Atherosclerosis
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2008-07-07T22:09:00Z
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/* Causes */
{{DiseaseDisorder infobox |
Name = Atherosclerosis |
Image = Endo dysfunction Athero.PNG |
Caption = Changes in endothelial dysfunction in atherosclerosis (note text comments about geometry error) |
DiseasesDB = 1039 |
ICD10 = {{ICD10|I|70||i|70}} |
ICD9 = {{ICD9|440}} |
MedlinePlus = 000171 |
eMedicineSubj = med |
eMedicineTopic = 182 |
MeshID = D050197 |
{{For having articles about atherosclerosis and platelets in Farsi please have a look at http://www.rezanejat.com/content.asp?ContentId=460 and http://www.rezanejat.com/content.asp?ContentId=461}}
}}
'''Atherosclerosis''' is a [[disease]] affecting [[artery|arterial]] [[blood vessel]]s. It is a chronic inflammatory response in the walls of arteries, in large part due to the accumulation of [[macrophage]] [[white blood cells]] and promoted by low density (especially small particle) [[lipoproteins]] (plasma proteins that carry cholesterol and [[triglycerides]]) without adequate removal of fats and cholesterol from the macrophages by functional [[high density lipoprotein]]s (HDL), (see [[apoA-1 Milano]]). It is commonly referred to as a "hardening" or "furring" of the arteries. It is caused by the formation of multiple [[atheroma|plaques]] within the [[arteries]].<ref>{{cite book
| last = Maton
| first = Anthea
| authorlink =
| coauthors = Jean Hopkins, Charles William McLaughlin, Susan Johnson, Maryanna Quon Warner, David LaHart, Jill D. Wright
| title = Human Biology and Health
| publisher = Prentice Hall
| date = 1993
| location = Englewood Cliffs, New Jersey, USA
| pages =
| url =
| doi =
| id =
| isbn = 0-13-981176-1}}</ref>
The '''[[atheroma|atheromatous plaque]]''' is divided into three distinct components:
# The [[atheroma]] ("lump of porridge", from ''Athera'', [[porridge]] in Greek,), which is the nodular accumulation of a soft, flaky, yellowish material at the center of large plaques, composed of [[macrophage]]s nearest the [[lumen (anatomy)|lumen]] of the artery
# Underlying areas of [[cholesterol]] crystals
# Calcification at the outer base of older/more advanced lesions.
The following terms are similar, yet distinct, in both spelling and meaning, and can be easily confused: arteriosclerosis, arteriolosclerosis, and atherosclerosis. '''Arteriosclerosis''' is a general term describing any hardening (and loss of elasticity) of medium or large arteries (from the Greek '''Arterio''', meaning ''artery'', and '''sclerosis''', meaning ''hardening''), '''arteriolosclerosis''' is any hardening (and loss of elasticity) of [[arteriole]]s (small arteries), '''atherosclerosis''' is a hardening of an artery specifically due to an atheromatous plaque. Therefore, atherosclerosis is a form of arteriosclerosis.
Atherosclerosis causes two main problems. First, the [[atheroma|atheromatous plaques]], though long compensated for by artery enlargement (see [[intima-media thickness|IMT]]), eventually lead to plaque ruptures and [[stenosis]] (narrowing) of the artery and, therefore, an insufficient blood supply to the organ it feeds. Second, if the compensating artery enlargement process is excessive, then a net [[aneurysm]] results.
These complications are chronic, slowly progressing and cumulative. Most commonly, soft plaque suddenly ruptures (see [[vulnerable plaque]]), causing the formation of a [[thrombus]] that will rapidly slow or stop blood flow, leading to death of the tissues fed by the artery in approximately 5 minutes. This catastrophic event is called an [[infarction]]. One of the most common recognized scenarios is called [[coronary thrombosis]] of a [[coronary artery]], causing [[myocardial infarction]] (a heart attack). Another common scenario in very advanced disease is [[claudication]] from insufficient blood supply to the legs, typically due to a combination of both stenosis and aneurysmal segments narrowed with [[thrombus|clots]]. Since atherosclerosis is a body-wide process, similar events occur also in the arteries to the brain, intestines, kidneys, legs, etc.
==Causes==
Atherosclerosis develops from low-density lipoprotein cholesterol (LDL), colloquially called "bad cholesterol". When this [[lipoprotein]] gets through the wall of an [[artery]], oxygen [[free radicals]] react with it to form oxidized-LDL. <ref>{{cite journal |
journal = Yakugaku Zasshi. |
volume = 2007 Dec;127(12):1997-2014 |
title = [Oxidative stress and atherosclerosis] |
author = Kunitomo M |
pmid = 18057788 }}</ref> The body's immune system responds by sending specialised white blood cells ([[macrophages]] and [[T-lymphocytes]]) to absorb the oxidised-LDL. Unfortunately, these white blood cells are not able to process the oxidised-LDL, and ultimately grow then rupture, depositing a greater amount of oxidised cholesterol into the artery wall. This triggers more white blood cells, continuing the cycle.
Eventually, the artery becomes inflamed. The cholesterol plaque causes the muscle cells to enlarge and form a hard cover over the affected area. This hard cover is what causes a narrowing of the artery, reduces the blood flow and increases blood pressure.
Some researchers believe that atherosclerosis may be caused by an infection of the vascular smooth muscle cells. Chickens, for example, develop atherosclerosis when infected with the [[Marek's disease]] herpesvirus. <ref>{{cite journal |author= Fabricant CG, Fabricant J |title= Atherosclerosis induced by infection with Marek's disease herpesvirus in chickens |journal= Am Heart J |volume= 1999 Nov;138(5 Pt 2):S465-8 |pmid= 10539849 |doi=}}</ref> [[Herpesvirus]] infection of arterial [[smooth muscle cells]] has been shown to cause cholesteryl ester (CE) accumulation. <ref>{{cite journal |
journal = J Biol Chem |
volume = 1995 Aug 18;270(33):19630-7 |
title = Altered cholesterol trafficking in herpesvirus-infected arterial cells. Evidence for viral protein kinase-mediated cholesterol accumulation |
author = Hsu HY, Nicholson AC, Pomerantz KB, Kaner RJ, Hajjar DP |
pmid = 7642651 }}</ref> [[Cholesteryl ester]] accumulation is associated with atherosclerosis.
