atheromas

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WordNet

1. a fatty deposit in the intima (inner lining) of an artery; can obstruct blood flow

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出典(authority):フリー百科事典『ウィキペディア（Wikipedia）』「2014/05/24 17:48:17」(JST)

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For the journal, see Atherosclerosis (journal).

Atherosclerosis
Classification and external resources
The progression of atherosclerosis (narrowing exaggerated)
ICD-10	I70
ICD-9	440, 414.0
DiseasesDB	1039
MedlinePlus	000171
MeSH	D050197

Atherosclerosis (also known as arteriosclerotic vascular disease or ASVD) is a specific form of arteriosclerosis in which an artery wall thickens as a result of invasion and accumulation of white blood cells (termed "fatty streaks" early on because of appearance being similar to that of marbled steak) and containing both living active WBCs (called inflammation) and remnants of dead cells, including cholesterol and triglycerides, eventually calcium and other crystallized materials, within the outer-most and oldest plaque. These changes reduce the elasticity of the artery walls but do not affect blood flow for decades because the artery muscular wall enlarges at the locations of plaque. However, the wall stiffening may eventually increase pulse pressure; widened pulse pressure being one possible result of advanced disease within the major arteries. It is a syndrome affecting arterial blood vessels, a chronic inflammatory response, i.e. white blood cells, in the walls of arteries, largely involving the accumulation of macrophages and white blood cells and promoted by low-density lipoproteins (LDL, plasma proteins that carry cholesterol and triglycerides) without adequate removal of fats and cholesterol from the macrophages by functional high-density lipoproteins (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 atheromatous plaques within the arteries. The plaque is divided into three distinct components:

1. The atheroma ("lump of gruel", from Greek ἀθήρα (athera), meaning "gruel"), which is the nodular accumulation of a soft, flaky, yellowish material at the center of large plaques, composed of macrophages nearest the lumen of the artery
2. Underlying areas of cholesterol crystals
3. 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 Greek ἀρτηρία (artēria), meaning "artery", and σκλήρωσις (sklerosis), meaning "hardening"); arteriolosclerosis is any hardening (and loss of elasticity) of arterioles (small arteries); atherosclerosis is a hardening of an artery specifically due to an atheromatous plaque. The term atherogenic is used for substances or processes that cause atherosclerosis.

Atherosclerosis is a chronic disease that remains asymptomatic for decades. Atherosclerotic lesions, or atherosclerotic plaques are separated into two broad categories: Stable and unstable (also called vulnerable). The pathobiology of atherosclerotic lesions is very complicated but generally, stable atherosclerotic plaques, 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 fibrous cap) is usually weak and prone to rupture. Ruptures of the fibrous cap expose thrombogenic material, such as collagen 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. Interestingly, chronically expanding lesions are often asymptomatic until lumen stenosis is so severe (usually over 80%) that blood supply to downstream tissue(s) is insufficient, resulting in ischemia.

These complications of advanced atherosclerosis are chronic, slowly progressive 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). The same process in an artery to the brain is commonly called stroke. Another common scenario in very advanced disease is claudication from insufficient blood supply to the legs. Atherosclerosis affects the entire artery tree, but mostly larger, high-pressure vessels such as the coronary, renal, femoral, cerebral, and carotid arteries. These are termed "clinically silent" because the person having the infarction does not notice the problem and does not seek medical help, or when they do, physicians do not recognize what has happened.

Signs and symptoms

Atherosclerosis is asymptomatic for decades because the arteries enlarge at all plaque locations, thus no affect on blood flow. Even most plaque ruptures do not produce symptoms until enough narrowing/closure of an artery, due to clots, occurs. Signs and symptoms only occur after severe narrowing/closure impedes blood flow to different organs enough to induce symptoms. Most of the time, patients realize that they have the disease only when they experience other cardio vascular disorders such as stroke or heart attack. These symptoms, however, still vary depending on which artery or organ is affected.

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 there.

