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For the journal, see Atherosclerosis (journal).

which tend to be asymptomatic, are rich in extracellular

matrix and smooth muscle cells, while, unstable plaques
are rich in macrophages and foam cells and the extracellular matrix separating the lesion from the arterial lumen (also known as the brous cap) is usually weak and
prone to rupture.[5] Ruptures of the brous cap expose
thrombogenic material, such as collagen,[6] to the circulation and eventually induce thrombus formation in the
lumen. Upon formation, intraluminal thrombi can occlude arteries outright (e.g. coronary occlusion), but
more often they detach, move into the circulation and
eventually occluding smaller downstream branches causing thromboembolism. Apart from thromboembolism,
chronically expanding atherosclerotic lesions can cause
complete closure of the lumen. Chronically expanding lesions are often asymptomatic until lumen stenosis is so severe (usually over 80%) that blood supply to downstream
tissue(s) is insucient, resulting in ischemia.

Atherosclerosis (also known as arteriosclerotic vascular disease or ASVD) is a specic form of

arteriosclerosis in which an artery wall thickens as a result of invasion and accumulation of white blood cells

The accumulation of the WBCs is termed fatty streaks

early on because of appearance being similar to that of
marbled streak. These accumulations contain both living,
active WBCs (producing inammation) and remnants of
dead cells, including cholesterol and triglycerides. The
remnants eventually include calcium and other crystallized materials, within the outer-most and oldest plaque.
The fatty streaks reduce the elasticity of the artery
walls. However, they do not aect blood ow for decades,
because the artery muscular wall enlarges at the locations
of plaque. The wall stiening may eventually increase
pulse pressure; widened pulse pressure is one possible re- These complications of advanced atherosclerosis are
chronic, slowly progressive and cumulative. Most comsult of advanced disease within the major arteries.
monly, soft plaque suddenly ruptures (see vulnerable
Atherosclerosis is therefore a syndrome aecting arte- plaque), causing the formation of a thrombus that will
rial blood vessels due to a chronic inammatory response rapidly slow or stop blood ow, leading to death of the tisof WBCs in the walls of arteries. This is promoted by sues fed by the artery in approximately ve minutes. This
low-density lipoproteins (LDL, plasma proteins that carry catastrophic event is called an infarction. One of the most
cholesterol and triglycerides) without adequate removal common recognized scenarios is called coronary thromof fats and cholesterol from the macrophages by func- bosis of a coronary artery, causing myocardial infarction
tional high-density lipoproteins (HDL). It is commonly (a heart attack). The same process in an artery to the brain
referred to as a hardening or furring of the arteries. is commonly called stroke. Another common scenario
It is caused by the formation of multiple atheromatous in very advanced disease is claudication from insucient
plaques within the arteries.[1][2]
blood supply to the legs. Atherosclerosis aects the entire
artery tree, but mostly larger, high-pressure vessels such
The plaque is divided into three distinct components:
as the coronary, renal, femoral, cerebral, and carotid arteries. These are termed "clinically silent" because the
1. The atheroma (lump of gruel, from Greek
person having the infarction does not notice the problem
(athera), meaning "gruel"), which is the nodular acand does not seek medical help, or when they do, physicumulation of a soft, aky, yellowish material at the
cians do not recognize what has happened.
center of large plaques, composed of macrophages
nearest the lumen of the artery
2. Underlying areas of cholesterol crystals

1 Denitions

3. Calcication at the outer base of older or more advanced lesions.

The following terms are similar, yet distinct, in both
spelling and meaning, and can be easily confused:
Atherosclerosis is a chronic disease that remains arteriosclerosis, arteriolosclerosis, and atherosclerosis.
asymptomatic for decades.[3] Atherosclerotic lesions, or Arteriosclerosis is a general term describing any hardatherosclerotic plaques, are separated into two broad cat- ening (and loss of elasticity) of medium or large arteregories: Stable and unstable (also called vulnerable).[4] ies (from Greek (artria), meaning artery,
The pathobiology of atherosclerotic lesions is very com- and (sklerosis), meaning hardening); arplicated but generally, stable atherosclerotic plaques, teriolosclerosis is any hardening (and loss of elasticity) of

arterioles (small arteries); atherosclerosis is a hardening
of an artery specically due to an atheromatous plaque.
The term atherogenic is used for substances or processes
that cause atherosclerosis.


and pelvis, also experience marked narrowing due to

plaque rupture and clots. Symptoms for the marked narrowing are numbness within the arms or legs, as well as

