Basic Science and Forensic Pathology Aspects of Atherosclerosis

Basic Science and Forensic
Pathology Aspects of Atherosclerosis
Luchenga Adam Mucheleng’anga
Clinical Fellow of Forensic Pathology
University of Toronto.

Disclaimer
This is not original work as it is book lifted from the
books listed at the end. This material is study notes
The PowerPoint is meant to ease the learning
process.

Arteriosclerosis
Arteriosclerosis literally means
“hardening of the arteries”;
it is a generic term for arterial
wall thickening and loss of
elasticity.
There are three general
patterns, with different clinical
and pathologic consequences:
Arteriolosclerosis affects small arteries
and arterioles, and may cause
downstream ischemic injury.
Mönckeberg medial sclerosis is
characterized by calcification of the walls
of muscular arteries, typically involving
the internal elastic membrane.
Atherosclerosis, from Greek root words
for “gruel” and “hardening,” is the most
frequent and clinically important pattern.

Atherosclerosis
Underlies the
pathogenesis of coronary,
cerebral and peripheral
vascular disease.
Because coronary artery
disease is an important
manifestation of
atherosclerosis,
epidemiologic data
related to atherosclerosis
mortality typically reﬂect
deaths caused by
ischemic heart disease.
Signifcant morbidity and
mortality are also caused
by aortic and carotid
atherosclerotic disease
and stroke.
The likelihood of
atherosclerosis is
determined by the
combination of acquired
(e.g., cholesterol levels,
smoking, hypertension)
and inherited (e.g., LDL
receptor gene mutations)
risk factors.

Atherosclerosis
Acting in concert they cause initimal lesions called
atheromas (also called atheromatous or
atherosclerotic plaques) that protrude into vessel
lumens.
An atheromatous plaque consists of a raised lesion
with a soft grumous core of lipid (mainly
cholesterol and cholesterol esters) covered by a
fibrous cap.
Besides mechanically obstructing blood ﬂow,
atherosclerotic plaques can rupture leading to
catastrophic obstructive vascular thrombosis.
Atherosclerotic plaque can also increase the
diffusion distance from the lumen to the media,
leading to ischemic injury and weakening of the
vessel wall, changes that may result in aneurysm
formation.

Epidemiology of
atherosclerosis
The prevalence and severity of
atherosclerosis and ischemic heart disease
among individuals and groups are related
to a number of risk factors.
Some of these factors are constitutional,
but others are acquired or related to
specific behaviours and potentially
amenable to intervention.
Risk factors have been identified through a
number of prospective analyses (e.g., the
Framingham Heart Study).
These risk factors have roughly
multiplicative effect.
Thus, two factors increase risk
approximately four-fold, and three (i.e.,
hyperlipidemia, hypertension, and
smoking), increase risk by a factor of seven.

Epidemiology
of
atherosclerosis
• Constitutional Risk Factors
• Genetics.
• Family history is the most important
independent risk factor for
atherosclerosis.
• Certain Mendelian disorders are
strongly associated with
atherosclerosis (e.g., familial
hypercholesterolemia, but these
account for only a small percentage of
cases.
• The well-established familial
predisposition to atherosclerosis and
ischemic heart disease is usually
polygenic, relating to familial
clustering of other established risk
factors, such as hypertension or
diabetes, or to inherited variants that
inﬂuence other pathophysiologic
processes, such as inﬂammation.

Epidemiology
of
atherosclerosis
• Age
• Is a dominant inﬂuence.
• Although the development of
atherosclerotic plaque is
typically a progressive process,
it does not usually become
clinically manifest until lesions
reach a critical threshold in
middle age or later.
• Thus, between ages 40 and 60,
the incidence of myocardial
infarction increases five-fold.
• Death rates from ischemic heart
disease rise with each decade
even into advanced age.

Epidemiology
of
atherosclerosis
• Gender.
• Other factors being equal,
premenopausal women are relatively
protected against atherosclerosis and
its consequences compared to age-
matched men.
• Thus, myocardial infarction and other
complications of atherosclerosis are
uncommon in premenopausal women
unless they are otherwise
predisposed by diabetes,
hyperlipidaemia, or severe
hypertension.
• After menopause, however, the
incidence of atherosclerosis related
diseases increases in women and at
older ages actually exceeds that of
men.

Epidemiology
of
atherosclerosis
• Gender.
• Although a favourable inﬂuence of
estrogen has long been proposed to
explain this effect, clinical trials of
estrogen replacement have not been
shown to protect against vascular
disease; indeed, in some studies,
post-menopausal estrogen
replacement actually increased
cardiovascular risk.
• The athero-protective effect of
estrogens may be related to the age
at which the therapy is initiated; in
younger postmenopausal women,
coronary atherosclerosis is diminished
by estrogen therapy, while older
women appear not to benefit.

Epidemiology
of
atherosclerosis
• Modifiable Major Risk Factors
• Hyperlipidaemia—and more specifically
hypercholesterolemia
• Is a major risk factor for atherosclerosis; even
in the absence of other risk factors,
hypercholesterolemia is sufficient to initiate
lesion development.
• The major component of serum
cholesterol associated with increased
risk is low-density lipoprotein (LDL)
cholesterol.
• LDL is the complex that delivers
cholesterol to peripheral tissues; in
contrast, high-density lipoprotein (HDL)
is the complex that mobilizes cholesterol
from the periphery (including atheromas)
and transports it to the liver for excretion
in the bile.
• Consequently, higher levels of HDL
(“good cholesterol”) correlate with
reduced risk.

Epidemiology
of
atherosclerosis
• Hyperlipidemia—and more specifically
• Is a major risk factor for atherosclerosis;
even in the absence of other risk factors,
hypercholesterolemia is sufficient to
initiate lesion development.
• Consequently, higher levels of HDL
(“good cholesterol”) correlate with
reduced risk.
• Understandably, dietary and
pharmacologic approaches that
lower LDL or total serum
cholesterol, or raise serum HDL,
are of considerable interest.
• High dietary intake of cholesterol
and saturated fats (present in egg
yolks, animal fats, and butter, for
example) raises plasma cholesterol
levels.

