thrombogenic atheromatous core induces an acute
superimposed and occlusive thrombus. Clinically, thrombosis
presents as unstable angina, myocardial infarction, or sudden
cardiac death. Conversely, stable atherosclerotic lesions progress
slowly and tend to be less complex and more structurally sound.
They have well developed, dense fibrous caps often with areas of
calcification. The slower growth also allows for the development
of collateral circulation. Therefore, stable plaques are less prone
to rupture and their occlusion is less life threatening (Figure 1).5
Atherosclerosis is a complex chronic process that involves
cellular, metabolic, and inflammatory factors. This review will
explore our current understanding of the roles of endothelial
dysfunction, lipid metabolism, inflammation, vascular smooth
muscle cells, matrix remodeling, and genetics in the pathogenesis
of atherosclerosis.
Endothelial dysfunction
Normal endothelium helps maintain vascular homeostasis,
secreting vasodilatory nitric oxide (NO) as well as vasoconstric-
tors such as endothelin and angiotensin II.1 The secretion of NO,
in particular, inhibits inflammation, proliferation and throm-
bosis. Animal models that inhibit the production or secretion of
NO led to vasoconstriction and hypertension, but also displayed
abnormalities in leukocyte and platelet interactions.7 Alterations
in NO secretion and vasoconstrictive/vasodilatory response are
among the earliest pathologies noted in vascular disease, often
preceding the formation of atherosclerotic lesions.7
Perturbations in hemodynamics play a major role in endo-
thelial dysfunction, and cardiovascular risk factors such as
smoking, hypertension, diabetes, obesity, and hypercholester-
olemia contribute to these perturbations.1,6,7 The role of hemo-
dynamics can be demonstrated by the non-random distribution
of atherosclerotic lesions, which have a strong predilection for
regions of turbulent, high pressure flow, such as the branch
points of the aorta (Figure 2).1,2,5e7 Endothelial cells are believed
to alter their gene expression in response to shear stress. Laminar
flow upregulates the production of nitric oxide and COX-2.6
Kruppel-like factor 2 (KLF2) is a transcription factor which is
highly expressed under laminar flow conditions and appears to
exert protective effects against atherosclerosis by downregulating
inflammation.2,6,7 Conversely, endothelial cells exposed to tur-
bulent flow induce activation of the pro-inflammatory NF-kB
pathway and undergo reorganization of cytoskeletal proteins.6
The evaluation of endothelial dysfunction is clinically rele-
vant, and is historically achieved by measuring endothelial cell
dependent vasodilation during coronary angiography.7 Less
invasive methods include the measuring of brachial artery
473 Ó 2017 Published by Elsevier Ltd.
 MINI-SYMPOSIUM: CARDIOVASCULAR PATHOLOGY

Figure 1 (a) H&E of a normal coronary artery (b) Movat stain demonstrating the internal elastic lamina (black) (c) Coronary artery with stable
calcified atherosclerotic plaque and thick fibrous cap (d) An unstable ruptured atherosclerotic plaque with acute and chronic thrombus formation
and significant lipid infiltration.

diameter by ultrasound.7 Ideally, the use of biomarkers would
supplant these more subjective, invasive or labor-intensive pro-
cedures. The search for biomarkers of endothelial dysfunction
and atherosclerosis has led to the evaluation of various cytokines
and inflammatory markers, such as hsCRP.7 However while
single markers often have good sensitivity, they lack the neces-
sary specificity for use in individual patients. The concept of
panel based biomarker testing via proteomics or metabolomics is
emerging, but is still in its infancy.7
Lipid metabolism
Hyperlipidemia is a major risk factor for atherosclerosis, and
abnormal lipid metabolism is an important component of
atherosclerosis. It has been known for some time that high
plasma levels of low density lipoproteins (LDL) are atherogenic,
while high density lipoproteins (HDL) appear to be atheropro-
tective.4 This is due to the function of HDLs in reverse cholesterol
transport, which brings cholesterol from the periphery to the
liver for degradation. Statins function through the lowering of
LDL by inhibition of HMG-CoA reductase, an enzyme involved in
the synthesis of cholesterol.4 Statins, diet and exercise can also
lead to a desirable increase in the plasma levels of HDL.4
Fatty streaks result from increased circulating lipid concen-
trations and lipid insudation of the intima, particularly from LDL.
Cholesterol and phospholipids within these early accumulations
are susceptible to oxidation by enzymes such as myeloperox-
idases, lipoxygenases, NADPH oxidases, and nitric oxide syn-
thases.4 Oxidized low density lipoproteins (LDLs) and reactive
oxygen species (ROS) that result are toxic and induce endothelial
dysfunction, inflammation and increased vascular permeability.4
There is subsequent upregulation of leukocyte adhesion mole-
cules by the endothelium, further inciting migration of lympho-
cytes and macrophages. Macrophages take up LDLs via
endocytosis and then transport them to lysosomes to be
degraded, but oxLDL are less susceptible to degradation. Thus a
macrophage transitions into a foam cell when it becomes inun-
dated with cholesterol faster than it can be degraded.4
MicroRNAs (miRNA) are now known to play a significant role
in the homeostasis of lipid metabolism, partly through altering the
balance between LDL and high density lipoproteins (HDL).
miRNA-122 was identified as being highly expressed in the liver
and appears to regulate both HDL and LDL through indirect tar-
geting of various genes involved in cholesterol synthesis,
including HMGCR, SREBP-1 and FAS.8 Other miRNA such as miR-
148a, miR-128-1, miR-130b and miR-301b appear to antagonize
LDL receptor (LDLR), which is important for hepatic uptake and
clearance of LDL. Thus inhibition of these miRNAs led to lower
levels of plasma LDL in mouse models.8 Beyond lipid metabolism,