==Symptoms==
Atherosclerosis typically begins in early adolescence, and is usually found in most major [[artery|arteries]], yet is asymptomatic and not detected by most diagnostic methods during life. The stage immediately prior to actual atherosclerosis is known as subclinical atherosclerosis. The majority of the process leading to subclinical atherosclerosis can happen without our knowing it, especially given the large variety of risk factors. <ref>Summary of [http://www.itamar-medical.com/Product.asp?pid=3983&ppid=3005 subclinical atherosclerosis] at Itamar Medical</ref>. Autopsies of healthy young men that died during the Korean and Vietnam Wars showed evidence of the disease.<ref name="pmid11390341">{{cite journal |author=Tuzcu EM, Kapadia SR, Tutar E, ''et al'' |title=High prevalence of coronary atherosclerosis in asymptomatic teenagers and young adults: evidence from intravascular ultrasound |journal=Circulation |volume=103 |issue=22 |pages=2705–10 |year=2001
|url=http://circ.ahajournals.org/cgi/reprint/103/22/2705
|pmid=11390341 |doi= |accessdate=2007-11-02}}</ref> <ref>{{cite web
|url=http://www.medicinenet.com/heart_attack_pathology_photo_essay/page2.htm
|title=Heart Attack Photo Illustration Essay on MedicineNet.com
|accessdate=2007-11-02
|author=Michael C. Fishbein, M.D.
|editor= Leslie J. Schoenfield
|format=
|work=
}}</ref> It most commonly becomes seriously symptomatic when interfering with the [[coronary circulation]] supplying the [[heart]] or [[cerebral circulation]] supplying the [[brain]], and is considered the most important underlying cause of [[Cerebrovascular accident|strokes]], [[myocardial infarction|heart attack]]s, various [[heart disease]]s including [[congestive heart failure]], and most [[cardiovascular disease]]s, in general. Atheroma in arm, or more often in leg arteries, which produces decreased blood flow is called [[Peripheral artery occlusive disease]] (PAOD).
According to United States data for the year 2004, for about 65% of men and 47% of women, the first [[symptom]] of atherosclerotic [[cardiovascular disease]] is [[myocardial infarction|heart attack]] or [[sudden cardiac death]] (death within one hour of onset of the symptom).
Most artery flow disrupting events occur at locations with less than 50% [[lumen (anatomy)|lumen]] narrowing (~20% [[stenosis]] is average). [The reader might reflect that the illustration above, like most illustrations of arterial disease, overemphasizes lumen narrowing, as opposed to compensatory external diameter enlargement (at least within smaller arteries, e.g., heart arteries) typical of the atherosclerosis process as it progresses, see Glagov<ref name=Glagov/> and the ASTEROID trial,<ref name=Nissen /> the [[IVUS]] photographs on page 8, as examples for a more accurate understanding. The relative geometry error within the illustration is common to many older illustrations, an error slowly being more commonly recognized within the last decade.]
[[Cardiac stress test]]ing, traditionally the most commonly performed non-invasive testing method for blood flow limitations, in general, detects only [[lumen (anatomy)|lumen]] narrowing of ~75% or greater, although some physicians claim that nuclear stress methods can detect as little as 50%.
==Atherogenesis==<!-- This section is linked [[Antioxidant]] -->
Atherogenesis is the developmental process of atheromatous plaques. It is characterized by a remodeling of [[artery|arteries]] involving the concomitant accumulation of fatty substances called plaques. One recent theory 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 [[inflammation]] 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 first, as the plaques grow, only [[intima-media thickness|wall thickening]] occurs without any narrowing, stenosis of the artery opening, called the lumen; [[stenosis]] is a late event, which may never occur and is often the result of repeated plaque rupture and healing responses, not just the atherosclerosis process by itself.
===Cellular===
The first step of atherogenesis is the development of [[fatty streak]]s, which are small subendothelial deposits of oxidized cholesterol and monocyte-derived macrophages. The exact cause for this process is unknown, and fatty streaks may appear and disappear.
LDL in blood plasma poses a risk for [[cardiovascular disease]] when it invades the [[endothelium]] and becomes [[oxidize]]d. A complex set of biochemical reactions regulates the oxidation of LDL, chiefly stimulated by presence of [[free radical]]s in the [[endothelium]] or blood vessel lining.
The initial damage to the blood vessel wall results in a "call for help," an inflammatory response. [[Monocyte]]s (a type of [[white blood cell]]) enter the artery wall from 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. The [[monocyte]]s differentiate [[macrophage]]s, which ingest [[oxidize]]d [[LDL]], slowly turning into large "foam cells" – so-described because of their changed appearance resulting from the numerous internal cytoplasmic [[vesicle (biology)|vesicle]]s and resulting high [[lipid]] content. Under the microscope, the lesion now appears as a fatty streak. Foam cells eventually die, and further propagate the inflammatory process.
There is also smooth muscle proliferation and migration from tunica media to intima responding to cytokines secreted by damaged endothelial cells. This would cause the formation of a fibrous capsule covering the fatty streak.
===Calcification and lipids===
Intracellular [[calcification|microcalcifications]] form within [[vascular smooth muscle]] cells of the surrounding muscular layer, specifically in the muscle cells adjacent to the atheromas. In time, as cells die, this leads to extracellular calcium deposits between the muscular wall and outer portion of the atheromatous plaques. A similar form of an intramural calcification, 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]] 2008).
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 inflammatory process. The process is worsened if there is insufficient [[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 fibrous cap normally forms between the fatty deposits and the artery lining (the [[endothelium|intima]]).
These capped fatty deposits (now called 'atheromas') produce enzymes that cause the artery to enlarge over time. As long as the artery enlarges sufficiently 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 with a circular opening. If the enlargement is beyond proportion to the atheroma thickness, then an [[aneurysm]] is created.<ref name="Glagov">{{cite journal |author=Glagov S, Weisenberg E, Zarins CK, Stankunavicius R, Kolettis GJ |title=Compensatory enlargement of human atherosclerotic coronary arteries |journal=N. Engl. J. Med. |volume=316 |issue=22 |pages=1371–5 |year=1987 |month=May |pmid=3574413 |doi= |url=}}</ref>
===Visible features===
[[Image:Atherosclerosis, aorta, gross pathology PHIL 846 lores.jpg|thumb|230px|Severe atherosclerosis of the [[aorta]]. [[Autopsy]] specimen.]]
Although arteries are not typically studied microscopically, two plaque types can be distinguished[http://www.pathologyatlas.ro/Coronary%20ATS%20Calcification.html]:
# The '''fibro-lipid (fibro-fatty) plaque''' is characterized by an accumulation of lipid-laden cells underneath the intima of the arteries, typically without narrowing the lumen due to compensatory expansion of the bounding muscular layer of the artery wall. Beneath the endothelium there is a "fibrous cap" covering the atheromatous "core" of the plaque. The core consists of lipid-laden cells (macrophages and smooth muscle cells) with elevated tissue cholesterol and cholesterol ester content, fibrin, proteoglycans, collagen, elastin, and cellular debris. In advanced plaques, the central core of the plaque usually contains extracellular cholesterol deposits (released from dead cells), which form areas of cholesterol crystals with empty, needle-like clefts. At the periphery of the plaque are younger "foamy" cells and capillaries. These plaques usually produce the most damage to the individual when they rupture.