Epidemiology
of
atherosclerosis
• Is a major risk factor for atherosclerosis; even
in the absence of other risk factors,
hypercholesterolemia is sufficient to initiate
lesion development.
• Conversely, diets low in cholesterol and/or high
in polyunsaturated fats lower plasma
cholesterol levels.
• Omega-3 fatty acids (abundant in fish oils) are
beneficial, whereas (trans)-unsaturated fats
produced by artificial hydrogenation of
polyunsaturated oils (used in baked goods and
margarine) adversely affect cholesterol
profiles.
• Exercise and moderate consumption of
ethanol raise HDL levels whereas obesity and
smoking lower it.
• Statins are a class of drugs that lower
circulating cholesterol levels by inhibiting
hydroxymethylglutaryl coenzyme A (HMG CoA)
reductase, the rate-limiting enzyme in hepatic
cholesterol biosynthesis.

Epidemiology
of
atherosclerosis
• Is a major risk factor for
atherosclerosis; even in the
absence of other risk factors,
hypercholesterolemia is sufficient
to initiate lesion development.
• In the past two decades,
statins have been used
widely to lower serum
cholesterol levels, arguably
one of the most significant
success stories of
translational research.

Epidemiology
of
atherosclerosis
• Hypertension
• Both systolic and diastolic levels
are important.
• On its own, hypertension can
increase the risk of ischemic heart
disease by approximately 60%
versus normotensive populations.
• Chronic hypertension is the most
common cause of left ventricular
hypertrophy, and hence the latter
is also a surrogate marker for
cardiovascular risk.

Epidemiology
of
atherosclerosis
• Cigarette smoking
• Well-established risk factor in
men and likely accounts for the
increasing incidence and severity
of atherosclerosis in women.
• Prolonged (years) smoking of one
pack of cigarettes or more daily
doubles the death rate from
ischemic heart disease.
• Smoking cessation reduces that
risk substantially.

Epidemiology
of
atherosclerosis
• Diabetes mellitus
• Induces hypercholesterolemia
and markedly increases the risk
of atherosclerosis.
• Other factors being equal, the
incidence of myocardial
infarction is twice as high in
patients with diabetes than in
those without.
• There is also an increased risk of
stroke and a 100-fold increased
risk of atherosclerosis-induced
gangrene of the lower
extremities

Epidemiology
of
atherosclerosis
• Additional Risk Factors
• As many as 20% of all cardiovascular
events occur in the absence of overt
risk factors (e.g., hypertension,
hyperlipidaemia, smoking, or
diabetes).
• Indeed, more than 75% of
cardiovascular events in previously
healthy women occur with LDL
cholesterol levels below 160 mg/dL
(levels generally considered to
connote low risk).
• Clearly, other factors also contribute to
risk; among those that are proven.

Epidemiology
of
atherosclerosis
• Inflammation.
• Present during all stages of
atherogenesis and is intimately linked
with atherosclerotic plaque formation
and rupture.
• With the increasing recognition that
inflammation plays a significant causal
role in ischemic heart disease,
assessment of systemic inflammation
has become important in overall risk
stratification.
• While a number of circulating markers
of inflammation correlate with
ischemic heart disease risk, C-
reactive protein (CRP) has emerged
as one of the simplest to measure and
one of the most sensitive.

Epidemiology
of
atherosclerosis
• Inﬂammation.
• CRP is an acute phase reactant
synthesized primarily by the liver.
• Its expression is increased by a
number of inﬂammatory mediators,
particularly IL-6, and it augments the
innate immune response by binding to
bacteria and activating the classical
complement cascade.
• Whether CRP has any causal role in
atherosclerosis is controversial.
• However, it is well established that
plasma CRP is a strong, independent
marker of risk for myocardial
infarction, stroke, peripheral arterial
disease, and sudden cardiac death,
even among apparently healthy
individuals.

Epidemiology
of
atherosclerosis
• Inﬂammation.
• Accordingly, CRP levels
have been incorporated into
risk stratification algorithms.
• CRP is also a useful marker
for gauging the effects of risk
reduction measures, such as
smoking cessation, weight
loss, exercise, and statins;
each one of these reduce
CRP levels.

Epidemiology
of
atherosclerosis
• Hyperhomocystinemia.
• Serum homocysteine levels correlate
with coronary atherosclerosis,
peripheral vascular disease, stroke,
and venous thrombosis.
• Homocystinuria, due to rare inborn
errors of metabolism, results in
elevated circulating homocysteine
(>100 µmol/L) and is associated with
premature vascular disease.
• Although low folate and vitamin B12
levels can increase homocysteine,
supplemental vitamin ingestion does
not affect the incidence of
cardiovascular disease.

Epidemiology
of
atherosclerosis
• Metabolic syndrome.
• Associated with central obesity, this
entity is characterized by insulin
resistance, hypertension,
dyslipidaemia (elevated LDL and
depressed HDL), hypercoagulability,
and a proinﬂammatory state.
• The dyslipidaemia, hyperglycemia,
and hypertension are all cardiac risk
factors, while the systemic
hypercoagulable and proinﬂammatory
state may contribute to endothelial
dysfunction and/or thrombosis.

Epidemiology
of
atherosclerosis
• Lipoprotein a [Lp(a)]
• An altered form of LDL that contains the
apolipoprotein B-100 portion of LDL
linked to apolipoprotein A (apo A); Lp(a)
levels are associated with coronary and
cerebrovascular disease risk,
independent of total cholesterol or LDL
levels.
• Factors affecting hemostasis.
• Several markers of hemostatic and/or
fibrinolytic function (e.g., elevated
plasminogen activator inhibitor 1) are
potent predictors of risk for major
atherosclerotic events, including
myocardial infarction and stroke.
• Platelet-derived factors, as well as
thrombin—through both its procoagulant
and proinﬂammatory effects—are
increasingly recognized as major
contributors to vascular pathology.