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 MINI-SYMPOSIUM: CARDIOVASCULAR PATHOLOGY

Figure 2 (a) Aorta with fatty streaks, a precursor of atherosclerotic plaques. (b) Severe atherosclerosis with calcifications and large areas of plaque
formation. The atherosclerotic lesions form first in areas adjacent to vascular branching. (c) Ulcerated plaques with adjacent early aortic aneurysm
formation.

miRNAs also regulates endothelial function and inflammatory 1), IL-6, IL-12, and MCP-1.2,9,10 The IL-1 family of cytokines
response, and are thus increasingly recognized as an important upregulates CAM expression and regulates the activation of
regulator of atherosclerosis-related pathways.8 The modulation of macrophages and lymphocytes.10 IL-6 has been implicated in
miRNAs has largely remained experimental at this time, but there angiogenesis, re-vascularization, and induction of C-reactive
is a possibility of translation into human therapeutics. protein (CRP) and vascular endothelial growth factor (VEGF)
expression.9 IL-12 has been implicated in the activation of T
Inflammation and macrophages cells.10 Macrophages also produce matrix metalloproteinases,
which can remodel the extracellular matrix and potentially
Endothelial dysfunction and abnormal lipid metabolism lead to
weaken plaque stability.2 The localization of macrophages near
the release of many pro-inflammatory molecules. The upregula-
sites of plaque rupture supports the notion that macrophages are
tion of several cell adhesion molecules (CAMs), such as ICAM1,
involved in matrix degradation and plaque instability.9
VCAM1 and P-selectin leads to increased binding of inflamma-
T lymphocytes comprise a significant portion of inflammatory
tory cells. Circulating monocytes and leukocytes initially bind
cells in atherosclerotic plaques. T cells are a significant producer
CAMs on the endothelial surface, but chemokines are required
of IFN-g and tumor necrosis factor alpha (TNF-a). These factors
for recruitment into the subendothelial space. Among the most
promote atherosclerosis by increasing macrophage activation
commonly expressed chemokines in these atherosclerotic lesions
and uptake of oxLDL. They can also induce macrophage
are monocyte chemoattractant protein-1 (MCP-1), macrophage
apoptosis, which contributes to the necrotic core and reduces
colony-stimulating factor (MCSF) and interferon-g (IFN-g). MCP-
plaque stability. Administration of exogenous IFN-g and upre-
1 activates leukocyte integrin, resulting in firm initial monocyte
gulation of TNF-a have both been shown to promote athero-
attachment.9 MCSF promotes scavenger receptor protein syn-
sclerosis.10 TNF-a also upregulates CAM expression and
thesis and differentiation of monocytes into macrophages. IFN-g
stimulates vascular smooth muscle cell (VSMC) migration.9 Thus
promotes plaque development and foam cell formation.9
a variety of inflammatory cells and cytokines are involved at all
Once monocytes enter the subendothelial space, they may
stages of atherosclerosis.
mature into macrophages and take up oxidized LDL (oxLDL) to
turn into foam cells. However, macrophages are not merely pas-
Vascular smooth muscle cells
sive storage “vessels” for LDL. They actively promote inflamma-
tion, T lymphocyte activation, and additional macrophage Vascular smooth muscle cells, similar to endothelial cells, can
migration through the secretion of cytokines like interleukin 1 (IL- become “activated” to play a role in atherosclerosis. Quiescent