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. Sub-clinically, 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 beneficial to both the child and his/her relatives. While coronary artery disease is more prevalent in men than women, atherosclerosis of the cerebral arteries and strokes equally affect both sexes.

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 light-headedness, breathlessness or palpitations. Abnormal heart rhythms called arrhythmias, [the heart is either beating too slow or too fast] another consequence of ischemia.

Carotid arteries supply blood to the brain and neck. Marked narrowing of the carotid arteries can present with symptoms such as a feeling of weakness, not being able to think straight, difficulty speaking, becoming dizzy and difficulty 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/closure of arteries going to the brain; lack of adequate of blood supply leads to the death of the cells of the affected tissue.

Peripheral arteries, which supply blood to the legs, arms, 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 pain.

Another significant location for the plaque formation are the renal arteries, which would supply blood to the kidneys. Plaque occurrence and accumulation leads to decreased kidney blood flow and chronic kidney disease, which, like all other ares, are typically asymptomatic until late stages.

According to United States data for 2004, in about 66% of men and 47% of women, the first symptom of atherosclerotic cardiovascular disease is a heart attack or sudden cardiac death (death within one hour of onset of the symptom). Cardiac stress testing, traditionally the most commonly performed non-invasive testing method for blood flow limitations, in general, detects only lumen narrowing of ~75% or greater, although some physicians claim that nuclear stress methods can detect as little as 50%.

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." 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 WWII.

Causes

Atherosclerosis and lipoproteins

See also: Lipoprotein

The atherosclerotic process is not fully understood. Atherosclerosis is initiated by inflammatory processes in the endothelial cells of the vessel wall in response to retained low-density lipoprotein (LDL) particles.

Lipoproteins in the blood vary in size. Some data suggests that small dense LDL (sdLDL) particles are more prone to pass between the endothelial cells, going behind the cellular monolayer of endothelium. LDL particles 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 to 6,000 fat molecules, including: cholesterol, phospholipids, cholesteryl esters, tryglycerides & all other fats in the water outside cells, to the tissues of the body) changes with time.

Once inside the vessel wall, LDL particles can become more prone to oxidation with resultant responses by the endothelial cells to attract monocyte white blood cells to leave the blood stream, penetrate into the arterial walls and transform into macrophages. The macrophage cells ingesting oxidized LDL particles triggers a cascade of immune responses which over time can produce an atheroma if HDL removal of fats from the macrophages does not keep up. The immune system specialized white blood cells (macrophages and T-lymphocytes) to absorb the oxidized LDL, forming specialized foam cells. If these white blood cells are not able to process the oxidized LDL & recruit HDL particles to remove the fats, they grow and then rupture, leaving behind the cellular membrane remnants and increasing the amount of oxidized materials, fats, including cholesterol, in the artery wall resulting in a snowballing progression attracting more white blood cells, continuing the cycle. Eventually, the artery becomes more and more inflamed. The progressive plaque induces the muscle cells to stretch out, compensating for the additional bulk and the endothelial lining thickens forming a greater separation between the plaque and lumen. The artery opening the artery does not change but the wall tend to become stiffer, less compliant to stretching with each heart beat.

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. Herpesvirus infection of arterial smooth muscle cells has been shown to cause cholesteryl ester (CE) accumulation, which is associated with atherosclerosis. Cytomegalovirus (CMV) infection is also associated with cardiovascular diseases.

Risk factors

Various anatomic and physiological risk factors for atherosclerosis are known. 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.

Risks multiply, with two factors increasing the risk of atherosclerosis fourfold. Hyperlipidemia, hypertension and cigarette smoking together increases the risk seven times.