Another signicant location for the plaque formation is

the renal arteries, which supply blood to the kidneys.
2 Signs and symptoms
Plaque occurrence and accumulation leads to decreased
kidney blood ow and chronic kidney disease, which,
Atherosclerosis is asymptomatic for decades because the like all other ares, are typically asymptomatic until late
arteries enlarge at all plaque locations, thus there is no stages.[8]
eect on blood ow. Even most plaque ruptures do not According to United States data for 2004, in about
produce symptoms until enough narrowing or closure of 66% of men and 47% of women, the rst symptom of
an artery, due to clots, occurs. Signs and symptoms only atherosclerotic cardiovascular disease is a heart attack or
occur after severe narrowing or closure impedes blood sudden cardiac death (death within one hour of onset of
ow to dierent organs enough to induce symptoms.[7] the symptom). Cardiac stress testing, traditionally the
Most of the time, patients realize that they have the dis- most commonly performed non-invasive testing method
ease only when they experience other cardiovascular dis- for blood ow limitations, in general, detects only lumen
orders such as stroke or heart attack. These symptoms, narrowing of 75% or greater, although some physicians
however, still vary depending on which artery or organ is claim that nuclear stress methods can detect as little as
Typically, atherosclerosis begins in childhood, as a thin
layer of white-yellowish streaks with the inner layers of
the artery walls (an accumulation of white blood cells,
mostly monocytes/macrophages) and progresses from
Clinically, given enlargement of the arteries for decades,
symptomatic atherosclerosis is typically associated with
men in their 40s and women in their 50s to 60s. Subclinically, the disease begins to appear in childhood, and
rarely is already present at birth. Noticeable signs can begin developing at puberty. Though symptoms are rarely
exhibited in children, early screening of children for cardiovascular diseases could be benecial to both the child
and his/her relatives.[9] While coronary artery disease is
more prevalent in men than women, atherosclerosis of the
cerebral arteries and strokes equally aect both sexes.[10]

Case studies have included autopsies of American soldiers killed in World War II and the Korean War. A
much-cited report involved autopsies of 300 American
soldiers killed in Korea. Although the average age of the
men was 22.1 years, 77.3 percent had gross evidence of
coronary arteriosclerosis.[13] Other studies done of soldiers in the Second Indochina War showed similar results,
although often worse than the ones from the earlier wars.
Theories include high rates of tobacco use and (in the case
of the Vietnam soldiers) the advent of processed foods
after World War II.

3 Causes

Marked narrowing in the coronary arteries, which are responsible for bringing oxygenated blood to the heart, can
produce symptoms such as the chest pain of angina and
shortness of breath, sweating, nausea, dizziness or lightheadedness, breathlessness or palpitations.[8] Abnormal
heart rhythms called arrhythmias (the heart is either beating too slow or too fast) are another consequence of
Carotid arteries supply blood to the brain and neck.[11]
Marked narrowing of the carotid arteries can present
with symptoms such as a feeling of weakness, not being able to think straight, diculty speaking, becoming
dizzy and diculty in walking or standing up straight,
blurred vision, numbness of the face, arms, and legs, severe headache and losing consciousness. These symptoms are also related to stroke (death of brain cells).
Stroke is caused by marked narrowing or closure of arteries going to the brain; lack of adequate blood supply
leads to the death of the cells of the aected tissue.[12]
Peripheral arteries, which supply blood to the legs, arms, Atherosclerosis and lipoproteins


