Atherosclerosis/ja

アテローム性動脈硬化症
Other names	Arteriosclerotic vascular disease (ASVD)
動脈硬化の進行（狭窄が誇張される）
Specialty	循環器学, angiology/ja
Symptoms	None
Complications	Coronary artery disease/ja, stroke/ja, peripheral artery disease/ja, kidney problems/ja
Usual onset	若者（年齢とともに悪化する）
Causes	飽和脂肪酸の蓄積、喫煙、高血圧、糖尿病
Risk factors	High blood pressure/ja, diabetes/ja, smoking/ja, obesity/ja, ファミリーヒストリー, 不健康な食事（特にトランス脂肪酸）、慢性的なビタミンC不足
Prevention	健康的な食事、運動、禁煙、標準体重の維持
Medication	Statin/ja, 血圧降下剤, aspirin/ja
Frequency	≈100% (>65歳)

アテローム性動脈硬化症は動脈硬化症の病型であり、動脈の壁に病変と呼ばれる異常が生じることを特徴とする。これらの病変は、アテローム性プラークの蓄積による動脈壁の狭小化につながることがある。発症時には通常症状はないが、発症した場合は一般に中年期頃から症状が始まる。重症になると、罹患した動脈が身体のどの部位にあるかによって、冠動脈疾患、脳卒中、末梢動脈疾患、腎障害を引き起こすことがある。

アテローム性動脈硬化症の正確な原因は不明であり、多因子性であると提唱されている。危険因子としては、コレステロール値異常、炎症性バイオマーカーの上昇、高血圧、糖尿病、喫煙（能動喫煙と受動喫煙の両方）、肥満、遺伝的因子、家族歴、生活習慣、不健康な食事などが挙げられる。アテロームは脂肪、コレステロール、カルシウム、および血液中に含まれる他の物質から構成されている。動脈が狭くなることで、酸素を豊富に含む血液が身体の一部に流れるのを制限する。診断は、身体検査、心電図、運動負荷試験などに基づいて行われる。

予防ガイドラインには、健康的な食事、運動、禁煙、正常体重の維持が含まれる。確立した疾患の治療には、スタチンなどのコレステロールを低下させる薬物療法、血圧治療薬、血栓形成のリスクを減らすための抗凝固療法などが含まれる。病状が進行すると、経皮的冠動脈インターベンション、冠動脈バイパス術、頸動脈内膜剥離術などの侵襲的な戦略が適用される。遺伝的要因もまた、この疾患プロセスに強く関与しており、完全に生活習慣の選択に基づくものではない。

アテローム性動脈硬化症は一般に若いときに始まり、加齢とともに悪化する。ほとんどすべての人が65歳までにある程度の影響を受ける。これは先進国における死因と障害の第一因である。この疾患は1575年に初めて報告されたが、その起源は200万年以上前、現生人類の祖先であるヒト科の祖先が進化する過程で起こったと思われる遺伝子変異にまでさかのぼり、この疾患状態は遺伝的に広く人類に固有のものであることを示唆する証拠がある。

徴候と症状

アテローム性動脈硬化症は何十年もの間無症状であるが、これは動脈がすべてのプラークの位置で拡大するため、血流に影響がないからである。ほとんどのプラーク破裂でさえ、血栓による動脈の十分な狭窄や閉鎖が起こるまでは症状を生じない。徴候や症状は、重度の狭窄や閉鎖によって、症状を誘発するのに十分なほどさまざまな臓器への血流が阻害された後に初めて生じる。ほとんどの場合、患者は脳卒中や心筋梗塞などの他の心臓血管障害を経験して初めて自分がこの病気にかかっていることに気づく。しかし、これらの症状は、どの動脈や臓器が冒されているかによって異なる。

初期のアテローム性動脈硬化症はおそらく小児期に始まる。子供の冠動脈では線維性病変やゼラチン性病変が観察されている。小児の冠動脈では脂肪縞が観察されている。冠動脈疾患は女性よりも男性に多くみられるが、脳動脈のアテローム性動脈硬化症や脳卒中は男女ともに同様に発症する。

心臓に酸素を含んだ血液を送る役割を担っている冠動脈の著しい狭窄は、狭心症の胸痛や息切れ、発汗、吐き気、めまいやふらつき、息苦しさや動悸などの症状を引き起こす。不整脈と呼ばれる心臓のリズム異常-心臓の拍動が遅すぎたり早すぎたりする-も虚血の結果である。