Epidemiology
of
atherosclerosis
• Other factors.
• Factors associated with a
less pronounced and/or
difficult-to-quantitate risk
include lack of exercise;
competitive, stressful life
style (“type A” personality);
and obesity (the latter also
being complicated by
hypertension, diabetes,
hypertriglyceridemia, and
decreased HDL).

Epidemiology
of
atherosclerosis
• Pathogenesis of Atherosclerosis
• The clinical importance of atherosclerosis
has stimulated enormous interest in
understanding the mechanisms that
underlie its evolution and complications.
• The contemporary view of atherogenesis
integrates the risk factors previously
discussed and is called the “response to
injury” hypothesis.
• This model views atherosclerosis as a
chronic inﬂammatory and healing response
of the arterial wall to endothelial injury.
• Lesion progression occurs through
interaction of modified lipoproteins,
monocyte-derived macrophages, and T
lymphocytes with endothelial cells and
smooth muscle cells of the arterial wall.

Epidemiology
of
atherosclerosis
• According to this schema,
atherosclerosis progresses in the
following sequence:
• Endothelial injury and
dysfunction, causing (among
other things) increased vascular
permeability, leukocyte
adhesion, and thrombosis
• Accumulation of lipoproteins
(mainly LDL and its oxidized
forms) in the vessel wall
• Monocyte adhesion to the
endothelium, followed by
migration into the intima and
transformation into
macrophages and foam cells

Epidemiology
of
atherosclerosis
• According to this schema, atherosclerosis
progresses in the following sequence:
• Platelet adhesion
• Factor release from activated
platelets, macrophages, and
vascular wall cells, inducing
smooth muscle cell recruitment,
either from the media or from
circulating precursors
• Smooth muscle cell proliferation,
extracellular matrix production, and
recruitment of T cells.
• Lipid accumulation both extracellularly
and within cells (macrophages and
smooth muscle cell)

Epidemiology
of
atherosclerosis
• Endothelial Injury.
• Endothelial cell injury is the cornerstone
of the response-to-injury hypothesis.
• Endothelial loss due to any kind of
injury—induced experimentally by
mechanical denudation, hemodynamic
forces, immune complex deposition,
irradiation, or chemicals—results in
intimal thickening.
• However, early human lesions begin at
sites of morphologically intact
endothelium.
• Thus, non-denuding endothelial
dysfunction underlies most human
atherosclerosis; the intact but
dysfunctional endothelial cells exhibit
increased endothelial permeability,
enhanced leukocyte adhesion, and
altered gene expression.

Epidemiology
of
atherosclerosis
• The specific pathways of and factors
contributing to endothelial cell
dysfunction in early atherosclerosis
are not completely understood:
etiologic culprits include toxins from
cigarette smoke, homocysteine, and
even infectious agents, according to
some (blame the bugs!).
• Inﬂammatory cytokines (e.g., tumor
necrosis factor [TNF]) can also
stimulate pro-atherogenic endothelial
gene expression.
• However, the two most important
causes of endothelial dysfunction are
hemodynamic disturbances and
hypercholesterolemia.

Epidemiology
of
atherosclerosis
• Hemodynamic Disturbances.
• The importance of hemodynamic
turbulence in atherogenesis is
illustrated by the observation that
plaques tend to occur at ostia of
exiting vessels, branch points,
and along the posterior wall of
the abdominal aorta, where there
are disturbed ﬂow patterns.
• In vitro studies have
demonstrated that nonturbulent
laminar ﬂow leads to the
induction of endothelial genes
whose products (e.g., the
antioxidant superoxide
dismutase) actually protect
against atherosclerosis.

Epidemiology
of
atherosclerosis
• Hemodynamic Disturbances.
• Such “atheroprotective”
genes could explain the
non-random localization
of early atherosclerotic
lesions.

Epidemiology
of
atherosclerosis
• Lipids.
• Lipids are transported in the
bloodstream bound to specifc
apoproteins (forming lipoprotein
complexes).
• Dyslipoproteinemias are
lipoprotein abnormalities that may
be present in the general
population (and indeed, are found
in many myocardial infarction
survivors) include
• Increased LDL
cholesterol levels
• Decreased HDL
cholesterol levels
• increased levels of the
abnormal lipoprotein (a).

Epidemiology
of
atherosclerosis
• Lipids.
• These may result from
mutations that lead to
defects in apoproteins or
lipoprotein receptors, or
arise from other
underlying disorders that
affect circulating lipid
levels, such as nephrotic
syndrome, alcoholism,
hypothyroidism, or
diabetes mellitus.
• All of these abnormalities are
associated with an increased
risk of atherosclerosis.

Epidemiology
of
atherosclerosis
• Lipids.
• The evidence implicating
hypercholesterolemia in atherogenesis
includes:
• The dominant lipids in
atheromatous plaques are
cholesterol and cholesterol esters.
• Genetic defects in lipoprotein
uptake and metabolism that cause
hyperlipoproteinemia are
associated with accelerated
atherosclerosis.
• For example, familial
hypercholesterolemia, caused
by defective LDL receptors
and inadequate hepatic LDL
uptake, can precipitate
myocardial infarctions before
age 20.

Epidemiology
of
atherosclerosis
• Lipids.
• Similarly, accelerated
atherosclerosis occurs in animal
models with engineered
deficiencies in apolipoproteins or
LDL receptors.
• Other genetic or acquired disorders
(e.g., diabetes mellitus,
hypothyroidism) that cause
hypercholesterolemia lead to
premature atherosclerosis.
• Epidemiologic analyses demonstrate a
significant correlation between the
severity of atherosclerosis and the levels
of total plasma cholesterol or LDL.
• Lowering serum cholesterol by diet or
drugs slows the rate of progression of
atherosclerosis, causes regression of
some plaques, and reduces the risk of
cardiovascular events.