Risk factors

See also: Lipoprotein

3.1 Risk factors

Various anatomic and physiological risk factors for

atherosclerosis are known.[19] These can be divided into
various categories: congenital vs acquired, modiable or
not, classical or non-classical. The points labelled '+' in
the following list form the core components of metabolic
Lipoproteins in the blood vary in size. Some data sug- syndrome.
gests that small dense LDL (sdLDL) particles are more
prone to pass between the endothelial cells, going be- Risks multiply, with two[20]factors increasing the risk of
Hyperlipidemia, hypertenhind the cellular monolayer of endothelium. LDL par- atherosclerosis fourfold.
increases the risk
ticles and their content are susceptible to oxidation by
free radicals, and the risk is higher while the particles
are in the wall than while in the bloodstream. However,
LDL particles have a half-life of only a couple of days,
and their content (LDL particles typically carry 3,000 3.1.1 Modiable
to 6,000 fat molecules, including: cholesterol, phospho Diabetes[20] or impaired glucose tolerance (IGT) +
lipids, cholesteryl esters, tryglycerides & all other fats in
the water outside cells, to the tissues of the body) changes
Dyslipoproteinemia[20] (unhealthy patterns of serum
with time.
proteins carrying fats & cholesterol): +
Once inside the vessel wall, LDL particles can become
more prone to oxidation. Endothelial cells respond by
High serum concentration of low-density
attracting monocyte white blood cells, causing them to
lipoprotein (LDL, bad if elevated concentraleave the blood stream, penetrate into the arterial walls
tions and small), and / or very low density
and transform into macrophages. The macrophages inlipoprotein (VLDL) particles, i.e., lipoprogestion of oxidized LDL particles triggers a cascade
tein subclass analysis
of immune responses which over time can produce an
Low serum concentration of functioning high
atheroma if HDL removal of fats from the macrophages
density lipoprotein (HDL protective if large
does not keep up. The immune systems specialized white
and high enough particles), i.e., lipoprotein
blood cells (macrophages and T-lymphocytes) absorb the
subclass analysis
oxidized LDL, forming specialized foam cells. If these
foam cells are not able to process the oxidized LDL
An LDL:HDL ratio greater than 3:1
and recruit HDL particles to remove the fats, they grow
and eventually rupture, leaving behind cellular membrane
Tobacco smoking, increases risk by 200% after sevremnants, oxidized materials, and fats (including choleseral pack years[20]
terol) in the artery wall. This attracts more white blood
cells, resulting in a snowballing progression that contin Elevated
ues the cycle, inaming the artery. The presence of the
plaque induces the muscle cells of the blood vessel to
stretch, compensating for the additional bulk, and the
Vitamin B6 deciency[22][23][24]
endothelial lining thickens, increasing the separation between the plaque and lumen. This somewhat osets the
Dietary iodine deciency and hypothyroidism,
narrowing caused by the growth of the plaque, but it
which cause elevated serum cholesterol and of lipid
causes the wall to stien and become less compliant to
stretching with each heart beat.
The atherosclerotic process is not fully understood.
Atherosclerosis is initiated by inammatory processes in
the endothelial cells of the vessel wall in response to retained low-density lipoprotein (LDL) particles.[14]

Some researchers believe that atherosclerosis may be

caused by an infection of the vascular smooth muscle 3.1.2 Nonmodiable
cells. Chickens, for example, develop atherosclerosis
Advanced age[20]
when infected with the Mareks disease herpesvirus.[16]
Herpesvirus infection of arterial smooth muscle cells
Male sex[20]
has been shown to cause cholesteryl ester (CE) accumulation, which is associated with atherosclerosis.[17]
Having close relatives who have had some complicaCytomegalovirus (CMV) infection is also associated with
tion of atherosclerosis (e.g. coronary heart disease
cardiovascular diseases.[18]
or stroke)[20]
Genetic abnormalities,[20] e.g. familial hypercholesterolemia



Lesser or uncertain

In contrast, according to Dr. Esselstyn, medical imaging

methods like angiograms and ultrasonograms show a reThe following factors are of relatively lesser importance, duction of fatty streaks and arteriosclerosis in coronary
are uncertain or unquantied:
arteries within months on an ultra high carb ultra low fat
Obesity[20] (in particular central obesity, also re- The role of dietary oxidized fats/lipid peroxidation
ferred to as abdominal or male-type obesity) +
(rancid fats) in humans is not clear. Laboratory animals
fed rancid fats develop atherosclerosis. Rats fed
DHA-containing oils experienced marked disruptions
to their antioxidant systems, and accumulated signif Postmenopausal estrogen deciency[20]
icant amounts of phospholipid hydroperoxide in their
High intake of saturated fat (may raise total and blood, livers and kidneys.[42] In another study, rabbits fed
LDL cholesterol)[33]
atherogenic diets containing various oils were found to
undergo the greatest amount of oxidative susceptibility of
Intake of trans fat (may raise total and LDL choles- LDL via polyunsaturated oils.[43] In a study involving rabterol while lowering HDL cholesterol)[20][34]
bits fed heated soybean oil, grossly induced atherosclerosis and marked liver damage were histologically and clin[20]
High carbohydrate intake
ically demonstrated.[44] However, Kummerow, a prominent researcher, claims that it is not dietary cholesterol,
Elevated serum levels of triglycerides +
but oxysterols, or oxidized cholesterols, from fried foods
Elevated serum levels of homocysteine
and smoking, that are the culprit.[45]
Elevated serum levels of uric acid (also responsible Rancid fats and oils taste very bad even in small amounts,
so people avoid eating them.[46] It is very dicult to meafor gout)
sure or estimate the actual human consumption of these
Elevated serum brinogen concentrations
Elevated serum lipoprotein(a) concentrations[20]