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 MINI-SYMPOSIUM: CARDIOVASCULAR PATHOLOGY
VSMCs maintain a contractile phenotype, with expression of
smooth muscle actin alpha (ACTA2) and smooth muscle myosin
heavy chain (MYH11).2 Normally there are only rare smooth
muscle cells in the intima, but in atherosclerotic plaques they can
be plentiful (Figure 3). Activated VSMCs downregulate these
markers and enter a synthetic state, where they proliferate and
produce extracellular matrix (ECM) proteins. This increases the
size of plaque lesion, but conversely also helps provide structural
stability.2,11,12
There is evidence that both VSMCs and macrophages can take
up lipids and form foam cells in the atherosclerotic plaque.
Cholesterol loading of cultured VSMCs suppresses the contractile
phenotype and induces expression of macrophage markers.
However, VSMC derived foam cells appear to have less phago-
cytic capacity compared to true macrophages.11,12 Conversely,
there is also evidence that at least a portion of smooth muscle
marker expressing cells within plaques are derived from myeloid
lineage. Mesenchymal stem cells, both locally and bone marrow
derived, are likely contributing at least a portion of these cells
and may partially explain the observed phenotypic plasticity.12
Various cytokines and growth factors, both autocrine and para-
crine, promote the proliferation and activation of VSMCs. These
include platelet derived growth factor (PDGF), transforming
growth factor-b (TGF-b), IFNg, TNFa, and basic fibroblastic
growth factor (bFGF).2,12
Apoptosis and necrosis of VSMCs can contribute both to the
necrotic core and also detract from the structural stability of the
plaque. Areas of rupture often show reduced VSMCs and
increased macrophages. Dying VSMC also upregulate inflam-
matory factors such as IL-1, which further promotes inflamma-
tion and endothelial dysfunction.12 Even viable VSMCs show
signs of premature aging, expressing senescence associated b-
galactosidase activity and upregulating their secretion of pro-
inflammatory IL-6 and MCP-1.12
Extracellular matrix and calcification
The cellular components of atherosclerotic plaques interact with
and actively modify their extracellular matrix (ECM). Matrix
metalloproteinases (MMPs) are a family of zinc-dependent en-
dopeptidases that function to degrade the ECM.13 Macrophages
Figure 3 Immunohistochemistry for smooth muscle actin showing
vascular smooth muscle cells present in the intimal plaque.
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are a major producer of these enzymes. Several MMPs are pur-
ported to promote atherosclerosis, including MMP-2, MMP-8,
and MMP-12.13,14 The mechanisms are unclear, but they appear
to promote the accumulation of macrophages, possibly through
the liberation of matrix entrapped growth factors and cyto-
kines.13 Not surprisingly, MMPs have been implicated in plaque
destabilization, with MMP-1, MMP-9, MMP-12 showing locali-
zation in the fibrous cap and shoulder of plaques. Increased
levels of these enzymes have been associated with thinning of
fibrous caps.13 Therefore, MMPs have the potential to be thera-
peutic targets.
It is well known atherosclerotic plaques undergo intimal
mineralization as they increase in complexity. This process is
regulated by the same set of enzymes that control both physio-
logical and pathological mineralization. Bone morphogenetic
proteins (BMP) are part of the transforming growth factor beta
superfamily and play a key role in activating osteogenic differ-
entiation and calcification. BMP-2 and BMP-4 are both detected
in arterial walls in both the endothelium and the media.15 These
proteins are in turn regulated by inhibitors as such matrix Gla
protein (MGP). Genetically engineered mouse models which lack
MGP have been shown to exhibit extensive arterial calcifica-
tion.15,16 Not surprisingly, phosphate signaling is also an
important regulator of mineralization. Hyperphosphatemia, such
as from renal failure, is a stimulator of vascular calcification.15
The nucleotide pyrophosphatase/phosphodiesterase 1 (NPP1)
gene is known to synthesize inorganic pyrophosphate, which is a
key inhibitor of calcification.15 Last but not least, the RANK/
RANKL signaling pathway which regulates osteoclast activity, is
also a factor in vascular calcification. Within this pathway,
osteoprotegerin is believed to inhibit vascular calcification.15
Calcification and matrix remodeling in atherosclerotic plaques
may have both protective and pathological qualities. For
instance, while calcification decreases arterial elasticity and
contributes to stenosis, it can also help strengthen the plaque and
reduce the risk of rupture.15,16 Large areas of plaque calcification,
particularly in the cap area, can be associated with better stability
(Figure 4).16 Depending on the stage of the plaque, the benefits
may outweigh the risks or vice versa. However, extensive
vascular calcification is still a marker of cardiovascular risk,
possibly as a surrogate for overall atherosclerotic disease
burden.16
Genetics
The traditional clinical risk factors for atherosclerosis and car-
diovascular disease, such as male gender, age, dyslipidemia,
diabetes, smoking, and hypertension remain relevant today.
Most of these risk factors are predictive of atherosclerosis and are
often co-existent. While not traditionally regarded as a genetic
disease, an understanding of the genetic factors of atherosclerosis
is beginning to take shape. As with many diseases, rare heredi-
tary conditions often teach us about the pathology of the non-
hereditary analog. When it comes to atherosclerosis, high
plasma LDL has long been identified as a clinical risk factor.
There are several monogenic conditions associated with familial
hypercholesterolemia. These include aberrations in LDLR,
apolipoprotein B (APOB), and PCSK9; the latter encodes a pro-
tein that degrades LDL receptor.17 Since LDLR interacts with
476 Ó 2017 Published by Elsevier Ltd.
 MINI-SYMPOSIUM: CARDIOVASCULAR PATHOLOGY

