Professional Documents
Culture Documents
1 Denitions
2
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.
CAUSES
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
ischemia.[11]
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
3.1
Risk factors
4 PATHOPHYSIOLOGY
3.1.3
Lesser or uncertain
Dietary
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
4.2
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.
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
created.[51]
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
4 PATHOPHYSIOLOGY
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
whole.
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.
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
7
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.
Diagnosis
Doppler ultrasound of right internal Carotid artery with calcied
and non-calcied plaques showing less than 70% stenosis
Prevention
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]
Treatment
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.
TREATMENT
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]
9.1
miRNA
Prognosis
Research
9
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
plaques.[81][82][83][84]
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]
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12 FOOTNOTES
Economics
[9] http://www.news-medical.net/news/20120201/
First-signs-of-atherosclerotic-heart-disease-may-appear-in-early-childhood.
aspx Retrieved Feb-27-13
11
See also
Angiogram
Arterial stiness
Arteriosclerosis
Atheroma
Coronary catheterization
Fatty streaks
Intravascular ultrasound
Monckebergs arteriosclerosis
apoA-1 Milano
12
Footnotes
[1] http://www.mercksource.com
[2] Maton, Anthea; Roshan L. Jean Hopkins; Charles
William McLaughlin; Susan Johnson; Maryanna Quon
Warner; David LaHart; Jill D. Wright (1993). Human
Biology and Health. Englewood Clis, NJ: Prentice Hall.
ISBN 0-13-981176-1. OCLC 32308337.
[3] Ross R (April 1993). The pathogenesis of atherosclerosis: a perspective for the 1990s. Nature 362 (6423):
8019. doi:10.1038/362801a0. PMID 8479518.
[4] Ross R; Ross, Russell (January 1999). Atherosclerosis An Inammatory Disease.
New England Journal of Medicine 340 (2):
11526.
doi:10.1056/NEJM199901143400207. PMID 9887164.
[5] Finn AV, Nakano M, Narula J, Kolodgie FD, Virmani
R (July 2010). Concept of vulnerable/unstable plaque.
Arterioscler. Thromb. Vasc. Biol. 30 (7): 128292.
doi:10.1161/ATVBAHA.108.179739. PMID 20554950.
[6] Didangelos A, Simper D, Monaco C, Mayr M (May
2009). Proteomics of acute coronary syndromes..
Current atherosclerosis reports 11 (3):
18895.
doi:10.1007/s11883-009-0030-x. PMID 19361350.
[7] Atherosclerosis. Harvard Health Publications Harvard
Health Publications. Health Topics A Z, (2011)
[8] Atherosclerosis. National Heart, Lung and Blood Institute. http://www.nhlbi.nih.gov/health/health-topics/
topics/atherosclerosis/signs.html (2011)
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[35] Bhatt DL, Topol EJ (July 2002). Need to test the arterial inammation hypothesis. Circulation 106 (1): 136
40. doi:10.1161/01.CIR.0000021112.29409.A2. PMID
12093783.
[22] Rinehart
JF,
Greenberg
LD
(May
1949).
Arteriosclerotic Lesions in Pyridoxine-Decient
Monkeys. Am. J. Pathol. 25 (3): 48191. PMC
1942913. PMID 18127137.
[23] Rinehart JF, Greenberg LD (1956). Vitamin B6 deciency in the rhesus monkey; with particular reference to
the occurrence of atherosclerosis, dental caries, and hepatic cirrhosis. Am. J. Clin. Nutr. 4 (4): 31825; discussion, 3258. PMID 13339702.
[24] Gruberg, E.R., Raymond, S.A. (1981). Beyond Cholesterol: Vitamin B6 , Arteriosclerosis, and Your Heart (1st
ed.). New York: St. Martins Press.
[40] Taubes G (March 2001). Nutrition. The soft science of dietary fat. Science 291 (5513): 253645.
doi:10.1126/science.291.5513.2536. PMID 11286266.
[25] Kocher T (1883). Uber Kropf exstirpation und ihre Folgen. Arch Klin Chir 29: 254337.
[26] Turner KB (1933). Studies on the prevention of cholesterol atherosclerosis in rabbits. J Exp Med 58 (1): 115
125. doi:10.1084/jem.58.1.115. PMC 2132282. PMID
19870177.
[42] Song JH, Fujimoto K, Miyazawa T (2000). Polyunsaturated (n-3) fatty acids susceptible to peroxidation are increased in plasma and tissue lipids of rats fed docosahexaenoic acid-containing oils. J. Nutr. 130 (12): 302833.
PMID 11110863.
[43] Yap SC, Choo YM, Hew NF, et al.
(1995).
Oxidative susceptibility of low density lipoprotein
from rabbits fed atherogenic diets containing coconut,
palm, or soybean oils. Lipids 30 (12): 114550.
doi:10.1007/BF02536616. PMID 8614305.
[44] Greco AV, Mingrone G (1990). Serum and biliary
lipid pattern in rabbits feeding a diet enriched with
unsaturated fatty acids. Exp Pathol 40 (1): 1933.
doi:10.1016/S0232-1513(11)80281-1. PMID 2279534.
[45] http://medicalxpress.com/news/
2013-08-scientist-orthodoxy-heart-disease.html
[46] Mattes RD (2005). Fat taste and lipid metabolism
in humans.
Physiol.
Behav.
86 (5): 6917.
doi:10.1016/j.physbeh.2005.08.058. PMID 16249011.
The rancid odor of an oxidized fat is readily detectable
12
12 FOOTNOTES
13
13 External links
emerging roles in
Curr Opin Lipidol
[82] Bommer GT, MacDougald OA. Regulation of lipid homeostasis by the bifunctional SREBF2-miR33a locus. Cell
Metab 2011;13:241e7.
[83] Rayner KJ, Sheedy FJ, Esau CC, et al. Antagonism
of miR-33 in mice promotes reverse cholesterol transport and regression of atherosclerosis. J Clin Invest
2011;121:2921e31.
[84] Rayner KJ, Esau CC, Hussain FN, et al. Inhibition of
miR-33a/b in non-human primates raises plasma HDL
and lowers VLDL triglycerides. Nature 2011;478:404e7.
Atherosclerosis at DMOZ
An open access review entitled Hypertension and the
Pathogenesis of Atherosclerosis on Pharma Mirror
Magazine.
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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