Highly unsaturated omega-3 rich oils such as sh oil are

being sold in pill form so that the taste of oxidized or
Chronic systemic inammation as reected by up- rancid fat is not apparent. The health food industrys diper normal WBC concentrations, elevated hs-CRP etary supplements are self regulated by the manufacture
and many other blood chemistry markers, most only and outside of FDA regulations.[48] To properly protect
research level at present, not clinically done.[35]
unsaturated fats from oxidation, it is best to keep them
cool and in oxygen free environments.
Elevated serum insulin levels +[36]
Long term exposure to inorganic arsenic is associated
Short sleep duration[37]
with atherosclerosis.[49]
Chlamydia pneumoniae infection[20]
PM. air pollution, ne particulates less than 2.5 m
in diameter, have been associated with thickening of
the carotid artery.[38]


The relation between dietary fat and atherosclerosis is

a controversial eld. The USDA, in its food pyramid, promotes a diet of about 64% carbohydrates from
total calories. The American Heart Association, the
American Diabetes Association and the National Cholesterol Education Program make similar recommendations. In contrast, Prof Walter Willett (Harvard School
of Public Health, PI of the second Nurses Health
Study) recommends much higher levels of fat, especially
of monounsaturated and polyunsaturated fat.[39] Writing in Science, Gary Taubes detailed that political considerations played into the recommendations of government bodies.[40] These diering views reach a consensus,
though, against consumption of trans fats.

4 Pathophysiology
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, developed over a period of several years through a complex series of cellular events occurring within the arterial wall, and in response to a variety of local vascular circulating factors.
One recent hypothesis suggests that, for unknown reasons, leukocytes, such as monocytes or basophils, begin
to attack the endothelium of the artery lumen in cardiac
muscle. The ensuing inammation leads to formation of
atheromatous plaques in the arterial tunica intima, a region of the vessel wall located between the endothelium
and the tunica media. The bulk of these lesions is made of
excess fat, collagen, and elastin. At rst, as the plaques
grow, only wall thickening occurs without any narrowing. Stenosis is a late event, which may never occur and


Calcication and lipids

is often the result of repeated plaque rupture and healing gration from the tunica media into the intima responding
responses, not just the atherosclerotic process by itself.
to cytokines secreted by damaged endothelial cells. This
causes the formation of a brous capsule covering the
fatty streak. Intact endothelium could prevent the pro4.1 Cellular
liferation by releasing nitric oxide.

4.2 Calcication and lipids

Calcication[2] forms among vascular smooth muscle
cells of the surrounding muscular layer, specically in the
muscle cells adjacent to atheromas and on the surface of
atheroma plaques and tissue.[2][3] In time, as cells die, this
leads to extracellular calcium deposits between the muscular wall and outer portion of the atheromatous plaques.
With the atheromatous plaque interfering with the regulation of the calcium deposition, it accumulates and crystallizes. A similar form of an intramural calcication,
presenting the picture of an early phase of arteriosclerosis, appears to be induced by a number of drugs that have
an antiproliferative mechanism of action (Rainer Liedtke
Micrograph of an artery that supplies the heart showing signicant atherosclerosis and marked luminal narrowing. Tissue has
been stained using Massons trichrome.

Early atherogenesis is characterized by the adherence

of blood circulating monocytes (a type of white blood
cell) to the vascular bed lining, the endothelium, then
by their migration to the sub-endothelial space, and further activation into monocyte-derived macrophages.[50]
The primary documented driver of this process is oxidized lipoprotein particles within the wall, beneath the
endothelial cells, though upper normal or elevated concentrations of blood glucose also plays a major role and
not all factors are fully understood. Fatty streaks may appear and disappear.
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 (such as Lp-LpA2) and free radicals in
the endothelium.