# The '''fibrous 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 fibrous plaque contains collagen fibers (eosinophilic), precipitates of calcium (hematoxylinophilic) and, rarely, lipid-laden cells.
In effect, the muscular portion of the artery wall forms small [[aneurysm]]s 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 compensate for the [[atheroma]]tous plaques.
However, [[atheroma]]s 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 calcification deposits between the outer portion of the atheroma and the muscular wall, as they progress, lead to a loss of elasticity and stiffening of the artery as a whole.
The calcification deposits, after they have become sufficiently 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 [[Hounsfield scale]] {some argue for 90 units) has been the radiographic density usually accepted as clearly representing tissue calcification within arteries. These deposits demonstrate unequivocal evidence of the disease, relatively advanced, even though the lumen of the artery is often still normal by angiographic or [[intravascular ultrasound]].
===Rupture and stenosis===
Although the disease process tends to be slowly progressive over decades, it usually remains asymptomatic until an atheroma obstructs the bloodstream in the artery. This is typically by rupture of an atheroma, clotting and fibrous organization of the clot within the lumen, covering the rupture but also producing [[stenosis]], or over time and after repeated ruptures, resulting in a persistent, usually localized stenosis. Stenoses can be slowly progressive, whereas plaque rupture is a sudden event that occurs specifically in atheromas with thinner/weaker fibrous caps that have become "unstable."
Repeated plaque ruptures, ones not resulting in total lumen 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 flow velocities at these narrowings. Most major blood-flow-stopping 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.
If the fibrous cap separating a soft atheroma from the bloodstream within the artery ruptures, tissue fragments are exposed and released, and blood enters the atheroma within the wall and sometimes results in a sudden expansion of the atheroma size. Tissue fragments are very clot-promoting, containing [[collagen]] and [[tissue factor]]; they activate [[platelet]]s and activate the [[coagulation|system of coagulation]]. The result is the formation of a [[thrombus]] (blood clot) overlying the atheroma, which obstructs blood flow acutely. With the obstruction of blood flow, downstream tissues are starved of [[oxygen]] and nutrients. If this is the [[myocardium]] (heart muscle), [[Angina pectoris|angina]] (cardiac chest pain) or [[myocardial infarction]] (heart attack) develops.
==Diagnosis of plaque-related disease==
[[Image:Calcificatio atherosclerotica.jpg|thumb|Microphotography of arterial wall with calcified (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 [[stenosis|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 [[stenosis|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 lipid matrix breaks through the thinning [[collagen]] gap and when the lipids come in contact with the blood, clotting occurs. After rupture the platelet adhesion causes the clotting cascade to contact with the lipid pool causing a [[thrombus]] to form. This thrombus will eventually grow and travel throughout the body. The [[thrombus]] will travel through different arteries and veins and eventually become lodged in an area that narrows. Once the area is blocked, blood and [[oxygen]] will not be able to supply the vessels and will cause death of cells and lead to [[necrosis]] and poisoning. Serious complicated plaques can cause death of organ tissues, causing serious complications to that organ system.
Greater than 75% lumen [[stenosis]] used to be considered by cardiologists as the hallmark of clinically significant disease because it is typically only at this severity of narrowing of the larger heart arteries that recurring episodes of [[Angina pectoris|angina]] and detectable abnormalities by [[stress test]]ing methods are seen.
However, clinical trials have shown that only about 14% of clinically-debilitating events occur at locations with this, or greater severity of [[stenosis|narrowing]].
The majority of events occur due to atheroma plaque rupture at areas without [[stenosis|narrowing]] sufficient enough to produce any [[Angina pectoris|angina]] or [[stress test]] abnormalities.
Thus, since the later-1990s, greater attention is being focused on the "vulnerable plaque."<ref name="MaseriFuster">{{cite journal |author=Maseri A, Fuster V |title=Is there a vulnerable plaque? |journal=Circulation |volume=107 |issue=16 |pages=2068–71 |year=2003 |pmid=12719286 |doi=10.1161/01.CIR.0000070585.48035.D1 |accessdate=2007-11-21}}</ref>
Though any artery in the body can be involved, usually only severe [[stenosis|narrowing]] or obstruction of some arteries, those that supply more critically-important organs are recognized. Obstruction of arteries supplying the heart muscle result in a [[myocardial infarction|heart attack]]. Obstruction of arteries supplying the brain result in a [[stroke]]. These events are life-changing, and often result in irreversible loss of function because lost heart muscle and brain cells do not grow back to any significant extent, typically less than 2%.
Over the last couple of decades, methods other than angiography and stress-testing have been increasingly developed as ways to better detect atherosclerotic disease before it becomes symptomatic. These have included both (a) anatomic detection methods and (b) physiologic measurement methods.
Examples of anatomic methods include: (1) coronary calcium scoring by CT, (2) carotid IMT ([[Intima-media thickness|intimal media thickness]]) measurement by ultrasound, and (3) IVUS.
Examples of physiologic methods include: (1) lipoprotein subclass analysis, (2) [[Glycosylated hemoglobin|HbA1c]], (3) [[C-reactive protein|hs-CRP]], and (4) [[homocysteine]].
The example of the metabolic syndrome combines both anatomic (abdominal girth) and physiologic (blood pressure, elevated blood glucose) methods.
Advantages of these two approaches: The anatomic methods directly measure some aspect of the actual atherosclerotic disease process itself, thus offer potential for earlier detection, including before symptoms start, disease staging and tracking of disease progression. The physiologic methods are often less expensive and safer and changing them for the better may slow disease progression, in some cases with marked improvement.
Disadvantages of these two approaches: The anatomic methods are generally more expensive and several are invasive, such as IVUS. The physiologic methods do not quantify the current state of the disease or directly track progression. For both, clinicians and third party payers have been slow to accept the usefulness of these newer approaches.