Epidemiology
of
atherosclerosis
• Lipids.
• The mechanisms by which
hyperlipidaemia contributes to
atherogenesis include the following:
• Chronic hyperlipidaemia,
particularly hypercholesterolemia,
can directly impair endothelial cell
function by increasing local
reactive oxygen species
production; besides causing
membrane and mitochondrial
damage, oxygen free radicals
accelerate nitric oxide decay,
damping its vasodilator activity.
• With chronic hyperlipidaemia,
lipoproteins accumulate within the
intima, where they may aggregate
or become oxidized by free
radicals produced by inﬂamatory
cells.

Epidemiology
of
atherosclerosis
• Lipids.
atherogenesis include the following:
• Such modified LDL is then
accumulated by macrophages
through a variety of scavenger
receptors (distinct from the LDL
receptor).
• Because the modified
lipoproteins cannot be
completely degraded, chronic
ingestion leads to the formation
of lipid-filled macrophages called
foam cells; smooth muscle cells
can similarly transform into lipid-
laden foam cells by ingesting
modified lipids through LDL-
receptor related proteins.

Epidemiology
of
atherosclerosis
• Lipids.
atherogenesis include the
following:
• Not only are the modifed
lipoproteins toxic to
endothelial cells, smooth
muscle cells, and
macrophages, but their
binding and uptake also
stimulates the release of
growth factors, cytokines,
and chemokines that create
a vicious cycle of monocyte
recruitment and activation.

Epidemiology
of
atherosclerosis
• Inflammation.
• Chronic inflammation contributes to
the initiation and progression of
atherosclerotic lesions.
• It is believed that inflammation is
triggered by the accumulation of
cholesterol crystals and free fatty
acids in macrophages and other cells.
• These cells sense the presence of
abnormal materials via cytosolic
innate immune receptors that are
components of the inflammasome
• The resulting inflammasome
activation leads to the production of
the pro-inflammatory cytokine IL-1,
which serves to recruit leukocytes,
including monocytes.

Epidemiology
of
atherosclerosis
• Inﬂammation.
• T lymphocytes are also activated,
but what these T cells recognize
and why these substances are
detected as foreign “invaders” is
not known.
• The net result of macrophage and
T cell activation is the local
production of cytokines and
chemokines that recruit and
activate more inﬂammatory cells.
• Activated macrophages produce
reactive oxygen species that
enhance LDL oxidation, and
elaborate growth factors that drive
smooth muscle cell proliferation.

Epidemiology
of
atherosclerosis
• Inflammation.
• Activated T cells in the growing
intimal lesions elaborate
inflammatory cytokines, e.g.,
interferon-γ, which, in turn, can
activate macrophages as well as
endothelial cells and smooth
muscle cells.
• These leukocytes and vascular
wall cells release growth factors
that promote smooth muscle cell
proliferation and synthesis of
extracellular matrix proteins.
• Thus, many of the lesions of
atherosclerosis are attributable to
the chronic inflammatory reaction
in the vessel wall.

Epidemiology
of
atherosclerosis
• Infection.
• Although circumstantial evidence has
been presented linking
atherosclerosis to herpesvirus,
cytomegalovirus, and Chlamydophila
pneumoniae, there is no established
causal role for infection.
• Smooth Muscle
• Proliferation and Matrix Synthesis.
• Intimal smooth muscle cell
proliferation and extracellular
matrix deposition convert a fatty
streak into a mature atheroma
and contribute to the progressive
growth of atherosclerotic lesions.

Epidemiology
of
atherosclerosis
• Smooth Muscle
• Proliferation and Matrix Synthesis.
• Several growth factors are
implicated in smooth muscle cell
proliferation, including platelet-
derived growth factor (PDGF,
released by locally adherent
platelets, as well as
macrophages, endothelial cells,
and smooth muscle cells),
fibroblast growth factor, and
transforming growth factor-α.
• These factors also stimulate
smooth muscle cells to
synthesize extracellular matrix
(notably collagen), which
stabilizes atherosclerotic
plaques.

Epidemiology
of
atherosclerosis
• Smooth Muscle
• Proliferation and Matrix
Synthesis.
• In contrast, activated
inﬂammatory cells in
atheromas may increase
the breakdown of
extracellular matrix
components, resulting in
unstable plaques.

Epidemiology
of
atherosclerosis
• Overview.
• The concept of atherosclerosis as a
chronic inflammatory response—and
ultimately an attempt at vascular
“healing”—driven by a variety of
insults, including endothelial cell
injury, lipid oxidation and
accumulation, and inflammation.
• Atheromas are dynamic lesions
consisting of dysfunctional endothelial
cells, proliferating smooth muscle
cells, and admixed T lymphocytes and
macrophages.
• All four cell types are capable of
liberating mediators that can influence
atherogenesis.

Epidemiology
of
atherosclerosis
• Overview.
• Thus, at early stages, intimal plaques
are little more than aggregates of
smooth muscle cells, macrophages,
and foam cells; death of these cells
releases lipids and necrotic debris.
• With progression, the atheroma is
modified by extracellular matrix
synthesized by smooth muscle cells;
connective tissue is particularly
prominent on the intimal aspect
forming a fibrous cap, although
lesions also typically retain a central
core of lipid-laden cells and fatty
debris that can become calcified.

Epidemiology
of
atherosclerosis
• Overview.
• The intimal plaque may
progressively encroach on
the vessel lumen, or may
compress the underlying
media, leading to its
degeneration; this in turn
may expose thrombogenic
factors such as tissue factor,
resulting in thrombus
formation and acute vascular
occlusion.