Cholesterol is delivered into the vessel wall by

cholesterol-containing low-density lipoprotein (LDL)
particles. To attract and stimulate macrophages, the
cholesterol must be released from the LDL particles
and oxidized, a key step in the ongoing inammatory
process. The process is worsened if there is insucient
high-density lipoprotein (HDL), the lipoprotein particle
that removes cholesterol from tissues and carries it back
to the liver.
The foam cells and platelets encourage the migration and
proliferation of smooth muscle cells, which in turn ingest
lipids, become replaced by collagen and transform into
foam cells themselves. A protective brous cap normally
forms between the fatty deposits and the artery lining (the

These capped fatty deposits (now called 'atheromas) produce enzymes that cause the artery to enlarge over time.
As long as the artery enlarges suciently to compensate
for the extra thickness of the atheroma, then no narrowing
("stenosis") of the opening (lumen) occurs. The artery
becomes expanded with an egg-shaped cross-section, still
Initial damage to the endothelium results in an inamwith a circular opening. If the enlargement is beyond promatory response. Monocytes enter the artery wall from
portion to the atheroma thickness, then an aneurysm is
the bloodstream, with platelets adhering to the area of
insult. This may be promoted by redox signaling induction of factors such as VCAM-1, which recruit circulating
monocytes, and M-CSF, which is selectively required for 4.3 Visible features
the dierentiation of monocytes to macrophages. The
monocytes dierentiate into macrophages, which ingest Although arteries are not typically studied microscopioxidized LDL, slowly turning into large foam cells cally, two plaque types can be distinguished:[52]
so-called because of their changed appearance resulting
1. The bro-lipid (bro-fatty) plaque is characterfrom the numerous internal cytoplasmic vesicles and resulting high lipid content. Under the microscope, the
ized by an accumulation of lipid-laden cells unlesion now appears as a fatty streak. Foam cells evenderneath the intima of the arteries, typically withtually die, and further propagate the inammatory proout narrowing the lumen due to compensatory excess. There is also smooth muscle proliferation and mipansion of the bounding muscular layer of the

compensate for the atheromatous plaques.
However, atheromas within the vessel wall are soft and
fragile with little elasticity. Arteries constantly expand
and contract with each heartbeat, i.e., the pulse. In addition, the calcication deposits between the outer portion
of the atheroma and the muscular wall, as they progress,
lead to a loss of elasticity and stiening of the artery as a
The calcication deposits,[2] after they have become
suciently advanced, are partially visible on coronary
artery computed tomography or electron beam tomography (EBT) as rings of increased radiographic density,
forming halos around the outer edges of the atheromatous plaques, within the artery wall. On CT, >130 units
on the Hounseld scale (some argue for 90 units) has been
the radiographic density usually accepted as clearly representing tissue calcication within arteries. These deposits demonstrate unequivocal evidence of the disease,
relatively advanced, even though the lumen of the artery
is often still normal by angiography.

4.4 Rupture and stenosis

Although the disease process tends to be slowly progressive over decades, it usually remains asymptomatic until
an atheroma ulcerates, which leads to immediate blood
Severe atherosclerosis of the aorta. Autopsy specimen.
clotting at the site of atheroma ulcer. This triggers a cascade of events that leads to clot enlargement, which may
quickly obstruct the ow of blood. A complete blockartery wall. Beneath the endothelium there is a
age leads to ischemia of the myocardial (heart) muscle
brous cap covering the atheromatous core of
and damage. This process is the myocardial infarction or
the plaque. The core consists of lipid-laden cells
heart attack.
(macrophages and smooth muscle cells) with elevated tissue cholesterol and cholesterol ester con- If the heart attack is not fatal, brous organization of the
tent, brin, proteoglycans, collagen, elastin, and cel- clot within the lumen ensues, covering the rupture but
lular debris. In advanced plaques, the central core of also producing stenosis or closure of the lumen, or over
the plaque usually contains extracellular cholesterol time and after repeated ruptures, resulting in a persistent,
deposits (released from dead cells), which form ar- usually localized stenosis or blockage of the artery lumen.
eas of cholesterol crystals with empty, needle-like Stenoses can be slowly progressive, whereas plaque ulcerclefts. At the periphery of the plaque are younger ation is a sudden event that occurs specically in atherofoamy cells and capillaries. These plaques usu- mas with thinner/weaker brous caps that have become
ally produce the most damage to the individual when unstable.
they rupture.
Repeated plaque ruptures, ones not resulting in total lu2. The brous plaque is also localized under the intima, within the wall of the artery resulting in thickening and expansion of the wall and, sometimes,
spotty localized narrowing of the lumen with some
atrophy of the muscular layer. The brous plaque
contains collagen bers (eosinophilic), precipitates
of calcium (hematoxylinophilic) and, rarely, lipidladen cells.
In eect, the muscular portion of the artery wall forms
small aneurysms just large enough to hold the atheroma
that are present. The muscular portion of artery walls
usually remain strong, even after they have remodeled to

men closure, combined with the clot patch over the rupture and healing response to stabilize the clot, is the process that produces most stenoses over time. The stenotic
areas tend to become more stable, despite increased ow
velocities at these narrowings. Most major blood-owstopping events occur at large plaques, which, prior to
their rupture, produced very little if any stenosis.
From clinical trials, 20% is the average stenosis at plaques
that subsequently rupture with resulting complete artery
closure. Most severe clinical events do not occur at
plaques that produce high-grade stenosis. From clinical
trials, only 14% of heart attacks occur from artery closure at plaques producing a 75% or greater stenosis prior

to the vessel closing.