Figure 4 (a) Fatty streak with dysfunctional endothelial cells, lipid insudation and the macrophage transformation into foam cells. (b) Stable plaque
with extensive calcification and thick fibrous cap overlying foam cells and necrotic core. (c) Acutely ruptured unstable plaque, with a collection of
fibrin and platelets forming a thrombus over the disrupted thin fibrous cap.

apoB, loss of function mutations in either can disrupt this
interaction and prevent the uptake and breakdown of LDL by the
liver. Conversely, gain of function mutations in PCSK9 can lead
to the excess degradation of LDLR, with the same net result of
increased plasma LDL.17 Consequently, these patients have a
markedly higher incidence of cardiovascular disease.
However, the majority of people who suffer from atheroscle-
rosis do not have a clearly defined monogenetic abnormality.
Population based genetics studies have relied extensively on
genome-wide association studies (GWAS) to help identify single
nucleotide polymorphisms (SNPs) that may serve as genetic
markers for increased cardiovascular disease risk. Typically,
these studies use a caseecontrol format, whereby researchers
look for statistically relevant associations of SNPs with cardio-
vascular disease.18 The observational nature of GWAS studies
limits the ability to draw causal conclusions. However, for genes
with a known relationship to a biomarker of interest (i.e. LDL
levels), epidemiologists can use the method of Mendelian
randomization to infer causality in a manner akin to a random-
ized control trial.18 Mendelian randomization relies on the fact
that any one allele has a 50% chance of being allocated by a
parent to its offspring regardless of traditional confounding fac-
tors. However, this methodology also assumes that a particular
genetic variant only influences outcome via a single biomarker in
question, which is not always true when it comes to genes
associated with lipid metabolism.17 Nonetheless, these methods
have uncovered dozens to hundreds of potentially relevant
genes, involved in processes ranging from lipid metabolism to
regulation of endothelial or smooth muscle cell phenotype.18 As
our understanding of the genetics of atherosclerosis progresses,
genetic factors may find a place on risk nomograms and thus
influence clinical decision making in the future.19
Conclusion
The pathogenesis of atherosclerosis involves the complex inter-
action of endothelium, lipid, macrophages, smooth muscle cells,
inflammation, extracellular matrix, and genetic factors. These
interactions explain the dynamic and continuously evolving na-
ture of atherosclerotic lesions from early fatty streaks to ather-
omas and eventually stable or vulnerable plaques. There have
been many recent developments in our understanding of these
processes. The application of new genetic and pathological
knowledge towards translational and clinical research will be key
towards progress in the therapeutics for atherosclerosis. A
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Practice points
C Atherosclerosis is a chronic disease that involves endothelial
injury, lipid deposition, inflammation, matrix alterations, and
genetic factors
C Plaques are formed by numerous cell types, including lympho-
cytes, macrophages, vascular smooth muscle, and endothelial
cells
C Stable atherosclerotic plaques have thick fibrous caps and
calcification
C Unstable plaques have increased inflammatory cells and lipid
infiltration with thin caps
478 Ó 2017 Published by Elsevier Ltd.