You are on page 1of 4

Others:

Lack of exercise; competitive, stressful


lifestyle (Type A personality -very
aggressive, you are always on your
toes); and obesity (complicated by
hypertension,
diabetes,
hypertriglyceridemia,
and
decreased
HDL)
* These are the risk factors that add up to
the development of atherosclerosis.

PATHOGENESIS OF ATHEROSCLEROSIS
Response
to
injury
hypothesis
(Endothelial cells)
* Recall HEMOSTASIS.
Once you open your endothelium, what will
happen? You expose your SUBENDOTHELIAL
layer. This layer is very active, not inert,
component of the blood vessel and it can
initiate a lot of reactions, aside from
hemostasis. It can also invite your
inflammation and your cholesterol.
* These are some of the things that can be
initiated when you have an endothelial
injury.
Atherosclerosis
as
a
chronic
inflammatory and healing response of
the arterial wall to endothelial injury
Interaction of modified lipoproteins,
monocyte-derived
macrophages,
and T lymphocytes with endothelial
cells and smooth muscle cells of the
arterial wall.
*These are the composition of your
atherosclerosis, it is just an interplay of
these factors.

This is the summary of the Pathogenesis:


Endothelial injury and dysfunction,
causing increased vascular permeability,
leukocyte adhesion, and thrombosis.
Hindi lang injury, pati na rin dysfunction.
Ibig sabihin ng dysfunction, there is no injury
in
the
endothelium,
but
itself,
is
dysfunctional, if this is the case, it can
activate coagulation already, even without
being injured.
Accumulation of lipoprotein (mainly
LDL and its oxidized forms) in the vessel
wall.
Oxidation of LDL is d/t the interaction of
other cells in the intima (Top most layer of
your Blood Vessel Wall). Usually they
accumulate here.
Monocyte
andhesion
to
the
endothelium, followed byt migration

into the intima and transformation into


macrophages and foam cells.
Platelet Adhesion
Factor release from activated
platelets, macrophages, and vascular
wall cells, including smooth muscle
cell recruitment, either from the
media or from circulating precursors.
Smooth Muscle Cell Proliferation,
extracellular matrix production, and
recruitment of T cells.
These are also important because they are
the one activating your cytokines. So
nagkakaroon ng smooth muscle recruitment
or migration and proliferation.
Diyan din sila pupunta sa intima, from the
lower one, going to the media, progressing,
dumadami na yung laman ng vessel. Kaya
yung intima, nagkaroon na ng media. Lahat
na are invited into the site.
More complex, more composition of your
atherosclerosis.

Lipid accumulation both extracellularly


and within cells (macrophages and
smooth muscle cell)

ENDOTHELIAL INJURY
- The cornerstone of the response to injury
hypothesis
- The intact but dysfunctional endothelial
cells
exhibit
increased
endothelial
permeability, enhanced leukocyte adhesion,
and altered gene expression.
TWO MOST IMPORTANT CAUSES
1. Hemodynamic disturbances
2. Hypercholesterolemia
HEMODYNAMIC DISTURBANCES
- Turbulence plaques occur at the ostia of
the existing vessels, branch points, and
along the posterior wall of the abdominal
aorta.
Mabilis na flow, and this is due to
hypertension
- non-turbulent laminar flow leads to the
induction of endothelial genes whose
products (eg., the antioxidant superoxide
dismutase)
actually
protect
against
atherosclerosis.
Opposite naman is sluggish, or stasis, so
mabagal yung blood flow, nagcocause din
sya ng injury. Bakit? Kasi the cells settle to
the bottom, syempre may platelet yun, mag
aadhere sa endothelium, it can activate your
platelets, leading to coagulation. Stasis is
caused by viscosity brought about by

hypercoagulability. So increased yung RBC,


flow is sluggish, causing stasis.
Lipids - Hypercholesterolemia
Pag increased ang cholesterol, mas mataas
ang risk factor for your endothelial injury.
- Transported in the bloodsteam bound to
specific apoproteins (forming lipoprotein
complexes).
Dyslipoproteinemias
are
lipoprotein
abnormalities.
Definition of Dyslipidemia:
1. Increase LDL cholesterol levels
2. Decreased HDL Cholesterol levels
3. Increase levels of the abnormal
Lipoprotein A
Anything that will increase the lipid will
bring about the 3 changes in your
dyslipidemia.