==Physiologic factors that increase risk==
Various anatomic, physiological & behavioral risk factors for atherosclerosis are known.<ref name=Blankenhorn>{{cite journal
|author=D H Blankenhorn and H N Hodis
|title= Atherosclerosis--reversal with therapy
|url=http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=1022223
|journal=West J Med|year=1993 August|volume=159(2)|pages= 172–179|accessdate=2007-11-19
|pmid= 8212682}}</ref>
These can be divided into various categories: congenital ''vs'' acquired, modifiable or not, classical or non-classical. The points labelled '+' in the following list form the core components of "[[metabolic syndrome]]":
* [[Senescence|Advanced age]]
* Having [[Diabetes]] or [[Impaired glucose tolerance]] (IGT) +
* [[lipoprotein|Dyslipoproteinemia]] (unhealthy patterns of serum proteins carrying fats & [[cholesterol]]): +
** High serum concentration of [[low-density lipoprotein]] (LDL, "bad if elevated concentrations and small"), and / or [[very low density lipoprotein]] (VLDL) particles, i.e., "lipoprotein subclass analysis"
** Low serum concentration of functioning [[high density lipoprotein]] (HDL "protective if large and high enough" particles), i.e., "lipoprotein subclass analysis"
** An LDL:HDL ratio greater than 3:1
* [[Male]] sex
* [[Tobacco smoking]]
* Having [[hypertension|high]] [[blood pressure]] +
* Being [[obesity|obese]] (in particular [[central obesity]], also referred to as ''abdominal'' or ''male-type'' obesity) +
* A [[sedentary lifestyle]]
* Having close relatives who have had some complication of atherosclerosis (eg. [[coronary heart disease]] or [[stroke]])
* Elevated serum levels of [[triglycerides]] +
* Elevated serum levels of [[homocysteine]]
* Elevated serum levels of [[uric acid]] (also responsible for gout)
* Elevated serum [[fibrinogen]] concentrations
* Elevated serum [[lipoprotein(a)]] concentrations
* Elevated serum [[C-reactive protein]] concentrations
* Elevated serum insulin levels + <ref name="Hyperinsulinaemia ">{{cite journal |author=Griffin M, Frazer A, Johnson A, Collins P, Owens D, Tomkin GH |title=Cellular cholesterol synthesis--the relationship to post-prandial glucose and insulin following weight loss |journal=Atherosclerosis. |volume=138 |issue=2 |pages=313–8 |year=1998 |pmid=9690914 | doi = 10.1016/S0021-9150(98)00036-7|accessdate=2008-04-23}}</ref>
** Chronic systemic [[inflammation]] as reflected by upper normal WBC concentrations, elevated [[C reactive protein|hs-CRP]] and many other blood chemistry markers, most only research level at present, not clinically done.<ref name=Bhatt> [http://circ.ahajournals.org/cgi/content/full/circulationaha;106/1/136 Deepak L. Bhatt, MD; Eric J. Topol, MD] ''Need to Test the Arterial Inflammation Hypothesis'', 2002, referenced on 4/1/06 </ref>
* [[Stress (medicine)|Stress]] or symptoms of [[clinical depression]]
* [[Hyperthyroidism]] (an over-active [[thyroid]])
===Dietary risk factors===
The relation between dietary fat and atherosclerosis is a contentious field.
The [[United States Department of Agriculture|USDA]], in its [[food pyramid]], promotes a low-fat diet, based largely on its view that fat in the diet is atherogenic.
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, [[Principal investigator|PI]] of the second [[Nurses' Health Study]]) recommends much higher levels, especially of [[Monounsaturated fat|monounsaturated]] and [[polyunsaturated fat]].<ref name="titleFood Pyramids: Nutrition Source, Harvard School of Public Health">{{cite web |url=http://www.hsph.harvard.edu/nutritionsource/pyramids.html |title=Food Pyramids: Nutrition Source, Harvard School of Public Health |accessdate=2007-11-25 |format= |work=}}</ref>
Writing in [[Science]], [[Gary Taubes]] detailed that political considerations played into the recommendations of government bodies.<ref name="Taubes">{{cite web |url=http://www.sciencemag.org/cgi/content/summary/291/5513/2536?ck=nck&siteid=sci&ijkey=ow64uv8o370SA&keytype=ref
|title=NUTRITION: The Soft Science of Dietary Fat |doi=DOI: 10.1126/science.291.5513.2536
|author=Taubes |volume=291 |pages=5513|journal=Science |accessdate=2007-11-25 |format= |work=}}</ref>
These differing views reach a consensus, though, against consumption of [[trans fat]]s.
The role of dietary oxidized fats / [[lipid peroxidation]] ([[rancidification|rancid fats]]) in humans is not clear.
Laboratory animals fed rancid fats develop atherosclerosis. Rats fed [[Docosahexaenoic acid| DHA]]-containing oils experienced marked disruptions to their [[antioxidant]] systems, as well as accumulated significant amounts of peroxide in their blood, livers and kidneys.<ref name="SongJH">{{cite journal |author=Song JH, Fujimoto K, Miyazawa T |title=Polyunsaturated (n-3) fatty acids susceptible to peroxidation are increased in plasma and tissue lipids of rats fed docosahexaenoic acid-containing oils |journal=J. Nutr. |volume=130 |issue=12 |pages=3028–33 |year=2000 |pmid=11110863 |doi= |accessdate=2007-12-10}}</ref>
In another study, rabbits fed atherogenic diets containing various oils were found to undergo the greatest amount of oxidative susceptibility of LDL via polyunsaturated oils.<ref name="YapSC">{{cite journal |author=Yap SC, Choo YM, Hew NF, ''et al'' |title=Oxidative susceptibility of low density lipoprotein from rabbits fed atherogenic diets containing coconut, palm, or soybean oils |journal=Lipids |volume=30 |issue=12 |pages=1145–50 |year=1995 |pmid=8614305 | doi = 10.1007/BF02536616|accessdate=2007-12-10}}</ref> In a study involving rabbits fed heated soybean oil, "grossly induced atherosclerosis and marked liver damage were histologically and clinically demonstrated".<ref name="Greco">{{cite journal |author=Greco AV, Mingrone G |title=Serum and biliary lipid pattern in rabbits feeding a diet enriched with unsaturated fatty acids |journal=Exp Pathol |volume=40 |issue=1 |pages=19–33 |year=1990 |pmid=2279534 |doi= |accessdate=2007-12-10}}</ref>
Rancid fats and oils taste very bad even in small amounts; people avoid eating them.<ref name="pmid16249011">{{cite journal |author=Mattes RD |title=Fat taste and lipid metabolism in humans |journal=Physiol. Behav. |volume=86 |issue=5 |pages=691–7 |year=2005 |pmid=16249011 |doi=10.1016/j.physbeh.2005.08.058 |url=http://linkinghub.elsevier.com/retrieve/pii/S0031-9384(05)00397-5
|quote=The rancid odor of an oxidized fat is readily detectable |accessdate=2007-12-04}}</ref>
It is very difficult to measure or estimate the actual human consumption of these substances.<ref name="pmid12589185">{{cite journal |author=Dobarganes C, Márquez-Ruiz G |title=Oxidized fats in foods |journal=Curr Opin Clin Nutr Metab Care |volume=6 |issue=2 |pages=157–63 |year=2003 |pmid=12589185 |doi=10.1097/01.mco.0000058585.27240.ee |accessdate=2007-11-25 |doi_brokendate=2008-06-27}}</ref> In addition, the majority of oils consumed in the United States are refined, bleached, deodorized and degummed by manufacturers. The resultant oils are colorless, odorless, tasteless and have a longer shelf life than their unrefined counterparts.<ref>[http://www.udoerasmus.com/articles/udo/hbaco.htm How Bad Are Cooking Oils?] by [[Udo Erasmus]], PhD</ref> This extensive processing serves to make peroxidated, rancid oils much more elusive to detection via the various human senses than the unprocessed alternatives.
