Atherosclerosis

Atherosclerosis- A Brief Review

Biochemistry for Medics
www.namrata.co
11/15/2012 Biochemistry for Medics 1

Normal Blood Vessel Wall
• Vessel walls are
organized into three
concentric layers:
intima, media, and
adventitia
• These are present to
some extent in all
vessels but are most
apparent in larger
arteries and veins.


Blood vessel walls
1. The three tunics:
a) Tunica intima
(1) Endothelium
(2) Subendothelial layer
b) Tunica media
(1) Smooth muscle
(2) Elastin
c) Tunica adventitia (externa)
(1) CT(Connective tissue) surrounding TM(Tunica Media)
(2) Arterioles in larger vessels


• Arterial walls are
thicker than
corresponding
veins at the same
level of branching
to accommodate
pulsatile flow and
higher blood
pressure.


Classes of Arteries
Arteries
a) Elastic arteries – large arteries near heart
b) Muscular (distributing) arteries – thick tunica
media
c) Arterioles- Diameter regulated by
vasoconstriction/dilation
Atherosclerosis affects mainly elastic and muscular
arteries and hypertension affects small muscular
arteries and arterioles.


Atherosclerosis
Atherosclerosis is a disease of large and
medium-sized muscular arteries and is
characterized by –
endothelial dysfunction,
vascular inflammation, and
the buildup of lipids, cholesterol, calcium, and
cellular debris within the intima of the vessel
wall.


Atherosclerosis

It is characterized by
intimal lesions called
atheromas (also called
Atheromatous or
atherosclerotic
plaques), that
protrude into vascular
lumina.


Atheromatous plaque

An Atheromatous plaque consists of a
raised lesion with a soft, yellow, grumous core
of lipid (mainly cholesterol and cholesterol
esters) covered by a firm, white fibrous cap.
Besides obstructing blood
flow, atherosclerotic plaques weaken the
underlying media and can themselves
rupture, causing acute thrombosis.


Atheromatous plaque

Atherosclerosis or Arteriosclerosis is a slow and
progressive building up of plaque, fatty
substances, cholesterol, cellular waste
products, calcium andBiochemistry forin the inner lining of
11/15/2012 fibrin Medics 10

Atherosclerosis
Atherosclerosis primarily affects elastic
arteries (e.g., aorta, carotid, and iliac arteries)
Large and medium-sized muscular arteries
(e.g., coronary and popliteal arteries).
In small arteries, atheromas can gradually
occlude lumina, compromising blood flow to
distal organs and cause ischemic injury.


Atherosclerosis

 Atherosclerosis also takes a toll through other
consequences of acutely or chronically diminished arterial
perfusion, such as mesenteric occlusion, sudden cardiac
death, chronic IHD, and ischemic encephalopathy.


Risk Factors for Atherosclerosis
Major risk factors (Non Modifiable)-
 Increasing Age
 Male gender
 Family history
 Genetic abnormalities


Lesser, Uncertain, or Nonquantitated Risks-
Obesity
Physical Inactivity
Postmenopausal estrogen deficiency
High carbohydrate intake
Lipoprotein(a)
Hardened (trans)unsaturated fat intake
Chlamydia pneumoniae infection


Potentially Controllable-
 Hyperlipidemia
Hypertension
Cigarette smoking
Diabetes
C-reactive protein


Age as a risk factor
Age is a dominant influence.
Although the accumulation of atherosclerotic
plaque is typically a progressive process, it does
not usually become clinically manifest until
lesions reach a critical threshold and begin to
precipitate organ injury in middle age or later.
Thus, between ages 40 and 60, the incidence of
myocardial infarction in men increases fivefold
Death rates from IHD rise with each decade even
into advanced age.

Gender
Premenopausal women are relatively protected
against atherosclerosis and its consequences
compared with age-matched men
Myocardial infarction and other complications of
atherosclerosis are uncommon in premenopausal
women unless otherwise predisposed by
diabetes, hyperlipidemia, or severe hypertension.
After menopause, the incidence of
atherosclerosis-related diseases increases and
with greater age exceeds that of men.

Genetics
The familial predisposition to atherosclerosis
and IHD is multifactorial.
In some instances it relates to familial
clustering of other risk factors, such as
hypertension or diabetes
In others it involves well-defined genetic
derangements in lipoprotein metabolism, such
as familial hypercholesterolemia that result in
excessively high blood lipid levels.