頸動脈は、脳と頸部に血液を供給している。頸動脈の狭窄が顕著になると、脱力感、考えがまとまらない、しゃべりにくい、めまい、歩行困難、まっすぐ立てない、目のかすみ、顔や手足のしびれ、激しい頭痛、意識障害などの症状が現れることがある。これらの症状は脳卒中（脳細胞の死）にも関係している。脳卒中は、脳に行く動脈の著しい狭窄や閉鎖によって引き起こされる。十分な血液が供給されないと、影響を受けた組織の細胞が死んでしまう。

脚、腕、骨盤に血液を供給する末梢動脈も、プラークの破裂や血栓のために著しい狭窄を経験する。狭窄の症状は、腕や脚のしびれや痛みである。プラーク形成のもう一つの重要な場所は、腎臓に血液を供給する腎動脈である。プラークの発生と蓄積は腎臓の血流低下と慢性腎臓病につながるが、これは他の部位と同様、一般的に末期になるまで無症状である。

2004年の米国のデータによると、男性の〜66％、女性の〜47％において、動脈硬化性心血管病の最初の症状は心臓発作または心臓突然死（症状発現から1時間以内の死亡と定義）であった。

事例研究としては、第二次世界大戦や朝鮮戦争で戦死した米兵の解剖がある。朝鮮戦争で戦死した300人の米軍兵士の剖検に関する報告がよく引用されている。兵士の平均年齢は22.1歳であったが、77.3パーセントに「冠動脈硬化の肉眼的証拠」があった。

危険因子

「Lipoprotein/ja」および「Lipoprotein (a)/ja」も参照

動脈硬化とリポタンパク質

アテローム性動脈硬化の過程はよく理解されていない。アテローム性動脈硬化症は、低比重リポ蛋白（LDL）粒子の滞留に伴う血管壁の内皮細胞における炎症過程と関連している。この滞留は、基礎にある炎症過程の原因、影響、あるいはその両方である可能性がある。

プラークが存在すると、血管の筋肉細胞が伸張し、増加した嵩を補う。その後、内皮が厚くなり、プラークと内腔の間の隔たりが大きくなる。この肥厚はプラークの成長による狭窄をいくらか相殺するが、それ以上に、心拍動のたびに血管壁が硬くなり、伸張に対する抵抗性が低下する。

調整可能

• Western pattern diet/ja
• Abdominal obesity/ja
• インスリン抵抗性
• 糖尿病
• 脂質異常症
• 高血圧
• Trans fat/ja
• Tobacco smokingja
• Bacterial infections/ja
• HIV/AIDS/ja

調整不可

• 南アジア系
• 高齢
• 遺伝子異常
• 家族歴
• 冠動脈の解剖学的構造と分岐パターン

少ないか不確か

• Thrombophilia/ja
• Saturated fat/ja
• 過剰なcarbohydrate/ja
• triglycerides/jaの上昇
• Systemic inflammation/ja
• Hyperinsulinemia/ja
• Sleep deprivation/ja
• Air pollution/ja
• Sedentary lifestyle/ja
• Arsenic poisoning/ja
• アルコール
• Chronic stress/ja
• Hypothyroidism/ja
• Periodontal disease/ja

食事

食事脂肪と動脈硬化の関係については議論がある。米国農務省はフードピラミッドの中で、総カロリーの約64%を炭水化物とする食事を推奨している。アメリカ心臓協会、アメリカ糖尿病協会、全米コレステロール教育プログラムも同様の推奨をしている。対照的に、ウォルター・ウィレット教授（ハーバード公衆衛生大学院、第二次看護師健康調査のPI）は、脂肪、特に一価不飽和脂肪酸と多価不飽和脂肪酸のはるかに高いレベルを推奨している。しかし、これらの食事勧告はトランス脂肪の消費に対してコンセンサスを得ている。

ヒトにおいて、酸化した脂肪（腐敗脂肪）を食べることの役割は明らかではない。 腐敗した脂肪を与えられたウサギは動脈硬化を早く発症する。DHA含有油を与えられたラットは、その抗酸化系が著しく破壊され、かなりの量のリン脂質を蓄積した。血液、肝臓、腎臓にヒドロペルオキシドが蓄積した。

Rabbits fed atherogenic diets containing various oils were found to undergo the most oxidative susceptibility of LDL via polyunsaturated oils. In another study, rabbits fed heated soybean oil "grossly induced atherosclerosis and marked liver damage were histologically and clinically demonstrated." However, Fred Kummerow 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 unpleasant in even 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, when being sold in pill form, can hide the taste of oxidized or rancid fat that might be present. In the US, the health food industry's dietary supplements are self-regulated and outside of FDA regulations. To properly protect unsaturated fats from oxidation, it is best to keep them cool and in oxygen-free environments.