== Prognosis==
[[dyslipidemia|Lipoprotein imbalances]], upper normal and especially elevated blood sugar, i.e., [[diabetes]] and high blood pressure are risk factors for atherosclerosis; [[homocysteine]], stopping smoking, taking [[anticoagulant]]s (anti-clotting agents), which target clotting factors, taking omega-3 oils from fatty fish or plant oils such as flax or canola oils, exercising and losing weight are the usual focus of treatments that have proven to be helpful in clinical trials. The target serum cholesterol level is ideally equal or less than 4mmol/L (160 mg/dL), and triglycerides equal or less than 2mmol/L (180 mg/dL).
Evidence has increased that people with [[diabetes]], despite their not having clinically-detectable atherosclotic disease, have more severe debility from atherosclerotic events over time than even non-diabetics that have already suffered atherosclerotic events. Thus [[diabetes]] has been upgraded to be viewed as an advanced atherosclerotic disease equivalent.
==Treatment==
If atherosclerosis leads to symptoms, some symptoms such as [[angina pectoris]] can be treated. Non-pharmaceutical means are usually the first method of treatment, such as cessation of smoking and practicing regular exercise. If these methods do not work, medicines are usually the next step in treating cardiovascular diseases, and, with improvements, have increasingly become the most effective method over the long term. However, medicines are criticized for their expense, patented control and occasional undesired effects.
===Statins===
In general, the group of medications referred to as [[statins]] has been the most popular and are widely prescribed for treating atherosclerosis. They have relatively few short-term or longer-term undesirable side-effects, and multiple comparative treatment/placebo trials have fairly consistently shown strong effects in reducing atherosclerotic disease 'events' and generally ~25% comparative mortality reduction in clinical trials, although one study design, ALLHAT.<ref name="pmid12479764">{{cite journal
|author=
|title=Major outcomes in moderately hypercholesterolemic, hypertensive patients randomized to pravastatin vs usual care: The Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT-LLT)
|journal=JAMA
|volume=288
|issue=23
|pages=2998–3007
|year=2002
|pmid=12479764
|doi=
|accessdate=2007-11-02
}}</ref> was less strongly favorable.
The newest statin, [[rosuvastatin]], has been the first to demonstrate regression of atherosclerotic plaque within the [[coronary arteries]] by [[IVUS]] (intravascular ultrasound evaluation),<ref name=Nissen>{{cite journal
|journal=JAMA
|url=http://jama.ama-assn.org/cgi/reprint/jama;295/13/1556.pdf?ijkey=Md42dlk7z9TzyL8&keytype=finite
|title= "Effect of Very High-Intensity Statin Therapy on Regression of Coronary Atherosclerosis–The ASTEROID Trial"
|author=Nissen}}</ref> The study was set up to demonstrate effect primarily on atherosclerosis volume within a 2 year time-frame in people with active/symptomatic disease (angina frequency also declined markedly) but not global clinical outcomes, which was expected to require longer trial time periods; these longer trials remain in progress.
However, for most people, changing their physiologic behaviors, from the usual high risk to greatly reduced risk, requires a combination of several compounds, taken on a daily basis and indefinitely. More and more human treatment trials have been done and are ongoing that demonstrate improved outcome for those people using more-complex and effective treatment regimens that change physiologic behaviour patterns to more closely resemble those that humans exhibit in childhood at a time before [[fatty streaks]] begin forming.
The [[statin]]s, and some other medications, have been shown to have [[antioxidant]] effects, possibly part of their basis for some of their therapeutic success in reducing cardiac 'events'.
The success of statin drugs in clinical trials is based on some reductions in mortality rates, however by trial design biased toward men and middle-age, the data is as, as yet, less strongly clear for women and people over the age of 70 [http://www.cmaj.ca/cgi/content/full/173/10/1207-a CMAJ]. For example, in the [[Scandinavian Simvastatin Survival Study|Scandinavian Simvastatin Survival Study (4S)]], the first large placebo controlled, randomized clinical trial of a statin in people with advanced disease who had already suffered a heart attack, the overall mortality rate reduction for those taking the statin, vs. placebo, was 30%. For the subgroup of people in the trial that had Diabetes Mellitus, the mortality rate reduction between statin and placebo was 54%. 4S was a 5.4-year trial that started in 1989 and was published in 1995 after completion. There were 3 more dead women at trial's end on statin than in the group on placebo drug whether chance or some relation to the statin remains unclear. The ASTEROID trial has been the first to show actual disease volume regression<ref name=Nissen /> (see page 8 of the paper, which shows cross-sectional areas of the total heart artery wall at start and 2 years of rosuvastatin 40 mg/day treatment); however, its design was not able to "prove" the mortality reduction issue since it did not include a placebo group, the individuals offered treatment within the trial had advanced disease and promoting a comparison placebo arm was judged to be unethical.
====Primary and Secondary Prevention—Studies====
Combinations of [[statin]]s, [[niacin]], intestinal cholesterol absorption-inhibiting supplements ([[ezetimibe]] and others, and to a much lesser extent [[fibrate]]s) have been the most successful in changing common but sub-optimal [[lipoprotein]] patterns and group outcomes.
In the many secondary prevention and several primary prevention trials, several classes of lipoprotein expression (less correctly termed "cholesterol-lowering") altering agents have consistently reduced not only heart attack, stroke and hospitalization but also all-cause mortality rates.