Modifiable

• Diabetes or Impaired glucose tolerance (IGT) +
• 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
• Tobacco smoking, increases risk by 200% after several pack years
• Elevated serum C-reactive protein concentrations
• Vitamin B₆ deficiency
• Dietary iodine deficiency and hypothyroidism, which cause elevated serum cholesterol and of lipid peroxidation

Nonmodifiable

• Advanced age
• Male sex
• Having close relatives who have had some complication of atherosclerosis (e.g. coronary heart disease or stroke)
• Genetic abnormalities, e.g. familial hypercholesterolemia

Lesser or uncertain

The following factors are of relatively lesser importance, are uncertain or unquantified:

• Obesity (in particular central obesity, also referred to as abdominal or male-type obesity) +
• Hypercoagulability
• Postmenopausal estrogen deficiency
• High intake of saturated fat (may raise total and LDL cholesterol)
• Intake of trans fat (may raise total and LDL cholesterol while lowering HDL cholesterol)
• High carbohydrate intake
• 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
• Chronic systemic inflammation as reflected by upper normal WBC concentrations, elevated hs-CRP and many other blood chemistry markers, most only research level at present, not clinically done.
• Hyperthyroidism (an over-active thyroid)
• Elevated serum insulin levels +
• Short sleep duration
• Chlamydia pneumoniae infection
• PM_2.5 air pollution, fine particulates less than 2.5 µm in diameter, have been associated with thickening of the carotid artery.

Dietary

The relation between dietary fat and atherosclerosis is a contentious field. The 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, PI of the second Nurses' Health Study) recommends much higher levels, especially of monounsaturated and polyunsaturated fat. Writing in Science, Gary Taubes detailed that political considerations played into the recommendations of government bodies. These differing views reach a consensus, though, against consumption of trans fats.

The role of dietary oxidized fats/lipid peroxidation (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 significant amounts of phospholipid hydroperoxide in their blood, livers and kidneys. 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. In a study involving rabbits fed heated soybean oil, "grossly induced atherosclerosis and marked liver damage were histologically and clinically demonstrated." However, Kummerow, a prominent researcher, claims that it is not dietary cholesterol, but oxysterols, or oxidized cholesterols, from fried foods and smoking, that are the culprit.

Rancid fats and oils taste very bad even in small amounts, so people avoid eating them. It is very difficult to measure or estimate the actual human consumption of these substances.

Highly unsaturated omega-3 rich oils such as fish oil are being sold in pill form so that the taste of oxidized or rancid fat is not apparent. The health food industry's dietary supplements are self regulated by the manufacture and outside of FDA regulations. To properly protect unsaturated fats from oxidation, it is best to keep them cool and in oxygen free environments. Long term exposure to inorganic arsenic can cause atherosclerosis.

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 build up 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 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 wall thickening occurs without any narrowing. Stenosis is a late event, which may never occur and is often the result of repeated plaque rupture and healing responses, not just the atherosclerotic process by itself.

Cellular

Micrograph of an artery that supplies the heart showing significant atherosclerosis and marked luminal narrowing. Tissue has been stained using Masson's 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. 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.

Initial damage to the endothelium results in an inflammatory response. Monocytes 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, and M-CSF, which is selectively required for the differentiation of monocytes to macrophages. The monocytes differentiate into macrophages, which ingest oxidized LDL, slowly turning into large "foam cells" – so-called because of their changed appearance resulting from the numerous internal cytoplasmic vesicles 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 the tunica media into the intima responding to cytokines secreted by damaged endothelial cells. This causes the formation of a fibrous capsule covering the fatty streak. Intact endothelium could prevent the proliferation by releasing nitric oxide.

Calcification and lipids

Calcification forms among vascular smooth muscle cells of the surrounding muscular layer, specifically in the muscle cells adjacent to atheromas and on the surface of atheroma plaques and tissue. 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 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 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.

Visible features

Severe atherosclerosis of the aorta. Autopsy specimen.

Although arteries are not typically studied microscopically, two plaque types can be distinguished:

1. 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.
2. 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 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 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 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 ulcerates, which leads to immediate blood clotting at the site of atheroma ulcer. This triggers a cascade of events that leads to clot enlargement, which may quickly obstruct the flow of blood. A complete blockage leads to ischemia of the myocardial (heart) muscle and damage. This process is the myocardial infarction or "heart attack".