Pathophysiology

Atherogenesis is the developmental process of atheromatous plaques. It is characterized by a remodeling of arteries leading to subendothelial accumulation of fatty substances called plaques. The buildup of an atheromatous plaque is a slow process, developed over a period of several years through a complex series of cellular events occurring within the arterial wall and in response to a variety of local vascular circulating factors. One recent hypothesis suggests that, for unknown reasons, leukocytes, such as monocytes or basophils, begin to attack the endothelium of the artery lumen in cardiac muscle. The ensuing inflammation leads to the 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 proliferate locally, 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.

In addition to these cellular activities, there is also smooth muscle proliferation and migration from the tunica media into the intima in response to cytokines secreted by damaged endothelial cells. This causes the formation of a fibrous capsule covering the fatty streak. Intact endothelium can prevent this smooth muscle 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 intramural calcification, presenting the picture of an early phase of arteriosclerosis, appears to be induced by many 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 it 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. Cholesterol crystals may also play a role.
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 remains 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 angiography.

Rupture and stenosis

Progression of atherosclerosis to late complications

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 the 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, before 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 before 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.

Accelerated growth of plaques

The distribution of atherosclerotic plaques in a part of arterial endothelium is inhomogeneous. The multiple and focal development of atherosclerotic changes is similar to that in the development of amyloid plaques in the brain and that of age spots on the skin. Misrepair-accumulation aging theory suggests that misrepair mechanisms play an important role in the focal development of atherosclerosis. Development of a plaque is a result of repair of injured endothelium. Because of the infusion of lipids into sub-endothelium, the repair has to end up with altered remodeling of local endothelium. This is the manifestation of a misrepair. Important is this altered remodeling makes the local endothelium have increased fragility to damage and have reduced repair efficiency. As a consequence, this part of endothelium has an increased risk factor of being injured and improperly repaired. Thus, the accumulation of misrepairs of endothelium is focalized and self-accelerating. In this way, the growing of a plaque is also self-accelerating. Within a part of the arterial wall, the oldest plaque is always the biggest, and is the most dangerous one to cause blockage of a local artery.

Components

The plaque is divided into three distinct components:

1. The atheroma ("lump of gruel", from Greek ἀθήρα (athera) '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 or more advanced lesions. 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. On the other hand, 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 occlude smaller downstream branches causing thromboembolism.

Apart from thromboembolism, chronically expanding atherosclerotic lesions can cause complete closure of the lumen. Chronically expanding lesions are often asymptomatic until lumen stenosis is so severe (usually over 80%) that blood supply to downstream tissue(s) is 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 the death of the tissues fed by the artery in approximately five minutes. This event is called an infarction.

Diagnosis

CT image of atherosclerosis of the abdominal aorta. Woman of 70 years old with hypertension and dyslipidemia.

Microphotography of arterial wall with calcified (violet color) atherosclerotic plaque (hematoxylin and 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 lesions. 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 travels 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 results in a heart attack, while the obstruction of arteries supplying the brain results in an ischaemic 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% was considered the hallmark of clinically significant disease in the past because recurring episodes of angina and abnormalities in stress tests 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 more than 75% stenosis. The 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 coronary calcium scoring by CT, carotid IMT (intimal media thickness) measurement by ultrasound, and intravascular ultrasound (IVUS). Examples of physiologic measurement methods include lipoprotein subclass analysis, HbA1c, hs-CRP, and 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 recent years, developments in nuclear imaging techniques such as PET and SPECT have provided ways of estimating the severity of atherosclerotic plaques.

Prevention

Up to 90% of cardiovascular disease may be preventable if established risk factors are avoided. Medical management of atherosclerosis first involves modification to risk factors–for example, via smoking cessation and diet restrictions. Prevention then is generally by eating a healthy diet, exercising, not smoking, and maintaining a normal weight.

Diet

Changes in diet may help prevent the development of atherosclerosis. Tentative evidence suggests that a diet containing dairy products has no effect on or decreases the risk of cardiovascular disease.

A diet high in fruits and vegetables decreases the risk of cardiovascular disease and death. Evidence suggests that the Mediterranean diet may improve cardiovascular results. There is also evidence that a Mediterranean diet may be better than a low-fat diet in bringing about long-term changes to cardiovascular risk factors (e.g., lower cholesterol level and blood pressure).

Exercise

A controlled exercise program combats atherosclerosis by improving circulation and functionality of the vessels. Exercise is also used to manage weight in patients who are obese, lower blood pressure, and decrease cholesterol. Often lifestyle modification is combined with medication therapy. For example, statins help to lower cholesterol. Antiplatelet medications like aspirin help to prevent clots, and a variety of antihypertensive medications are routinely used to control blood pressure. If the combined efforts of risk factor modification and medication therapy are not sufficient to control symptoms or fight imminent threats of ischemic events, a physician may resort to interventional or surgical procedures to correct the obstruction.