The first of the large secondary prevention comparative statin/placebo treatment trials was the Scandinavian Simvastatin Survival Study (4S) <ref>{{cite journal
| journal =European Heart Journal |year= 1997 |issue=18(11)|pages=1725–1727;
| title =Cholesterol lowering after participation in the Scandinavian Simvastatin Survival Study (4S) in Finland
| author=T. E. Strandberg, S. Lehto, K. Pyörälä, A. Kesäniemi, H. Oksa
| url=http://eurheartj.oxfordjournals.org/cgi/content/abstract/18/11/1725
| accessdate=2007-11-18
| pmid =9402446}} </ref>
with over 15 more extending through the more recent ASTEROID <ref name="ASTEROID">{{cite journal
|author=Nissen SE, Nicholls SJ, Sipahi I, ''et al''
|title=Effect of very high-intensity statin therapy on regression of coronary atherosclerosis: the ASTEROID trial
|journal=JAMA
|volume=295 |issue=13 |pages=1556–65 |year=2006 |pmid=16533939 |doi=10.1001/jama.295.13.jpc60002
|url=http://jama.ama-assn.org/cgi/reprint/jama;295/13/1556.pdf?ijkey=Md42dlk7z9TzyL8&keytype=finite |format=PDF}}</ref>
trial published in 2006.
The first primary prevention comparative treatment trial was AFCAPS/TexCAPS <ref name=CAPS>{{cite journal
|doi= 10.1001/jama.279.20.1615
|journal = JAMA |volume= 279 No. 20|date= May 27, 1998
|title=Primary Prevention of Acute Coronary Events With Lovastatin in Men and Women With Average Cholesterol Levels—Results of AFCAPS/TexCAPS
|author=John R. Downs, MD; Michael Clearfield, DO; Stephen Weis, DO; Edwin Whitney, MD; Deborah R. Shapiro, DrPH; Polly A. Beere, MD, PhD; Alexandra Langendorfer, MS; Evan A. Stein, MD; William Kruyer, MD; Antonio M. Gotto, Jr, MD, DPhil; for the AFCAPS/TexCAPS Research Group
|pages=1615–1622
|pmid=9613910}}</ref>
with multiple later comparative statin/placebo treatment trials
including EXCEL.<ref name="pmid1985608">{{cite journal
|author=Bradford RH, Shear CL, Chremos AN, ''et al''
|title=Expanded Clinical Evaluation of Lovastatin (EXCEL) study results. I. Efficacy in modifying plasma lipoproteins and adverse event profile in 8245 patients with moderate hypercholesterolemia
|journal=Arch. Intern. Med. |volume=151 |issue=1 |pages=43–9 |year=1991 |pmid=1985608 | doi = 10.1001/archinte.151.1.43|accessdate=2007-11-21
}}</ref>,
ASCOT <ref name="pmid15855581">{{cite journal
|author=Sever PS, Poulter NR, Dahlöf B, ''et al''
|title=Reduction in cardiovascular events with atorvastatin in 2,532 patients with type 2 diabetes: Anglo-Scandinavian Cardiac Outcomes Trial--lipid-lowering arm (ASCOT-LLA)
|journal=Diabetes Care |volume=28 |issue=5 |pages=1151–7 |year=2005 |pmid=15855581 | doi = 10.2337/diacare.28.5.1151|accessdate=2007-11-21
}}</ref>
and SPARCL.<ref> {{cite web
|url=http://www.medscape.com/viewarticle/536377
|publisher = [[Medscape]]
|author=Linda Brookes, MSc
|title=SPARCL: Stroke Prevention by Aggressive Reduction in Cholesterol Levels
|accessdate= 2007-11-19}}</ref>
<ref> {{cite journal|
url=http://content.karger.com/ProdukteDB/produkte.asp?Aktion=ShowAbstract&ProduktNr=224153&ArtikelNr=72562
|title=Design and Baseline Characteristics of the Stroke Prevention by Aggressive Reduction in Cholesterol Levels (SPARCL) Study
|journal=Cerebrovascular Diseases|year= 2003|volume=16|pages=389–395 |doi=10.1159/000072562|accessdate=2007-11-19}}</ref>
While the statin trials have all been clearly favorable for improved human outcomes, only ASTEROID showed evidence of atherosclerotic regression (slight). For both human and animal trials, those which have shown evidence of disease regression had all utilized more aggressive combination agent treatment strategies, nearly always including niacin.<ref name="Blankenhorn" />
===Diet and dietary supplements===
Vitamin B3, AKA [[niacin]], in pharmacologic doses, (generally 1,000 to 3,000 mg/day), sold in many OTC and prescription formulations, tends to improve (a) HDL levels, size and function, (b) shift LDL particle distribution to larger particle size and (c) lower [[lipoprotein(a)]], an atheroslerosis promoting genetic variant of LDL. Additionally, individual responses to daily niacin, while mostly evident after a month at effective doses, tends to continue to slowly improve further over time. (However, careful patient understanding of how to achieve this without nuisance symptoms is needed, though not often achieved.) Research work on increasing HDL particle concentration and function, beyond the usual niacin effect/response, even more important, is slowly advancing.
Dietary changes to achieve benefit have been more controversial, generally far less effective and less widely adhered to with success. One key reason for this is that most cholesterol, typically 80-90%, within the body is created and controlled by internal production by all cells in the body (true of all animals), with typically slightly greater relative production by hepatic/liver cells. (Cell structure relies on fat membranes to separate and organize intracellular water, proteins and nucleic acids and cholesterol is one of the components of all animal cell membranes.)
Caldwell B Esselstyn Jr. MD has had an article published in Preventive Cardiology 2001;4: 171-177 in which he has published angiograms showing regression of atherosclerosis brought about by a very low fat vegan diet in some cases with cholesterol lowering medications.<ref>http://www.heartattackproof.com/resolving_cade.htm Resolving the Coronary Artery Disease Epidemic through Plant-Based Nutrition Caldwell B. Esselstyn, Jr., MD</ref>
While the absolute production quantities vary with the individual, group averages for total human body content of cholesterol within the U.S. population commonly run about ~35,000 mg (assuming lean build; varies with body weight and build) and ~1,000 mg/day ongoing production. Dietary intake plays a smaller role, 200-300 mg/day being common values; for pure vegetarians, essentially 0 mg/day, but this typically does not change the situation very much because internal production increases to largely compensate for the reduced intake. For many, especially those with greater than optimal body mass and increased glucose levels, reducing carbohydrate (especially simple forms) intake, not fats or cholesterol, is often more effective for improving lipoprotein expression patterns, weight and blood glucose values. For this reason, medical authorities much less frequently promote the low dietary fat concepts than was commonly the case prior to about year 2005. However, evidence has increased that processed, particularly industrial non-enzymatic [[hydrogenation]] produced trans fats, as opposed to the natural [[cis]]-configured fats, which living cells primarily produce, is a significant health hazard.
Dietary supplements of Omega-3 oils, especially those from the muscle of some deep salt water living fish species, also have clinical evidence of significant protective effects as confirmed by 6 [[double blind]] [[placebo]] [[scientific control|controlled]] human clinical trials.