Lipoprotein A
- Result from mutations that lead to defects
in apoproteins or lipoprotein receptors, or
arise from the underlying disorders that
affect the circulating lipid levels, such as
nephrotic
syndrome,
alcoholism,
hypothyroidism, or Diabetic melitus.
HYPERCHOLESTEROLEMIA
(aka
Dyslipidemia accdg to Doc Eclarin)
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
Familial hypercholesterolemia, caused by
defective LDL receptors and inadequate
hepatic LDL uptake, can precipitate
myocardial infarctions before age 20
Accelerated atherosclerosis occurs in
animal
models
with
engineered
deficiencies in apolipoproteins or LDL
receptors.
Other genetic or acquired disorders (eg.
DM,
hypothyroidism)
that
cause
hypercholesterolemia lead to premature
atherosclerosis.
Significant correlation between the
severity of atherosclerosis and the
levels of total plasma cholesterol or
LDL.
Dinedetermine
natin
yung
level
ng
cholesterol or LDL, kasi, the higher level, the
greater or the faster the development of
atherosclerosis. Severity depends of the diet

and level of cholesterol and LDL in the


body.
Lowering serum cholesterol by diet or
drugs slow the rate of progression of
some plaques, and reduces the risk of
cardiovascular events
This is beneficial. Sometimes, sinuswerte
ka, natutunaw. So there will be regression of
your atherosclerotic plaque. And it will stop
the propagation of your cholesterol plaque.
Hyperlipidemia
contributes
to
atherogenesis.
Chronic
hyperlipidemia
(hypercholesterolemia)
impair
endothelial cell function by increasing
local reactive oxygen species production
Causing
membrane
and
mitochondrial damage
Oxygen free readicals accelerate
nitric oxide decay, damping its
vasodilator activity
Lipoproteins accumulate within the
intima, where they may aggregate or
become oxidized by free radicals
produced by inflammatory cells
Modified
LDL
accumulated
by
macrophages through a variety of
scavenger receptors
INFLAMMATION
Initiation
and
progression
of
athersclerotic lesions
Sense the presence of abnormal
materials
via
cytosolic
innate
immune
receptors
that
are
components of the inflammasome
Inflammasome activation production
of the proinflammatory cytokine IL-I,
which serves to recruit leukocytes,
including monocytes
T Lymphocytes are also activated
Atherosclerosis are attributable to the
chronic inflammatory reaction in the
vessel wall
INFECTION
- herpes virus, cytomegalovirus, and
Chlamidophila pneumoniae
- no established causal role for infection
Not established. It is more on the
inflammation. So kahit na walang infection in
the body, basta may inflammation, it still can
progress.
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
Accumulation of your smooth muscle from
the intima or from the circulation, both of
them can accumulate in the intima. Di ba,
inherent yung smooth muscle sa intima?
Yung iba, galing sa blood circulation.
Intimal smooth muscle cells have a
proliferative and synthetic phenotype
distinct from the underlying medial
smooth muscle cells
Growth factors are implicated platelet - derived growth factor
fibroblast
growth
factor
and
transforming growth factor - alpha
Also stimulate smooth muscle cells to
synthesize
extracellular
matrix
(notably collagen), which stabilizes
atherosclerotic plaques
Activated inflammatory cells in
atheromas
may
increase
the
breakdown of extracellular matrix,
components, resulting in unstable
plaques

Intimal Plaques - aggregates of smooth


muscle cells, macrophages, and
foam cells; death of these cells releases
lipids and necrotic debris
*** Composition of the Plaque
With progression, the atheroma modified
by
extracellular
matrix
synthesized by smooth muscle cells;
connective
tissue
is
particularly
prominent on the intimal aspect forming
a fibrous cap - become calcified
Intimal
plaque
may
progressively
encroach on the vessel lumen, or may
compress the underlying media, leading
to its degeneration.
May expose thrombogenic factors such
as tissue factor, resulting in thrombus
formation and acute vascular occlusion
MORPHOLOGY

This is just an overall picture of cholesterol


recruitment of your polynuclear cells,
smooth muscle, pwedeng sa circulation
galing,
pwedeng
migration.
Yung
mononuclear cells will become activated, so
theres accumulation of your lipid and they
will become oxidized, and they become the
FOAM CELLS. Nagkakaroon ng changes sa
configuration of the cell. And eventually, will
become plaque.
SUMMARY
Atheromas - consisting of dysfunctional
endothelial cells, proliferating smooth
muscle cells, and T Lymphocytes and
macrophages
*MEMORIZE DAW! PWEDENG ESSAY!

FATTY STREAKS
Eto yung nakikita niyo sa baby. Sa simula,
pagconsume ng milk, fatty streak na kaagad
yan, kasi lipid - filled foamy cells
macrophages. Kahit yung first few days to
few months ng bata meron na kaagad nito.
Composed
of
lipid-filled
foamy
machrophages
Multiple minute flat yellow spots,
eventually coalesce into elongated
streaks 1cm long or longer

ATHEROSCLEROTIC PLAQUE
Intimal
thickening
and
lipid
accumulation, which together form
plaques
Continuous accumulation of cholesterol,
intimal thickening and lipid accumulation.
White yellow and enroach on the lumen
of the artery, superimposed thrombus
over ulcerated plaqes is red brown
Vary in size but can coalesce to form
larger masses