Morphology of
Atherosclerosis
• Fatty streaks.
• Fatty streaks are composed of
lipid-filled foamy macrophages.
• Beginning as multiple minute ﬂat
yellow spots, they eventually
coalesce into elongated streaks 1
cm long or longer.
• These lesions are not
sufficiently raised to cause any
significant ﬂow disturbances.
• Although fatty streaks can evolve
into plaques, not all are
destined to become advanced
lesions.

Morphology of
Atherosclerosis
• Fatty streaks.
• Aortas of infants can exhibit
fatty streaks, and such lesions
are present in virtually all
adolescents, even those without
known risk factors.
• The observation that coronary
fatty streaks begin to form in
adolescence, at the same
anatomic sites that later tend
to develop plaques, suggests
a temporal evolution of these
lesions.

Morphology of
Atherosclerosis
• Atherosclerotic Plaque.
• The key processes in
atherosclerosis are intimal
thickening and lipid
accumulation, which together
form plaques.
• Atheromatous plaques are white-
yellow and encroach on the
lumen of the artery;
superimposed thrombus over
ulcerated plaques is red-brown.
• Plaques vary in size but can
coalesce to form larger masses.
• Atherosclerotic lesions are
patchy, usually involving only a
portion of any given arterial wall
and are rarely circumferential; on
cross-section, the lesions therefore
appear “eccentric”

Morphology of
Atherosclerosis
• The focality of atherosclerotic
lesions—despite the uniform exposure
of vessel walls to such factors as
cigarette smoke toxins, elevated
LDL, and hyperglycemia—is
attributable to the vagaries of
vascular hemodynamics.
• Local ﬂow disturbances, such as
turbulence at branch points,
make certain portions of a vessel
wall more susceptible to plaque
formation.
• Although focal and sparsely
distributed at first, with time
atherosclerotic lesions can become
larger, more numerous, and more
broadly distributed.
• Moreover, in any given vessel,
lesions at various stages often
coexist.

Morphology of
Atherosclerosis
• In descending order, the most
extensively involved vessels are the
lower abdominal aorta, the coronary
arteries, the popliteal arteries, the
internal carotid arteries, and the vessels
of the circle of Willis.
• In humans, the abdominal aorta
is typically involved to a much
greater degree than the
thoracic aorta.
• Vessels of the upper
extremities are usually spared,
as are the mesenteric and renal
arteries, except at their ostia.

Morphology of
Atherosclerosis
• Although most individuals tend to
have a consistent degree of
atherosclerotic burden in the
affected vasculature, severity of
disease in one arterial
distribution does not always
predict its severity in another.
• Atherosclerotic plaques have three
principal components:
• smooth muscle cells,
macrophages, and T cells
• extracellular matrix, including
collagen, elastic fibers, and
proteoglycans
• intracellular and extracellular lipid.

Morphology of
Atherosclerosis
• These components occur in
varying proportions and
configurations in different
lesions.
• Typically, there is a superficial
fibrous cap composed of smooth
muscle cells and relatively dense
collagen.
• Beneath and to the side of the
cap (the “shoulder”) is a more
cellular area containing
macrophages, T cells, and
smooth muscle cells.

Morphology of
Atherosclerosis
• Deep to the fibrous cap is a
necrotic core, containing lipid
(primarily cholesterol and cholesterol
esters), debris from dead cells,
foam cells (lipid laden
macrophages and smooth muscle
cells), fibrin, variably organized
thrombus, and other plasma
proteins; the cholesterol content
is frequently present as
crystalline aggregates that are
washed out during routine tissue
processing and leave behind only
empty “clefts.”
• The periphery of the lesions
demonstrate neovascularization
(proliferating small blood
vessels).

Morphology of
Atherosclerosis
• Most atheromas contain
abundant lipid, but some
plaques (“fibrous plaques”) are
composed almost exclusively of
smooth muscle cells and fibrous
tissue.
• Plaques generally continue to
change and progressively enlarge
through cell death and
degeneration, synthesis and
degradation (remodelling) of
extracellular matrices, and
organization of any superimposed
thrombus.
• Moreover, atheromas often
undergo calcification.
• Patients with advanced coronary
calcification have increased risk
for coronary events.

Morphology of
Atherosclerosis
• Atherosclerotic plaques are
susceptible to the following
clinically important pathologic
changes:
• Rupture, ulceration, or erosion .
• Hemorrhage into a plaque.
• Atheroembolism.
• Aneurysm formation.

Consequences
of Atherosclerotic
Disease
Large elastic arteries (e.g., aorta,
carotid, and iliac arteries) and large and
medium-sized muscular arteries (e.g.,
coronary and popliteal arteries) are the
major targets of atherosclerosis.
Symptomatic atherosclerotic disease
most often involves the arteries
supplying the heart, brain, kidneys, and
lower extremities.
Myocardial infarction (heart attack),
cerebral infarction (stroke), aortic
aneurysms, and peripheral vascular
disease (gangrene of the legs) are the
major consequences of atherosclerosis.

Consequences of
Atherosclerotic
Disease
• Atherosclerotic Stenosis.
• In small arteries, atherosclerotic
plaques can gradually occlude
vessel lumina, compromising blood
ﬂow and causing ischemic injury.
• At early stages of stenosis,
outward remodelling of the vessel
media tends to preserve the size of
the lumen.
• However, there are limits on the
extent of remodelling, and
eventually the expanding atheroma
impinges on the lumen to such a
degree that blood ﬂow is
compromised.
• Critical stenosis is the stage at
which the occlusion is sufficiently
severe to produce tissue ischemia.