There is also a variety of evidence, though less robust, that [[homocysteine]] and [[uric acid]] levels, including within the normal range promote atherosclerosis and that lowering these levels is helpful, up to a point.
In animals [[Vitamin C]] deficiency has been confirmed as an important role in development of [[hypercholesterolemia]] and atherosclerosis, but due to ethical reasons placebo-controlled human studies are impossible to do.<ref>{{cite journal |author=Ginter E |title=Chronic vitamin C deficiency increases the risk of cardiovascular diseases |journal=Bratisl Lek Listy |volume=108 |issue=9 |pages=417–21 |year=2007 |pmid=18225482 |doi=}}</ref>
[[Vitamin C]] acts as an [[antioxidant]] in vessels.<ref>{{cite journal |author=Böhm F, Settergren M, Pernow J |title=Vitamin C blocks vascular dysfunction and release of interleukin-6 induced by endothelin-1 in humans in vivo |journal=Atherosclerosis |volume=190 |issue=2 |pages=408–15 |year=2007 |pmid=16527283 |doi=10.1016/j.atherosclerosis.2006.02.018}}</ref>
Trials on [[Vitamin E]] have been done, but they have failed to find a beneficial effect, for various reasons, but for some patients at high risk for atherosclerosis there may be some benefits.<ref>{{cite journal |author=Robinson I, de Serna DG, Gutierrez A, Schade DS |title=Vitamin E in humans: an explanation of clinical trial failure |journal=Endocr Pract |volume=12 |issue=5 |pages=576–82 |year=2006 |pmid=17002935 |doi=}}</ref>
Menaquinone ([[Vitamin K|Vitamin K2]]), but not phylloquinone ([[Vitamin K|Vitamin K1]]), intake is associated with reduced risk of CHD [[mortality]], all-cause [[mortality]] and severe aortic calcification.<ref>{{cite journal |author=Geleijnse JM, Vermeer C, Grobbee DE, ''et al'' |title=Dietary intake of menaquinone is associated with a reduced risk of coronary heart disease: the Rotterdam Study |journal=J. Nutr. |volume=134 |issue=11 |pages=3100–5 |year=2004 |pmid=15514282 |doi=}}</ref><ref>{{cite journal |author=Erkkilä AT, Booth SL |title=Vitamin K intake and atherosclerosis |journal=Curr. Opin. Lipidol. |volume=19 |issue=1 |pages=39–42 |year=2008 |pmid=18196985 |doi=10.1097/MOL.0b013e3282f1c57f |doi_brokendate=2008-06-27}}</ref><ref>{{cite journal |author=Wallin R, Schurgers L, Wajih N |title=Effects of the blood coagulation vitamin K as an inhibitor of arterial calcification |journal=Thromb. Res. |volume= 122|issue= |pages= 411|year=2008 |pmid=18234293 |doi=10.1016/j.thromres.2007.12.005}}</ref>
It has been suggested that excess [[iron]] may be involved in development of atherosclerosis<ref name="pmid17259340">{{cite journal |author=Brewer GJ |title=Iron and copper toxicity in diseases of aging, particularly atherosclerosis and Alzheimer's disease |journal=Exp. Biol. Med. (Maywood) |volume=232 |issue=2 |pages=323–35 |year=2007 |pmid=17259340 |doi=}}</ref><ref name="pmid17685184">{{cite journal |author=Sullivan JL, Mascitelli L |title=[Current status of the iron hypothesis of cardiovascular diseases] |language=Italian |journal=Recenti Prog Med |volume=98 |issue=7-8 |pages=373–7 |year=2007 |pmid=17685184 |doi=}}</ref>, but one study found reducing body iron stores in patients with symptomatic [[Peripheral artery occlusive disease|peripheral artery disease]] through [[phlebotomy]] did not significantly decrease all-cause mortality or death plus nonfatal myocardial infarction and stroke.<ref name="pmid17299195">{{cite journal |author=Zacharski LR, Chow BK, Howes PS, ''et al'' |title=Reduction of iron stores and cardiovascular outcomes in patients with peripheral arterial disease: a randomized controlled trial |journal=JAMA |volume=297 |issue=6 |pages=603–10 |year=2007 |pmid=17299195 |doi=10.1001/jama.297.6.603}}</ref> Further studies may be warranted.
===Surgical intervention===
Other physical treatments, helpful in the short term, include minimally invasive [[angioplasty]] procedures that may include [[stents]] to physically expand narrowed arteries<ref>{{cite web|url=http://www.cypherusa.com/cypher-j2ee/cypherjsp/main_splash/stent.jsp |title=Heart disease and stents |accessdate=2008-04-01 |publisher=[[Cypher Stent]] }}</ref> and major invasive surgery, such as [[Coronary artery bypass surgery|bypass surgery]], to create additional blood supply connections that go around the more severely narrowed areas.
===Prophylaxis===
Patients at risk for atherosclerosis-related diseases are increasingly being treated [[prophylaxis|prophylactically]] with low-dose [[aspirin]] and a [[statin]]. The high incidence of cardiovascular disease led Wald and Law<ref name="Polypill">Wald NJ, Law MR. A strategy to reduce cardiovascular disease by more than 80%. ''[[British Medical Journal|BMJ]]'' 2003;326:1419. PMID.</ref> to propose a ''[[Polypill]]'', a once-daily pill containing these two types of drugs in addition to an [[ACE inhibitor]], [[diuretic]], [[beta blocker]], and [[folic acid]]. They maintain that high uptake by the general population by such a ''Polypill'' would reduce cardiovascular mortality by 80%. It must be emphasized however that this is purely theoretical, as the Polypill has never been tested in a clinical trial.
Medical treatments often focus predominantly on the symptoms. However, over time, the treatments which focus on decreasing the underlying atherosclerosis processes, as opposed to simply treating the symptoms resulting from the atherosclerosis, have been shown by clinical trials to be more effective.
In summary, the key to the more effective approaches has been better understanding of the widespread and insidious nature of the disease and to combine multiple different treatment strategies, not rely on just one or a few approaches. 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 has generally produced better results, both before and especially after people are symptomatic. However, treating asymptomatic people remains controversial in the medical community.
== Recent research ==
June 22nd http://www.news-medical.net/?id=39374. Discovery of a new protein and how immune reacts to cholesterol deposits.
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 [[ApoA-1 Milano|Apo-A1 Milano]] HDL in people with unstable angina produced fairly dramatic reduction in measured coronary plaque volume in only 6 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 trials—probably 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 researched.