If the heart attack is not fatal, fibrous organization of the clot within the lumen ensues, covering the rupture but also producing stenosis or closure of the lumen, or over time and after repeated ruptures, resulting in a persistent, usually localized stenosis or blockage of the artery lumen. Stenoses can be slowly progressive, whereas plaque ulceration 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. These tissue fragments are 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 flow acutely. With the obstruction of blood flow, 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

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 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 fibrous 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 flow. If the blood flow 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 flow can occur in any artery within the body. Obstruction of arteries supplying the heart muscle result in a heart attack, while the obstruction of arteries supplying the brain result in a stroke.

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

Lumen stenosis that is greater than 75% were considered as the hallmark of clinically significant 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.

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 measurement.

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.

Prevention

Combinations of statins, niacin, intestinal cholesterol absorption-inhibiting supplements (ezetimibe and others, and to a much lesser extent fibrates) 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-altering (less correctly termed "cholesterol-lowering") 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) with over fifteen more studies extending through to the more recent ASTEROID trial published in 2006. The first primary prevention comparative treatment trial was AFCAPS/TexCAPS with multiple later comparative statin/placebo treatment trials including EXCEL, ASCOT and SPARCL. 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.

Treatment

Medical treatments often focus on alleviating symptoms. However measures which focus on decreasing underlying atherosclerosis—as opposed to simply treating symptoms—are more effective. Non-pharmaceutical means are usually the first method of treatment, such as stopping 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.

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 taken on a daily basis and indefinitely has generally produced better results, both before and especially after people are symptomatic.

Statins

The group of medications referred to as statins are widely prescribed for treating atherosclerosis. They shown benefit in reducing cardiovascular disease and mortality in those with high cholesterol with few side effects.

This data is primarily in middle-age men and the conclusions are less clear for women and people over the age of 70.

Monocyte counts, as well as cholesterol markers such as LDL:HDL ratio and apolipiprotein B: apolipoprotein A-1 ratio can be used as markers to monitor the extent of atherosclerotic regression which proves useful in guiding patient treatments.

Diet

Changes in diet may help prevent the development of atherosclerosis.

Surgery

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

Other

There is recent evidence that some anticoagulants, particularly warfarin, which inhibit clot formation by interfering with Vitamin K metabolism, may actually promote arterial calcification in the long term despite reducing clot formation in the short term.

Prognosis

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.

Research

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 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 necessarily 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. 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.

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 effective in suppressing growth or killing these bacteria have not been successful in improving outcomes.

The immunomodulation approaches mentioned above, because they deal with innate responses of the host to promote atherosclerosis, have far greater prospects for success.

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. It is involved in atherosclerotic initiation and pregression including lipid metabolism, insulin signaling and glucose homeostatis, cell type progression and proliferation, and myeloid cell differentialtion. It was found in rodant that the inhibition of miR-33 will raise HDL level and the expression of miR-33 is down regulated in human with atherosclerotic plaques.

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. miR-33a/b regulates cholesterol/lipid homeostatis by binding in the 3’UTRs 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 Apolupoprotein-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. 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 efflux to apoA-1. On the other hand, by inhibiting miR-33 function, the level of ABCA1 is increased and increases the cholesterol efflux to apoA-1. Suppression of miR-33 will lead to less cellular cholesterol and higher plasma HDL level through the regulation of ABCA1 expression.

Economics

In 2011, coronary athersclerosis was one of the top ten most expensive conditions seen during inpatient hospitalizations in the U.S., with aggregate inpatient hospital costs of $10.4 billion.

See also

• Angiogram
• Arterial stiffness
• Arteriosclerosis
• Atheroma
• Coronary catheterization
• Fatty streaks
• Intravascular ultrasound
• Monckeberg's arteriosclerosis

Footnotes

External links

• 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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• 2. 潜因性脳卒中 cryptogenic stroke
• 3. 心臓手術の神経学的合併症 neurologic complications of cardiac surgery
• 4. アテローム性動脈硬化症の潜在的な病原因子としての肺炎クラミジア感染 chlamydophila chlamydia pneumoniae infection as a potential etiologic factor in atherosclerosis
• 5. 心臓手術の神経学的合併症の予防 prevention of neurologic complications of cardiac surgery

English Journal

• CARD8 gene encoding a protein of innate immunity is expressed in human atherosclerosis and associated with markers of inflammation.