Consequences of
Atherosclerotic
Disease
• Atherosclerotic Stenosis.
• In the coronary (and other)
circulations, this typically occurs at
when the occlusion produces a 70%
decrease in luminal cross-sectional
area; with this degree of stenosis,
chest pain may develop with exertion
(so-called stable angina.
• Although acute plaque rupture is the
most dangerous consequence,
atherosclerosis also takes a toll
through chronically diminished
arterial perfusion: mesenteric
occlusion and bowel ischemia,
sudden cardiac death, chronic
ischemic heart disease, ischemic
encephalopathy, and intermittent
claudication (diminished perfusion of
the extremities) are all consequences
of ﬂow-limiting stenoses.
• The effects of vascular occlusion
ultimately depend on arterial supply
and the metabolic demand of the
affected tissue.

Consequences of Atherosclerotic Disease
• Acute Plaque Change.
• Plaque erosion or rupture is typically promptly followed by
partial or complete vascular thrombosis, resulting in acute
tissue infarction (e.g., myocardial or cerebral infarction).
• Plaque changes fall into three general categories:
• Rupture/fissuring, exposing highly thrombogenic plaque
constituents
• Erosion/ulceration, exposing the thrombogenic
subendothelial basement membrane to blood
• Hemorrhage into the atheroma, expanding its volume.

Consequences of
Atherosclerotic
Disease
• It is now recognized that plaques
that are responsible for myocardial
infarction and other acute coronary
syndromes are often asymptomatic
before the acute change.
• Thus, pathologic and clinical
studies show that the majority of
plaques that undergo abrupt
disruption and coronary occlusion
previously showed only mild to
moderate noncritical luminal
stenosis.
• The worrisome conclusion is that a
large number of now asymptomatic
adults may be at risk for a
catastrophic coronary event.
• Unfortunately, it is presently
impossible to identify such
individuals.

Consequences of
Atherosclerotic
Disease
• Plaques rupture when they are
unable to withstand mechanical
stresses generated by vascular
shear forces.
• The events that trigger abrupt
changes in plaques and
subsequent thrombosis are
complex and include both intrinsic
factors (e.g., plaque structure and
composition) and extrinsic
elements (e.g., blood pressure,
platelet reactivity, vessel spasm).
• The composition of plaques is
dynamic and can contribute to risk
of rupture.

Consequences of
Atherosclerotic
Disease
• Thus, plaques that contain large
areas of foam cells and
extracellular lipid, and those in
which the fibrous caps are thin or
contain few smooth muscle cells or
have clusters of inﬂammatory cells,
are more likely to rupture; these
are referred to as “vulnerable
plaques”.
• The fibrous cap undergoes
continuous remodelling that can
stabilize the plaque, or conversely,
render it more susceptible to
rupture.
• Collagen is the major structural
component of the fibrous cap, and
accounts for its mechanical
strength and stability.
• Thus, the balance of collagen
synthesis versus degradation
affects cap integrity.

Consequences of
Atherosclerotic
Disease
• Collagen in atherosclerotic plaque is
produced primarily by smooth muscle
cells so that loss of these cells results
in a less sturdy cap.
• Moreover, collagen turnover is
controlled by metalloproteinases
(MMPs), enzymes elaborated largely
by macrophages and smooth muscle
cells within the atheromatous plaque;
conversely, tissue inhibitors of
metalloproteinases (TIMPs) produced
by endothelial cells, smooth muscle
cells, and macrophages modulate
MMP activity.
• In general, plaque inﬂammation
results in a net increase in collagen
degradation and reduced collagen
synthesis, thereby destabilizing the
mechanical integrity of the fibrous
cap.

Consequences of
Atherosclerotic
Disease
• The inflammation induced by
cholesterol deposits themselves
may contribute to plaque
destabilization.
• Conversely, statins may have a
beneficial therapeutic effect not
only by reducing circulating
cholesterol levels, but also by
stabilizing plaques through a
reduction in plaque inflammation.
• Influences extrinsic to plaques also
contribute to acute plaque
changes.
• Thus, adrenergic stimulation can
increase systemic blood pressure
or induce local vasoconstriction,
thereby increasing the physical
stresses on a given plaque.

Consequences of
Atherosclerotic
Disease
• Indeed, the adrenergic stimulation
associated with wakening and
rising can cause blood pressure
spikes (followed by heightened
platelet reactivity) that have been
causally linked to the pronounced
circadian periodicity for onset of
acute MI (peaking between 6 AM
and noon).
• Intense emotional stress can also
contribute to plaque disruption; this
is most dramatically illustrated by
the uptick in the incidence of
sudden death associated with
natural or other disasters.
• It is also important to note that not
all plaque ruptures result in
occlusive thromboses with
catastrophic consequences.

• Indeed, plaque disruption and an ensuing superficial platelet
aggregation and thrombosis are probably common, repetitive,
and often clinically silent complications of atheroma.
• Healing of these subclinical plaque disruptions—and
resorption of their overlying thrombi— is an important
mechanism in the growth of atherosclerotic lesions.

Consequences of
Atherosclerotic
Disease
• Thrombosis.
• Partial or total thrombosis
superimposed on a disrupted
plaque is a central factor in
acute coronary syndromes.
• In its most serious form,
thrombosis leads to total
occlusion of the affected
vessel.
• In contrast, in other coronary
syndromes , luminal
obstruction by the thrombus
is incomplete, and may even
wax and wane with time.
• Mural thrombi in a coronary
artery can also embolize.

• Thrombosis.
• Indeed, small embolic fragments of thrombus can often be
found in the distal intramyocardial circulation or in association
with microinfarcts in patients with atherosclerosis who die
suddenly.
• Finally, thrombin and other factors associated with thrombosis
are potent activators of smooth muscle cells and can thereby
contribute to the growth of atherosclerotic lesions.

• Vasoconstriction.
• Vasoconstriction compromises lumen size, and, by increasing
the local mechanical forces, can potentiate plaque disruption.
Vasoconstriction at sites of atheroma may be stimulated by
• circulating adrenergic agonists
• locally released platelet contents
• endothelial cell dysfunction with impaired secretion of
endothelial derived relaxing factors (nitric oxide) relative to
contracting factors (endothelin)
• mediators released from perivascular inﬂammatory cells.