[[Niacin]] has HDL raising effects (by 10 - 30%) and showed clinical trial benefit in the Coronary Drug Project and is commonly used in combination with other lipoprotein agents to improve efficacy of changing lipoprotein for the better. However most individuals have nuisance symptoms with short term flushing 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 necessary helpful. For example, the drug [[torcetrapib]] is the most effective 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.<ref>{{cite journal |last=Barter M.D. Ph.D. |first=Philip J. |coauthors=Mark Caulfield, M.D., M.B., B.S., Mats Eriksson, M.D., Ph.D., Scott M. Grundy, M.D., Ph.D., John J.P. Kastelein, M.D., Ph.D., Michel Komajda, M.D., Jose Lopez-Sendon, M.D., Ph.D., Lori Mosca, M.D., M.P.H., Ph.D., Jean-Claude Tardif, M.D., David D. Waters, M.D., Charles L. Shear, Dr.P.H., James H. Revkin, M.D., Kevin A. Buhr, Ph.D., Marian R. Fisher, Ph.D., Alan R. Tall, M.B., B.S., Bryan Brewer, M.D., Ph.D. |year=2007 |month=November |title=Effects of Torcetrapib in Patients at High Risk for Coronary Events |journal=New England Journal of Medicine |pmid=17984165 |url=http://content.nejm.org/cgi/content/full/NEJMoa0706628 |accessdate= 2007-11-13 |doi=10.1056/NEJMoa0706628 |volume=357 |pages=2109}}</ref>
The ERASE trial is a newer trial of an HDL booster which has shown promise.<ref name=Hughes>{{cite web
|publisher = HeartWire
|title=ERASE: New HDL mimetic shows promise
|year=March 26, 2007
|author=Sue Hughes
|url=http://www.theheart.org/article/779839.do}}</ref>
The ASTEROID trial used a high-dose of [[rosuvastatin]]—the statin with typically the most potent dose/response correlation track record (both for LDLipoproteins and HDLipoproteins.)
It found plaque (intima + media volume) reduction.<ref name=Nissen />
Several additional rosuvastatin treatment/placebo trials for evaluating other clinical outcomes are in progress.
The actions of macrophages drive atherosclerotic plaque progression.
''Immunomodulation of atherosclerosis'' is the term for techniques which modulate immune system function in order to suppress this macrophage action.<ref name=Nilsson>{{cite journal
|title= Immunomodulation of Atherosclerosis – Implications for Vaccine Development—ATVB In Focus
|author =Jan Nilsson; Göran K. Hansson; Prediman K. Shah
|doi = 10.1161/01.ATV.0000149142.42590.a2
|url=http://atvb.ahajournals.org/cgi/content/abstract/atvbaha;25/1/18
|journal= Arteriosclerosis, Thrombosis, and Vascular Biology|year= 2005|volume= 5|pages=18–28
|accessdate=2007-11-13
|pmid= 15514204
|doi_brokendate= 2008-06-26}}</ref>
Immunomodulation has been pursued with considerable success in both mice and rabbits since about 2002.
Plans for human trials, hoped for by about 2008, are in progress.
Research on genetic expression and control mechanisms is progressing. Topics include
*[[Peroxisome proliferator-activated receptors| 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 [[nanobacterium|nanobacteria]] in the arteries, e.g., [[Chlamydophila pneumoniae]], though trials of current antibiotic treatments known to be usually effective in suppressing growth or killing these bacteria have not been successful in improving outcomes.<ref>{{cite web |url=https://openaccess.leidenuniv.nl/dspace/bitstream/1887/9729/11/01.pdf
|publisher= The digital repository of Leiden University
|title= Lipids, inflammation and atherosclerosis
|author=M Stitzinger |year=2007
|accessdate=2007-11-02 |format= pdf|work=|quote= Results of clinical trials investigating anti-chlamydial antibiotics as an
addition to standard therapy in patients with coronary artery disease have
been inconsistent. Therefore, Andraws et al. conducted a meta-
analysis of these clinical trials and found that evidence available to date
does not demonstrate an overall benefit of antibiotic therapy in reducing
mortality or cardiovascular events in patients with coronary artery
disease.}}</ref>
The immunomodulation approaches mentioned above, because they deal with innate responses of the host to promote atherosclerosis, have far greater prospects for success.
== French Paradox and Red Wine ==
[[French Paradox]] study shows 44% lower cases of heart disease in the French even though they consume a diet rich in saturated fats. In 1999, rates of death from coronary heart disease among males aged 35–74 years was 115 per 100,000 people in the US but only 83 per 100,000 in France. [[Resveratrol]] is one of the key active antioxidants. [http://news.bbc.co.uk/1/hi/health/1719675.stm BBC.Why wine is good for you.] [http://www.sciencedaily.com/releases/2005/03/050325222705.htm Red Wine Protects The Heart] [http://www.sciencedaily.com/releases/2003/09/030909070840.htm]
==References==
{{reflist|2}}
===General references===
*{{cite journal
|author=Stevens RJ, Douglas KM, Saratzis AN, Kitas GD
|title=Inflammation and atherosclerosis in rheumatoid arthritis
|journal=Expert reviews in molecular medicine
|volume=7
|issue=7
|pages=1–24
|year=2005
|pmid=15876361
|doi=10.1017/S1462399405009154
|accessdate=2007-11-02
}}
*{{cite book|author=Mol, A |year=2002 |title=The Body Multiple: Ontology in medical practice
|location=London|publisher=Duke University Press}}
==External links==
* [http://www.pathologyatlas.ro/Coronary%20ATS.html Atlas of Pathology]
* [http://www.athero.org/ International Atherosclerosis Society]
* [http://www.rkliedtke.de/Arterial_Vascular_Effects_us.html Arterial Vascular Effects of Non-steroidal Antiphlogistic Drugs - A Biochemical Model on an Intramural Induction of Arteriosclerosis], Rainer K Liedtke, MD
==See also==
<div style="-moz-column-count:2; column-count:2;">
*[[Monckeberg's arteriosclerosis]]
*[[Artery]]
*[[Atheroma]]
*[[Fatty streaks]]
*[[Heart]]
*[[Coronary circulation]]
*[[Coronary catheterization]]
*[[Angiogram]]
*[[IVUS]]
*[[Arterial stiffness]]
</div>
{{Vascular diseases}}
[[Category:Cardiovascular diseases]]
[[Category:Angiology]]
[[Category:Cardiology]]
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[[el:Αρτηριοσκλήρυνση]]
[[es:Aterosclerosis]]
[[fa:آترواسکلروسیس]]
[[ko:동맥경화]]
[[it:Aterosclerosi]]
[[he:טרשת עורקים]]
[[ka:ათეროსკლეროზი]]
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[[ja:動脈硬化症]]
[[no:Åreforkalkning]]
[[pl:Miażdżyca]]
[[pt:Aterosclerose]]
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