MECHANISM OF

ATHEROSCLEROSIS
FLORENCE RAJARETNAM, M.Sc;M.Phil.

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 Know Your Lipid Profile
Fasting Blood Level Ideal, Healthy Level

Total Cholesterol < 200 mg/dl

LDL-Cholesterol < 100 mg/dl

HDL-Cholesterol 60 mg/dl

Triglycerides < 150 mg/dl

Atherosclerosis (or arteriosclerotic
vascular disease) is a condition where

the arteries become narrowed and

hardened which can significantly reduce
the blood supply to vital organs such as
the heart, brain and intestines.

the arteries are narrowed when fatty

deposits called plaques build up inside.

Plaques typically contain cholesterol

from low-density lipoproteins (LDL),
smooth-muscle cells and fibrous tissue,
and sometimes calcium. 3
Arteriosclerosis and atherosclerosis

Arteriosclerosis and atherosclerosis are

different conditions:

Arteriosclerosis is the stiffening or

hardening of the artery walls.

Atherosclerosis is the narrowing of the

artery because of plaque build-up.

Atherosclerosis is a specific type of

arteriosclerosis.
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All patients with atherosclerosis have
arteriosclerosis,

but those with arteriosclerosis might not

necessarily have atherosclerosis.

However, the two terms are frequently

used with the same meaning.

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Atherosclerosis starts when the
endothelium becomes damaged, allowing
LDL cholesterol to accumulate in the
artery wall.

The body sends macrophage white blood

cells to clean up the cholesterol, but
sometimes the cells get stuck there at the
affected site.

Over time this results in plaque being built

up, consisting of LDL cholesterol and
macrophage white blood cells.
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The plaque clogs up the artery, disrupting
the flow of blood around the body.

This potentially causes blood clots that

can result in life-threatening conditions
such as heart attack, stroke and other
cardiovascular diseases.

The condition can affect the entire artery

tree, but mainly affects the larger high-
pressure arteries.

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Mechanism
Atherogenesis is the developmental
process of atheromatous plaques.

It is characterized by a remodeling of
arteries leading to subendothelial
accumulation of fatty substances called
plaques

The buildup of an atheromatous plaque is

a slow process over a period of
several years starting from early childhood

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 Low density lipoprotein (LDL) particles
in blood plasma invade the endothelium
and become oxidized, creating risk of
cardiovascular disease.

A complex set of biochemical reactions

regulates the oxidation of LDL, involving
enzymes and free radicals in the
endothelium.

Initial damage to the endothelium

results in an inflammatory response.

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Monocytes enter the artery wall from the
bloodstream, with platelets adhering to the
area of damage.

The monocytes differentiate into

macrophages, which ingest oxidized LDL,
slowly turning into large "foam cells" .

The foam cells are so-called because of

their changed appearance due to
numerous internal cytoplasmic vesicles
and high lipid content.

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If these foam cells are not able to
process the oxidized LDL and recruit HDL
particles to remove the fats,

they grow and eventually rupture,

leaving behind cellular membrane
remnants, oxidized materials, and fats
(including cholesterol) in the artery wall.

Cholesterol is delivered into the vessel

wall by cholesterol-containing low-density
lipoprotein (LDL) particles.

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To attract and stimulate macrophages,
the cholesterol must be released from the
LDL particles and oxidized, a key step in
the ongoing inflammatory process.

The process is worsened if there is

insufficient high-density lipoprotein (HDL),
which are protective because HDL remove
cholesterol from tissues and carries it back
to the liver.

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Diseases in which prolonged elevated
levels of VLDL, IDL, chylomicron
remnants, or LDL occur in the blood

eg, diabetes mellitus, lipid nephrosis,

hypothyroidism, and other conditions of
hyperlipidemia)

are often accompanied by premature or

more severe atherosclerosis.

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There is an inverse relationship between
HDL concentrations and coronary heart
disease, making the LDL:HDL cholesterol
ratio a good predictive parameter. .

high levels of LDL cholesterol are

atherogenic,

high levels of HDL cholesterol are

protective

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Lipoprotein(a)
is essentially an LDL particle that is
covalently bound to apoprotein(a).

It is called "lipoprotein little a" to avoid

confusion with the apoprotein A found in
LDL .

The structure of apoprotein(a) is very

similar to that of plasminogen, a
precursor of the protease plasmin that
degrades fibrin, a major component of
blood clots.

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Lipoprotein(a), however, cannot be
converted to active plasmin.

There are reports that high

concentrations of lipoprotein(a) correlate
with an increased risk of coronary artery
disease, even in patients in whom the lipid
profile is otherwise normal.

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DYSLIPIDEMIA
Is defined as an abnormal plasma lipid
status.
Common lipid abnormalities include
elevated levels of
total cholesterol, LDL cholesterol ,
Lp(a) cholesterol and triglycerides;
or
low levels of HDL cholesterol and an
occurrence of small dense LDL particles.

These abnormalities can be found alone

or in combination.

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Hyperlipidemias may basically be
classified as either

familial (also called primary) caused by

specific
or
acquired (also called secondary)
when resulting from another underlying
disorder that leads to alterations in
plasma lipid and lipoprotein metabolism.

Hyperlipidemia may be idiopathic, that

is, without known cause.
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Hyperlipidemias are also classified
according to which types of lipids are
elevated,
hypercholesterolemia,

hypertriglyceridemia

or both in combined hyperlipidemia.