• The Forensic Aspects of Atherosclerosis

Atherosclerotic cardiovascular disease
DISEASES OF THE HEART
ACCOUNT FOR
APPROXIMATELY 90 PERCENT
OF ALL SUDDEN DEATHS DUE
TO NATURAL DISEASE, WITH
ATHEROSCLEROTIC
CORONARY ARTERY DISEASE
BEING THE UNDERLYING
CAUSE OF APPROXIMATELY 75
TO 90 PERCENT OF SUDDEN
CARDIAC DEATHS.
THIS IS THE PREDOMINANT
PATHOLOGY SEEN IN
NATURAL DEATHS
INVESTIGATED BY CORONERS.
THE REMAINING CARDIAC
RELATED DEATHS CAN BE
ATTRIBUTED TO
HYPERTENSION, VALVULAR
DISEASE,
NONATHEROSCLEROTIC
CORONARY ARTERY DISEASE,
MYOCARDITIS,
CARDIOMYOPATHY, OR
CONDUCTION SYSTEM
DISORDERS.
DEATH DUE TO
ATHEROSCLEROTIC
CORONARY ARTERY DISEASE
IS OF GREATEST INCIDENCE IN
THE 35- TO 64-YEAR AGE
RANGE.

Only 25 to 40 percent of individuals
dying suddenly of atherosclerotic
coronary artery disease will have
evidence of an acute myocardial
infarct.
The remainder have suffered a
cardiac arrhythmia, usually
ventricular tachycardia
degenerating to ventricular
fibrillation, originating from an
ischemic (but not infarcted) focus of
myocardium.
They can be symptomatic for as
little as 6 to 10 seconds,
representing the time from the
onset of their terminal arrhythmia
to loss of consciousness.
In those who are symptomatic,
overwhelming tiredness is the most
common complaint, followed by
shortness of breath.

• Chest pain is only the third most commonly reported symptom.
• Sudden death is the first and only symptom of the underlying
atherosclerotic coronary artery disease in approximately 25 to 40
percent of individuals who die in this way.
• The only significant finding at autopsy is severe atherosclerotic
narrowing of the coronary arteries, which can be extensive or can
be localized to as little as a single focus of greater than 75 percent
narrowing in one vessel.
• In some there may even be less than 75 percent atherosclerotic
narrowing of the coronary arteries.

Attributing the death to atherosclerotic coronary artery disease is
reasonable in this instance if the death is sudden and there are no other
significant autopsy or toxicology findings.
A coronary thrombus may be present, in which case an infarct may have
developed had the individual survived longer.
The myocardium is generally histologically unremarkable, although there
may be sites of contraction band necrosis, which are not specific for acute
ischemia, and sites of patchy nontransmural myocardial fibrosis, suggesting
the presence of chronic ongoing ischemia.

Atherosclerotic cardiovascular
disease
• Although underlying risk factors, such as
hypertension, smoking, diabetes mellitus,
hypercholesterolemia, and a family history of
cardiovascular disease should be searched for in all
cases, this is particularly relevant if significant
atherosclerotic coronary disease is found in males
less than 35 years of age or in premenopausal
women.
• A search for a history of cocaine abuse and
postmortem screening of blood for cocaine is
advisable in these cases, as cocaine use has been
associated with the early onset of atherosclerosis
and with acute coronary thrombosis.
• In addition, cholesterol and triglyceride levels can be
measured in postmortem blood samples.

• The results of such postmortem screenings must be interpreted
with caution, because it is often not possible to establish when
individuals last ate prior to their death.
• Family members should be advised of significantly elevated
cholesterol or triglyceride levels so that they themselves can seek
medical attention in order to rule out a familial hyperlipidemia.

Atherosclerotic
cardiovascular
disease
• So what is significant coronary artery
narrowing?
• It is generally accepted that 75
percent narrowing of a coronary
artery, by any disease process, is
significant and can result in clinical
expression of disease, including
sudden death.
• One must then ask, “Does 75
percent refer to the area or diameter
of the vessel and what does 75
percent narrowing look like?”
• Estimates of coronary artery
narrowing are made with respect to
the cross-sectional luminal area of
the vessel.

Atherosclerotic
cardiovascular disease
• So what is significant coronary artery narrowing?
• When one considers that the area of a circle = pr 2
(where r = the radius), then one can calculate that
reducing the diameter of a coronary artery by 50
percent with a concentric plaque is the equivalent of
reducing its area by 75 percent.
• This is why radiologists look for a site of 50 percent
narrowing of the diameter of a coronary artery on an
angiogram when trying to establish the presence or
absence of significant coronary artery disease.
• Although it is nice to be able to accurately estimate
various degrees of coronary artery narrowing, the
most important point is recognizing whether the
narrowing is greater than or equal to 75 percent.

Atherosclerotic
cardiovascular
disease
• A 29-year-old male
• Was playing hockey when he left the ice
complaining of chest discomfort.
• He collapsed on the bench and was in
ventricular fibrillation when paramedics
arrived.
• All attempts at resuscitation were
unsuccessful.
• He smoked one package of cigarettes
per day, but had no other significant
past medical history.
• At autopsy, there was greater than 75
percent atherosclerotic narrowing of the
left anterior descending coronary artery.
• There were no other cardiac
abnormalities.