• Paramel GV, Folkersen L, Strawbridge RJ, Elmabsout AA, Särndahl E, Lundman P, Jansson JH, Hansson GK, Sirsjö A, Fransén K.Source*Department of Clinical Medicine, School of Health and Medical Sciences, Örebro University, Örebro, Sweden.
• Clinical science (London, England : 1979).Clin Sci (Lond).2013 Oct 1;125(8):401-7. doi: 10.1042/CS20120572.
• Inflammation is a key factor in the development of atherosclerotic coronary artery disease. It is promoted through the inflammasome, a molecular machine that produces IL (interleukin)-1β in response to cholesterol crystal accumulation in macrophages. The CARD8 (caspase recruitment domain 8) protein
• PMID 23611467

• Immunological aspects of atherosclerosis.

• Woollard KJ.SourceDivision of Immunology & Inflammation, Department of Medicine, Imperial College London, Hammersmith Campus, Du Cane Road, London W12 0NN, U.K.
• Clinical science (London, England : 1979).Clin Sci (Lond).2013 Sep 1;125(5):221-35. doi: 10.1042/CS20120576.
• Cardiovascular disease is the leading cause of death in several countries. The underlying process is atherosclerosis, a slowly progressing chronic disorder that can lead to intravascular thrombosis. There is overwhelming evidence for the underlying importance of our immune system in atherosclerosis.
• PMID 23668229

• Periodontitis and atherosclerosis: an observational study.

• Pinho MM, Faria-Almeida R, Azevedo E, Conceição Manso M, Martins L.SourceDivision of Periodontology, Department of Dentistry, Faculty of Health Sciences, University Fernando Pessoa, Porto, Portugal.
• Journal of periodontal research.J Periodontal Res.2013 Aug;48(4):452-7. doi: 10.1111/jre.12026. Epub 2012 Dec 30.
• BACKGROUND: Poor oral health has been related with cardiovascular diseases. Specifically, periodontitis has been implicated in the pathogenesis of atherosclerosis. Our aim was to evaluate the relationship between the degree of carotid atherosclerosis and severity of periodontitis in a patient cohort
• PMID 23278448

Japanese Journal

• Optical Coherence Tomography of De Novo Lesions and In-Stent Restenosis in Coronary Saphenous Vein Grafts (OCTOPUS Study)

• Circulation Journal advpub(0), 2016
• NAID 130005158928

• 大動脈弁手術時の Compromised Aorta に対する片側脳分離体外循環停止法

• 日本心臓血管外科学会雑誌 45(1), 16-20, 2016
• NAID 130005124814

• Statins Reduce Extensive Aortic Atheromas in Patients with Abdominal Aortic Aneurysms

• Annals of Vascular Diseases 6(4), 711-717, 2013
• NAID 130004488026

Related Links

• Atheromas | Define Atheromas at Dictionary.com

atheroma / ˌæθ əˈroʊ mə / Show Spelled [ath-uh-roh-m uh] Show IPA noun, plural atheromas, atheromata / ˌæθ əˈroʊ mə tə / Show Spelled [ath-uh-roh-m uh-t uh] ... "encysted tumor," 1706, from L., from Gk. atheroma, from athere ...

• atheromas - Definition of atheromas - Dictionary definitions ...

atheromas Variant of atheroma noun pl. atheromas or atheromata a condition marked by deposits of small fatty nodules on the inner walls of the arteries, often accompanied by degeneration of the affected areas; also, such a nodule ...

Related Pictures

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★リンクテーブル★

リンク元

「粥腫」

「粥腫」

　　[★]

英

atheromas, atheroma

同

アテローム、粉瘤

関

粥状硬化症

• calcificationの引き金となる
• the calcification is virtually inevitable in the atheromas of advanced atherosclerosis (BPT.26)