Elevated levels of Lipoprotein(a) may

also be classified as a form of
hyperlipidemia

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Frederickson -WHO classification
Type I: incr. chylomicrons, reduced HDL,
absence of lipoprotein lipase; deficiency
of apo CII (hyperchylomironemia)
Type II-A: raised LDL; decreased
catabolism of LDL (receptor deficiency
or polygenic)
Type II-B: raised VLDL + LDL; often
reduced HDL; increased production of
VLDL + impaired LDL catabolism

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Type III: raised IDL
(dysbetalipoproteinemia); abnormal
apolipoprotein E; impaired catabolism of
IDL; elevated cholesterol and triglycerides
(formerly known as broad beta disease)
Type IV: raised VLDL; often reduced HDL;
impaired VLDL catabolism; dietary
indiscretion ( formerly known as
hyperprebetalipoproteinemia)
Type V: raised chylomicrons + VLDL;
reduced HDL; reduced lipoprotein lipase +
VLDL hypersecretion (formerly known as
mixed lipemia)
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Familial hypercholesterolemia ( FH)

A hereditary form of high LDL

termed hyperlipoproteinemia type II
(after the Fredrickson classification).

is a genetic disorder characterized by

high cholesterol levels, specifically very
high levels of low-density lipoprotein in
the blood and early cardiovascular
disease.

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There is mutation in
the LDLR (Low Density Lipoprotein
Receptor) gene that encodes the
LDL receptor protein, which
normally removes LDL from the
circulation,
or
apolipoprotein B (ApoB), which is
the part of LDL that binds with the
receptor

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LDL receptor
The Low-Density Lipoprotein (LDL)
Receptor mediates the endocytosis of
cholesterol-rich LDL.

It is a cell-surface receptor that

recognizes the apoprotein B100, which is
embedded in the outer phospholipid layer
of LDL particles.

The receptor also recognizes the apoE

protein found in chylomicron remnants and
VLDL remnants (IDL).

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 The plasma LDL levels are inversely
related to the activity of LDL receptor
(LDLR).

Homozygotes have LDLR activity of less

than 2%,

Heterozygotes have defective LDL

processing with receptor activity being
225%.

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Function
LDL receptor complexes are present in
clathrin-coated pits (or buds) on the cell
surface

when bound to LDL-cholesterol , are

pinched off to form clathrin-coated
vesicles inside the cell.

The LDL-cholesterol is bound and

internalized by endocytosis.

Once the coated vesicle is internalized it

sheds its clathrin coat and fuses with an
acidic endosome. 28
The change in pH causes a
conformational change in the receptor
that releases the bound LDL particle.

The receptors are then either destroyed

or they can be recycled via the endocytic
cycle back to the surface of the cell
where the neutral pH will cause the
receptor to revert to its native
conformation ready to receive another
LDL particle.

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Synthesis of receptors in the cell is
regulated by the level of free intracellular
cholesterol

if it is in excess for the needs of the cell

then the transcription of the receptor gene
will be inhibited.

LDL receptors are translated by

ribosomes on the endoplasmic reticulum
and are

modified by the Golgi apparatus before

travelling in vesicles to the cell surface.
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The degree of atherosclerosis
approximately depends of the number of LDL
receptors still expressed and the
functionality of these receptors.

The plasma LDL levels are inversely related

to the activity of LDL receptor (LDLR).

Heterozygotes have defective LDL

processing with receptor activity being 2
25%.
the receptor function is only mildly
impaired, and LDL levels will remain
relatively low.
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A single abnormal copy (heterozygote) of
FH causes cardiovascular disease by the
age of 50 in about 40% of cases.

Homozygotes have LDLR activity of less

than 2%, or the receptor is not expressed
at all.[

Having two abnormal copies

(homozygote) causes accelerated
atherosclerosis in childhood, including its
complications

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LDL receptor and atherosclerosis

LDL cholesterol normally circulates

in the body for 2.5 days, before its
uptake and digestion in the liver.

In FH, since the LDL receptor function

is reduced or absent, LDL circulates for
an average duration of 4.5 days,
resulting in significantly increased level
of LDL cholesterol in the blood with
normal levels of other lipoproteins.

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Apolipoprotein B
Apolipoprotein B, in its ApoB100 form, is
the main apolipoprotein of the LDL
particle.

FH is often associated with the mutation

of ApoB100.

The mutation is located on a part of the

protein that normally binds with the LDL
receptor.

binding is reduced as a result of the

mutation which causes the increased
level of LDL cholesterol. 35
Hypertriglyceridemia
denotes high blood levels of triglycerides,
Elevated levels of triglycerides are
associated with atherosclerosis, even in
the absence of hypercholesterolemia and
predispose to cardiovascular disease.

Very high triglyceride levels also

increase the risk of acute pancreatitis.

Hypertriglyceridemia itself is usually

symptomless, although high levels may be
associated with skin lesions known as
xanthomas.
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Hypertriglyceridemia results from
increased production of very low-density
lipoprotein (VLDL)

reduced VLDL clearance,

or

more commonly the dual effect of both

processes.

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 The two main sources of plasma
triglycerides are
exogenous (i.e., from dietary fat) and
carried in chylomicrons,

and endogenous (from the liver) and

carried in very-low-density lipoprotein
(VLDL) particles. .

After a meal, over 90% of the circulating

triglycerides originate in the intestine and
are secreted in chylomicrons

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 Whereas, during periods of fasting,
endogenous triglycerides are secreted by
the liver as predominantly VLDL .

Both VLDL and chylomicron particles

are cleared by a common pathway that
involves tissue lipoprotein lipases which
requires Apo C-II for its activation

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The increase in plasma of triglyceride-rich
lipoproteins results from

increased production from the liver

and intestine

or

through decreased peripheral catabolism

(mainly from reduced lipoprotein lipase
activity).

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 Moderate hypertriglyceridemia is
almost certainly an independent risk
factor for cardiovascular disease.

triglyceride-rich lipoproteins and their

remnants may directly contribute to the
formation of arterial-wall foam cells.

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