A 35-YEAR-OLD
HYPERTENSIVE MALE
COLLAPSED AND DIED
SUDDENLY IN HIS
PRISON CELL AFTER
COMPLAINING OF
RECENT FLU-LIKE
SYMPTOMS
ASSOCIATED WITH LEFT
SHOULDER AND BACK
PAIN.
AT AUTOPSY AN
OCCLUSIVE
ANTEMORTEM
THROMBUS WAS
FOUND AT A SITE OF
SIGNIFICANT
ATHEROSCLEROTIC
NARROWING WITHIN
THE LEFT CIRCUMFLEX
CORONARY ARTERY.
HISTOLOGICALLY,
THERE WAS EVIDENCE
OF A PLAQUE FISSURE,
WHICH IS THOUGHT TO
PLAY A ROLE IN THE
PATHOGENESIS OF
ATHEROSCLEROSIS-
ASSOCIATED THROMBI.
THERE WAS GROSS AND
HISTOLOGIC EVIDENCE
OF AN ACUTE
TRANSMURAL
MYOCARDIAL INFARCT
EXTENDING FROM THE
BASE TO THE APEX OF
THE LATERAL FREE
WALL OF THE LEFT
VENTRICLE, WITH
SLIGHT EXTENSION
ONTO THE ANTERIOR
AND POSTERIOR
WALLS.
THIS IS THE MORE
CLASSIC PRESENTATION
OF ATHEROSCLEROTIC
CORONARY ARTERY
DISEASE, ASSOCIATED
WITH AN ACUTE
MYOCARDIAL INFARCT,
KNOWN TO CLINICIANS
AND PATHOLOGISTS IN
PATIENTS ADMITTED TO
HOSPITAL WITH
PERSISTENT CHEST
PAIN.

A 58-YEAR-OLD MALE
COLLAPSED
SUDDENLY IN THE
EMERGENCY ROOM
OF A RURAL HOSPITAL
WHERE HE HAD
PRESENTED
COMPLAINING OF
UPPER BACK PAIN. AN
ECG OBTAINED PRIOR
TO HIS COLLAPSE WAS
INTERPRETED AS
NORMAL.
AT AUTOPSY,
APPROXIMATELY 500
MILLILITERS OF FLUID
AND CLOTTED BLOOD
WAS FOUND WITHIN
THE PERICARDIAL SAC.
THERE WAS
SIGNIFICANT
NARROWING OF EACH
MAJOR CORONARY
ARTERY, TOGETHER
WITH OCCLUSIVE
ANTEMORTEM
THROMBUS IN THE
PROXIMAL THIRD OF
THE RIGHT CORONARY
ARTERY.
A TRANSMURAL
INFARCT EXTENDED
FROM THE BASE TO
THE APEX OF THE
POSTERIOR FREE
WALL OF THE LEFT
VENTRICLE, WITH
DISSECTION OF
BLOOD FROM THE
LEFT VENTRICULAR
CHAMBER THROUGH
THE NECROTIC
MYOCARDIUM AND
INTO THE
PERICARDIAL SAC.
RUPTURE OF AN
ACUTE MYOCARDIAL
INFARCT (I.E.,
CARDIORRHEXIS)
THROUGH A FREE
WALL OF THE LEFT
VENTRICLE IS ONE OF
THE TWO MOST
COMMON CAUSES OF
HEMOPERICARDIUM
COMPLICATING
NATURAL DISEASE
SEEN BY FORENSIC
PATHOLOGISTS(THE
SECOND IS AORTIC
DISSECTION).
MOST COMMONLY,
THE RUPTURE
OCCURS WITHIN 3 TO
7 DAYS OF THE ONSET
OF THE TERMINAL
INFARCT.

In some cases of arrhythmic sudden cardiac death due to
atherosclerotic coronary artery disease, wherein there is an apparent
lack of any previous cardiac history, definitive evidence of chronic
ischemic heart disease may be found.
Apart from significant atherosclerotic narrowing of coronary arteries,
there may be evidence of previous infarcts or of more widespread
myocardial fibrosis with left ventricular hypertrophy and dilatation.
In these cases, the question is not so much why the person died, but
how he or she managed to live so long in the face of such serious
cardiac disease.

Atherosclerotic cardiovascular
disease
• Apart from atherosclerotic coronary artery disease,
atherosclerosis can also present as the underlying cause of a
sudden natural death in the form of a ruptured abdominal aortic
aneurysm.

• This 81-year-old male
• Was complaining of back and abdominal pain.
• He became unresponsive as his family transported him to
hospital, and he subsequently died in the emergency room.
• At autopsy, a large retroperitoneal hematoma was identified.
• An atherosclerotic abdominal aortic aneurysm, which
measured approximately 7 centimeters in diameter, was found
just proximal to the bifurcation of the abdominal aorta.

• This 81-year-old male
• There was an obvious rupture of the right anterolateral surface
of the aneurysm, thus accounting for the retroperitoneal
hematoma.
• The intimal surface of the aneurysm exhibited the typical
appearance of extensive complicated atherosclerotic plaque
associated with adherent laminated antemortem thrombus.

Atherosclerotic
cardiovascular
disease
• Do
• Remember that the majority of
sudden deaths caused by
atherosclerotic coronary artery
disease are not associated with a
coronary thrombus or an acute
myocardial infarct.
• Remember that the first and only
symptom of significant coronary
artery disease can be sudden
death.
• Look for risk factors of
atherosclerosis (including cocaine
abuse) in the medical history and
at autopsy, particularly when
significant disease is found in
males less than 35 years of age
and in premenopausal females.

Do
Have a clear image in your mind of what
75 percent narrowing (i.e., significant
narrowing) of a coronary artery actually
looks like.
Don’t
Assume that the absence of an acute
myocardial infarct means a death cannot
be attributed to atherosclerotic coronary
artery disease.
Be surprised by the extent of
atherosclerosis and ischemic heart
disease that can be found at autopsy in
individuals with no prior cardiac
symptoms or history.

• Pathologic basis of disease
• ISBN 978-1-4557-2613-4
• I. Kumar, Vinay, 1944- editor. II. Abbas, Abul K., editor. III. Aster,
Jon C., editor.

• Forensic Pathology, Principles and Practice
• David Dolinak, M.D.
• Evan W. Matshes, M.D.
• Emma O. Lew, M.D.

Basic Science and Forensic Pathology Aspects of Atherosclerosis

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