occur in any artery within the body. Obstruction of arIf the brous cap separating a soft atheroma from the teries supplying the heart muscle result in a heart attack,
bloodstream within the artery ruptures, tissue fragments while the obstruction of arteries supplying the brain result
are exposed and released. These tissue fragments are in a stroke.
very clot-promoting, containing collagen and tissue factor; they activate platelets and activate the system of coagulation. The result is the formation of a thrombus (blood
clot) overlying the atheroma, which obstructs blood ow
acutely. With the obstruction of blood ow, downstream
tissues are starved of oxygen and nutrients. If this is the
myocardium (heart muscle), angina (cardiac chest pain)
or myocardial infarction (heart attack) develops.

Doppler ultrasound of right internal Carotid artery with calcied
and non-calcied plaques showing less than 70% stenosis

Microphotography of arterial wall with calcied (violet colour)

atherosclerotic plaque (haematoxillin & eosin stain)

Areas of severe narrowing, stenosis, detectable by

angiography, and to a lesser extent "stress testing" have
long been the focus of human diagnostic techniques for
cardiovascular disease, in general. However, these methods focus on detecting only severe narrowing, not the underlying atherosclerosis disease. As demonstrated by human clinical studies, most severe events occur in locations with heavy plaque, yet little or no lumen narrowing
present before debilitating events suddenly occur. Plaque
rupture can lead to artery lumen occlusion within seconds
to minutes, and potential permanent debility and sometimes sudden death.
Plaques that have ruptured are called complicated
plaques. The extracellular matrix of the lesion breaks,
usually at the shoulder of the brous cap that separates the
lesion from the arterial lumen, where the exposed thrombogenic components of the plaque, mainly collagen will
trigger thrombus formation. The thrombus then travel
downstream to other blood vessels, where the blood clot
may partially or completely block blood ow. If the
blood ow is completely blocked, cell deaths occur due
to the lack of oxygen supply to nearby cells, resulting in
necrosis. The narrowing or obstruction of blood ow can

Lumen stenosis that is greater than 75% were considered

as the hallmark of clinically signicant disease in the past
because recurring episodes of angina and abnormalities
in stress test are only detectable at that particular severity
of stenosis. However, clinical trials have shown that only
about 14% of clinically debilitating events occur at sites
with >75% stenosis. Majority of cardiovascular events
that involve sudden rupture of the atheroma plaque do
not display any evident narrowing of the lumen. Thus,
greater attention has been focused on vulnerable plaque
from the late 1990s onwards.[53]
Besides the traditional diagnostic methods such as angiography and stress-testing, other detection techniques
have been developed in the past decades for earlier detection of atherosclerotic disease. Some of the detection
approaches include anatomical detection and physiologic
Examples of anatomical detection methods include (1)
coronary calcium scoring by CT, (2) carotid IMT (intimal
media thickness) measurement by ultrasound, and (3)
intravascular ultrasound (IVUS). Examples of physiologic measurement methods include (1) lipoprotein
subclass analysis, (2) HbA1c, (3) hs-CRP, and (4)
homocysteine. Both anatomic and physiologic methods
allow early detection before symptoms show up, disease
staging and tracking of disease progression. Anatomic
methods are more expensive and some of them are invasive in nature, such as IVUS. On the other hand, physiologic methods are often less expensive and safer. But they
do not quantify the current state of the disease or directly
track progression. In the recent years, ways of estimating
the severity of atherosclerotic plaques is also made possible with the developments in nuclear imaging techniques
such as PET and SPECT.