Hyperlipidemia
Hyperlipidemia-more
specifically, hypercholesterolemia-is a major risk
factor for atherosclerosis;
Even in the absence of other risk
factors, hypercholesterolemia is sufficient to
stimulate lesion development.
The major component of serum cholesterol
associated with increased risk is low-density
lipoprotein (LDL) cholesterol ("bad cholesterol")

Hyperlipidemia
LDL cholesterol has an essential physiologic role
delivering cholesterol to peripheral tissues.
In contrast, high-density lipoprotein (HDL, "good
cholesterol") mobilizes cholesterol from
developing and existing atheromas and
transports it to the liver for excretion in the bile.
Consequently, higher levels of HDL correlate with
reduced risk.


Factors affecting plasma lipid levels
High dietary intake of cholesterol and saturated
fats (present in egg yolks, animal fats, and
butter, for example) raises plasma cholesterol
levels.
Diets low in cholesterol and/or with higher ratios
of 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.

Factors affecting plasma lipid levels
Exercise and moderate consumption of
ethanol both raise HDL levels, whereas obesity
and smoking lower it.
 Statins are a class of drugs that lower
circulating cholesterol levels by inhibiting
hydroxy methylglutaryl coenzyme A
reductase, the rate-limiting enzyme in hepatic
cholesterol biosynthesis.


Hypertension
On its own, hypertension can increase the risk
of IHD by approximately 60% in comparison
with normotensive populations
Left untreated, roughly half of hypertensive
patients will die of IHD or congestive heart
failure, and another third will die of stroke.


Cigarette Smoking
Cigarette smoking is a well-established risk factor
in men
An increase in the number of women who smoke
probably accounts for the increasing incidence
and severity of atherosclerosis in women.
Prolonged (years) smoking of one pack of
cigarettes or more daily increases the death rate
from IHD by 200%.
Smoking cessation reduces that risk substantially.

Diabetes Mellitus
Diabetes mellitus induces
hypercholesterolemia as well as a markedly
increased predisposition to atherosclerosis.
Other factors being equal, the incidence of
myocardial infarction is twice as high in
diabetic as in Nondiabetic individuals.
There is also an increased risk of strokes and a
100-fold increased risk of atherosclerosis-
induced gangrene of the lower extremities.


Additional Risk Factors
Despite the identification of
hypertension, diabetes, smoking, and
hyperlipidemia as major risk factors, as many
as 20% of all cardiovascular events occur in
the absence of any of these.
other "nontraditional" factors contribute to
risk.


Lipoprotein a or Lp(a)
Lipoprotein a or Lp(a), is an altered form of
LDL that contains the apolipoprotein B-100
portion of LDL linked to apolipoprotein A;
Increased Lp(a) levels are associated with a
higher risk of coronary and cerebro vascular
disease, independent of total cholesterol or
LDL levels.


Additional Risk Factors
 Stressful lifestyle ("type A" personality);
 Obesity - Due to
o Hypertension
o Diabetes
o Hypertriglyceridemia and
o Decreased HDL.


Pathogenesis of Atherosclerosis
The contemporary view of atherogenesis is
expressed by the response-to-injury hypothesis.
This model views atherosclerosis as a chronic
inflammatory response of the arterial wall to
endothelial injury.
 Lesion progression occurs through interactions of
modified lipoproteins, monocyte-derived
macrophages, T lymphocytes, and the normal
cellular constituents of the arterial wall.

1) Endothelial Injury
 Initial triggering event in the development of
Atherosclerotic lesions
 Causes ascribed to endothelial injury in include
mechanical trauma, hemodynamic
forces, immunological and chemical
mechanisms, metabolic agents like chronic
hyperlipidemia, homocystine, circulating toxins
from systemic infections, viruses, and tobacco
products.

2. Intimal Smooth Muscle Cell Proliferation
 Endothelial injury causes adherence aggregation and
platelet release reaction at the site of exposed sub
endothelial connective tissue.
 Proliferation of intimal smooth muscle cells is
stimulated by various mitogens released from
platelets adherent at the site of endothelial injury.
 These mitogens include platelet derived growth
factor (PDGF), fibroblast growth factor, TNF-ά.
 Proliferation is also facilitated by nitric oxide and
endothelin released from endothelial cells.