Medical management of atherosclerosis involves modication to risk factors like smoking cessation and diet restrictions. Additionally, a controlled exercise program
combats atherosclerosis by improving circulation and
functionality of the vessels. Exercise is also used to manage weight in patients who are either obese, lower blood
pressure, and decrease cholesterol. Often lifestyle modication is combined with medication therapy. For example, statins help to lower cholesterol, antiplatelet medications like Aspirin help to prevent clots, and a variety of
antihypertensive medications are routinely used to control blood pressure. If the combined eorts of risk factor
modication and medication therapy are not sucient to
control symptoms, or ght imminent threats of ischemic
events, a physician may resort to interventional or surgical
procedures to correct the obstruction.[54]
Combinations of statins, niacin, intestinal cholesterol
absorption-inhibiting supplements (ezetimibe and others, and to a much lesser extent brates) have been
the most successful in changing common but suboptimal lipoprotein patterns and group outcomes. In
the many secondary prevention and several primary prevention trials, several classes of lipoprotein-expressionaltering (less correctly termed cholesterol-lowering)
agents have consistently reduced not only heart attack,
stroke and hospitalization but also all-cause mortality
rates. The rst of the large secondary prevention comparative statin/placebo treatment trials was the Scandinavian Simvastatin Survival Study (4S)[55] with over
fteen more studies extending through to the more
recent ASTEROID[56] trial published in 2006. The
rst primary prevention comparative treatment trial was
AFCAPS/TexCAPS[57] with multiple later comparative statin/placebo treatment trials including EXCEL,[58]
ASCOT[59] and SPARCL.[60][61] While the statin trials
have all been clearly favorable for improved human outcomes, only ASTEROID and SATURN showed evidence
of atherosclerotic regression (slight). Both human and
animal trials that showed evidence of disease regression
used more aggressive combination agent treatment strategies, which nearly always included niacin.[19]


Medical treatments often focus on alleviating symptoms. However measures which focus on decreasing underlying atherosclerosisas opposed to simply treating
symptomsare more eective.[62] Non-pharmaceutical
means are usually the rst method of treatment, such as
stopping smoking and practicing regular exercise.[63][64]
If these methods do not work, medicines are usually the
next step in treating cardiovascular diseases, and, with
improvements, have increasingly become the most eective method over the long term.


The key to the more eective approaches has been better

understanding of the widespread and insidious nature of
the disease and to combine multiple dierent treatment
strategies, not rely on just one or a few approaches.[65]
In addition, for those approaches, such as lipoprotein
transport behaviors, which have been shown to produce
the most success, adopting more aggressive combination
treatment strategies taken on a daily basis and indenitely
has generally produced better results, both before and especially after people are symptomatic.[62]

7.1 Statins
The group of medications referred to as statins are widely
prescribed for treating atherosclerosis. They shown benet in reducing cardiovascular disease and mortality in
those with high cholesterol with few side eects.[66]
These data are primarily in middle-age men and the conclusions are less clear for women and people over the age
of 70.[67]
Monocyte counts, as well as cholesterol markers such as
LDL:HDL ratio and apolipiprotein B: apolipoprotein A1 ratio can be used as markers to monitor the extent of
atherosclerotic regression which proves useful in guiding
patient treatments.[68]

7.2 Diet
Changes in diet may help prevent the development of
atherosclerosis. There is tentative evidence that a diet
that contains dairy products usually occurs with a better
diet overall and decreases the risk of cardiovascular disease.[69][70]
A diet high in fruits and vegetables decreases the risk of
cardiovascular disease and death.[71] Evidence suggests
that the Mediterranean diet may improve cardiovascular outcomes.[72] There is also evidence that a Mediterranean diet may be better than a low-fat diet in bringing about long-term changes to cardiovascular risk factors
(e.g., lower cholesterol level and blood pressure).[73]

7.3 Surgery
Other physical treatments, include angioplasty procedures that may include stents and bypass surgery.

7.4 Other
There is evidence that some anticoagulants, particularly
warfarin, which inhibit clot formation by interfering with
Vitamin K metabolism, may actually promote arterial
calcication in the long term despite reducing clot formation in the short term.[74][75][76]




Diabetics, despite not having clinically detectable

atherosclerotic disease, have more severe debility from
atherosclerotic events over time than non-diabetics
who have already had atherosclerotic events. Thus
diabetes has been upgraded to be viewed as an advanced
atherosclerotic disease equivalent.


An indication of the role of HDL on atherosclerosis has

been with the rare Apo-A1 Milano human genetic variant
of this HDL protein. A small short-term trial using bacterial synthetized human Apo-A1 Milano HDL in people
with unstable angina produced fairly dramatic reduction
in measured coronary plaque volume in only six weeks
vs. the usual increase in plaque volume in those randomized to placebo. The trial was published in JAMA in early
2006. Ongoing work starting in the 1990s may lead to
human clinical trialsprobably by about 2008. These
may use synthesized Apo-A1 Milano HDL directly, or
they may use gene-transfer methods to pass the ability to
synthesize the Apo-A1 Milano HDLipoprotein.
Methods to increase high-density lipoprotein (HDL) particle concentrations, which in some animal studies largely
reverses and remove atheromas, are being developed and
Niacin has HDL raising eects (by 1030%) and showed
clinical trial benet in the Coronary Drug Project and
is commonly used in combination with other lipoprotein
agents to improve ecacy of changing lipoprotein for the
better. However most individuals have nuisance symptoms with short term ushing reactions, especially initially, and so working with a physician with a history of
successful experience with niacin implementation, careful selection of brand, dosing strategy, etc. are usually
critical to success.
However, increasing HDL by any means is not necessarily helpful. For example, the drug torcetrapib is the most
eective agent currently known for raising HDL (by up
to 60%). However, in clinical trials it also raised deaths
by 60%. All studies regarding this drug were halted in
December 2006.[77] See CETP inhibitor for similar approaches.
The actions of macrophages drive atherosclerotic plaque
progression. Immunomodulation of atherosclerosis is the
term for techniques that modulate immune system function to suppress this macrophage action.[78]
Research on genetic expression and control mechanisms
is progressing. Topics include
PPAR, known to be important in blood sugar and
variants of lipoprotein production and function;

The multiple variants of the proteins that form the
lipoprotein transport particles.

Some controversial research has suggested a link between atherosclerosis and the presence of several different nanobacteria in the arteries, e.g., Chlamydophila
pneumoniae, though trials of current antibiotic treatments
known to be usually eective in suppressing growth or
killing these bacteria have not been successful in improving outcomes.[79]
The immunomodulation approaches mentioned above,
because they deal with innate responses of the host to promote atherosclerosis, have far greater prospects for success.

9.1 miRNA
miRNAs have complementary sequences in the 3 utr
and 5 utr of target mRNAs of protein-coding genes, and
cause mRNA cleavage or repression of translational machinery. In diseased vacular vessels, miRNAs are dysregulated and highly expressed. miR-33 is found in cardiovascular diseases.[80] It is involved in atherosclerotic
initiation and progression including lipid metabolism, insulin signaling and glucose homeostatis, cell type progression and proliferation, and myeloid cell dierentiation. It was found in rodents that the inhibition of
miR-33 will raise HDL level and the expression of miR33 is down-regulated in humans with atherosclerotic
miR-33a and miR-33b are located on intron 16 of human
sterol regulatory element-binding protein 2 (SREBP2)
gene on chromosome 22 and intron 17 of SREBP1
gene on chromosome 17.[85] miR-33a/b regulates cholesterol/lipid homeostatis by binding in the 3UTRs of genes
involved in cholesterol transport such as ATP binding
Cassette (ABC) transporters and enhance or represses
its expression. Study have shown that ABCA1 mediates transport of cholesterol from peripheral tissues to
Apolipoprotein-1 and it is also important in the reverse
cholesterol transport pathway, where cholesterol is deliverd from peripheral tissue to the liver, where it can
be excreted into bile or converted to bile acids prior
to excretion.[80] Therefore, we know that ABCA1 plays
an important role in preventing cholesterol accumulation
in macrophages. By enhancing miR-33 function, the
level of ABCA1 is decreased, leading to decrease cellular cholesterol eux to apoA-1. On the other hand, by
inhibiting miR-33 function, the level of ABCA1 is increased and increases the cholesterol eux to apoA-1.
Suppression of miR-33 will lead to less cellular cholesterol and higher plasma HDL level through the regulation
of ABCA1 expression.[86]





[9] http://www.news-medical.net/news/20120201/
aspx Retrieved Feb-27-13

In 2011, coronary atherosclerosis was one of the top ten

most expensive conditions seen during inpatient hospi- [10] Flora, G., Baker, A.B., Loewenson, R.B., and Klassen, A.
talizations in the U.S., with aggregate inpatient hospital
C. A Comparative Study of Cerebral Atherosclerosis in
costs of $10.4 billion.[87]
Males and Females. Circulation 38, 859-869 http://circ.
ahajournals.org/content/38/5/859.full.pdf (1968)


See also

Arterial stiness
Coronary catheterization
Fatty streaks
Intravascular ultrasound
Monckebergs arteriosclerosis
apoA-1 Milano



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Atherosclerosis at DMOZ
An open access review entitled Hypertension and the
Pathogenesis of Atherosclerosis on Pharma Mirror
A four-minute animation of the atherosclerosis process, entitled Pathogenesis of Acute MI, commissioned by Paul M. Ridker, MD, MPH, FACC,
FAHA, at the Harvard Medical School, can be
viewed at pri-med.com.





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