3) Role of Blood Monocytes
Though blood monocytes do not possess
receptors for normal LDL, LDL does appear in the
monocyte cytoplasm to form foam cell.
Plasma LDL on entry into the intima undergoes
oxidation.
Oxidized LDL formed in the intima is readily taken
up by scavenger receptor on the monocyte to
transform it to a lipid laden foam cell.


Oxidized LDL stimulates the release of growth
factors, cytokines, and chemokines by
endothelial cells (EC)and macrophages that
increase monocyte recruitment into lesions.
Oxidized LDL is cytotoxic to ECs and smooth
muscle cells (SMCs )and can induce
Endothelial dysfunction.


4) Role of Hyperlipidemia
Chronic hyperlipidemia in itself may initiate
endothelial injury and dysfunction by causing
increased permeability.
 Increased serum concentration of LDL and
VLDL promote formation of foam cells, while
high serum concentration of HDL has anti-
atherogenic effect.


Progression of Atherosclerosis
 Fatty Streaks- Fatty streaks are composed of lipid-filled
foam cells but are not significantly raised and thus do
not cause any disturbance in blood flow
 Fatty streaks can appear in the aortas of infants
younger than 1 year and are present in virtually all
children older than 10 years, regardless of
geography, race, sex, or environment.
 The relationship of fatty streaks to atherosclerotic
plaques is uncertain; although they may evolve into
precursors of plaques, not all fatty streaks are destined
to become advanced atherosclerotic lesions.


Atherosclerotic Plaque-The key processes in
atherosclerosis are intimal thickening and lipid
accumulation Atheromatous plaques (also
called fibrous or fibro fatty plaques) impinge
on the lumen of the artery and grossly appear
white to yellow
Plaques vary from 0.3 to 1.5 cm in diameter but
can coalesce to form larger masses.


Components of Atherosclerotic
plaque
 Atherosclerotic plaques have three principal
components:
Cells, including SMCs, macrophages, and T cells
 ECM, including collagen, elastic fibers, and
proteoglycans and
Intracellular and extracellular lipid
These components occur in varying proportions
and configurations in different lesions.


Changes in Atherosclerotic Plaque
Atherosclerotic plaques are susceptible to the following
pathologic changes with clinical significance:
 Rupture, ulceration, or erosion
 Hemorrhage
 Atheroembolism
 Aneurysm formation
 Atherosclerosis is a slowly evolving lesion usually requiring
many decades to become significant.
 However, acute plaque changes
(e.g., rupture, thrombosis, or hematoma formation) can
rapidly precipitate clinical sequelae (the so-called "clinical
horizon“)


Atherosclerosis- Symptoms
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.


Prevention of Atherosclerotic Vascular
Disease
Primary prevention aims at either delaying
atheroma formation or encouraging
regression of established lesions in persons
who have not yet suffered a serious
complication of atherosclerosis
Secondary prevention is intended to prevent
recurrence of events such as myocardial
infarction or stroke in symptomatic patients


Prevention of Atherosclerotic
Vascular Disease
Primary prevention of atherosclerosis
 Cessation of cigarette smoking
 Control of hypertension
 Weight loss
 Exercise, and lowering total and LDL blood cholesterol
levels while increasing HDL (e.g., by diet or through
statins).
 Statin use may also modulate the inflammatory state of
the vascular wall.
 Risk factor stratification and reduction should even
begin in childhood.


Prevention of Atherosclerotic
Vascular Disease
Secondary prevention involves use of –
Aspirin (anti-platelet agent),
Statins, and beta blockers (to limit cardiac
demand),
Surgical interventions (e.g., coronary artery
bypass surgery, carotid endarterectomy).
These can successfully reduce recurrent
myocardial or cerebral events.

Summary
 Atherosclerosis is an intima-based lesion organized into
a fibrous cap and an atheromatous (gruel-like) core and
composed of SMCs, ECM, inflammatory
cells, lipids, and necrotic debris.
 Atherogenesis is driven by an interplay of inflammation
and injury to vessel wall cells.
 Atherosclerotic plaques accrue slowly over decades but
may acutely cause symptoms due to
rupture, thrombosis, hemorrhage, or embolization.
 Risk factor recognition and reduction can reduce the
incidence and severity of atherosclerosis-related
disease.


Atherosclerosis

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