Treatment

Treatment of established disease may include medications to lower cholesterol such as statins, blood pressure medication, or medications that decrease clotting, such as aspirin. A number of procedures may also be carried out such as percutaneous coronary intervention, coronary artery bypass graft, or carotid endarterectomy.

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 is to combine multiple different treatment strategies. 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 have shown benefit in reducing cardiovascular disease and mortality in those with high cholesterol with few side effects. Secondary prevention therapy, which includes high-intensity statins and aspirin, is recommended by multi-society guidelines for all patients with history of ASCVD (atherosclerotic cardiovascular disease) to prevent recurrence of coronary artery disease, ischemic stroke, or peripheral arterial disease. However, prescription of and adherence to these guideline-concordant therapies is lacking, particularly among young patients and women.

Statins work by inhibiting HMG-CoA (hydroxymethylglutaryl-coenzyme A) reductase, a hepatic rate-limiting enzyme in cholesterol's biochemical production pathway. By inhibiting this rate-limiting enzyme, the body is unable to produce cholesterol endogenously, therefore reducing serum LDL-cholesterol. This reduced endogenous cholesterol production triggers the body to then pull cholesterol from other cellular sources, enhancing serum HDL-cholesterol. These data are primarily in middle-age men and the conclusions are less clear for women and people over the age of 70.

Surgery

When atherosclerosis has become severe and caused irreversible ischemia, such as tissue loss in the case of peripheral artery disease, surgery may be indicated. Vascular bypass surgery can re-establish flow around the diseased segment of artery, and angioplasty with or without stenting can reopen narrowed arteries and improve blood flow. Coronary artery bypass grafting without manipulation of the ascending aorta has demonstrated reduced rates of postoperative stroke and mortality compared to traditional on-pump coronary revascularization.

Other

There is 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. Also, small molecules such as 3-hydroxybenzaldehyde and protocatechuic aldehyde have shown vasculoprotective effects to reduce risk of atherosclerosis.

Epidemiology

Cardiovascular disease, which is predominantly the clinical manifestation of atherosclerosis, is one of the leading causes of death worldwide.

Almost all children older than age 10 in developed countries have aortic fatty streaks, with coronary fatty streaks beginning in adolescence.

In 1953, a study was published which examined the results of 300 autopsies performed on U.S. soldiers who had died in the Korean War. Despite the average age of the soldiers being just 22 years old, 77% of them had visible signs of coronary atherosclerosis. This study showed that heart disease could affect people at a younger age and was not just a problem for older individuals.

In 1992, a report had shown that microscopic fatty streaks were seen in the left anterior descending artery in over 50% of children aged 10–14 and 8% had even more advanced lesions with more accumulations of extracellular lipid.

In a 2005 report of a study done between 1985 and 1995, it was found that around 87% of aortas and 30% of coronary arteries in age group 5–14 years had fatty streaks which increased with age.

Etymology

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) 'artery', and σκλήρωσις (sklerosis) '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 (from Ancient Greek ἀθήρα (athḗra) 'gruel'). The term atherogenic is used for substances or processes that cause formation of atheroma.

Economics

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

Research

Lipids

An indication of the role of high-density lipoprotein (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 synthesized human Apo-A1 Milano HDL in people with unstable angina produced a fairly dramatic reduction in measured coronary plaque volume in only six weeks vs. the usual increase in plaque volume in those randomized to placebo. The trial was published in JAMA in early 2006. Ongoing work starting in the 1990s may lead to human clinical 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 HDL particle concentrations, which in some animal studies largely reverses and removes atheromas, are being developed and researched. 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.

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.

Involvement of lipid peroxidation chain reaction in atherogenesis triggered research on the protective role of the heavy isotope (deuterated) polyunsaturated fatty acids (D-PUFAs) that are less prone to oxidation than ordinary PUFAs (H-PUFAs). PUFAs are essential nutrients – they are involved in metabolism in that very form as they are consumed with food. In transgenic mice, that are a model for human-like lipoprotein metabolism, adding D-PUFAs to diet indeed reduced body weight gain, improved cholesterol handling and reduced atherosclerotic damage to the aorta.

miRNA

MicroRNAs (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 vascular vessels, miRNAs are dysregulated and highly expressed. miR-33 is found in cardiovascular diseases. It is involved in atherosclerotic initiation and progression including lipid metabolism, insulin signaling and glucose homeostatis, cell type progression and proliferation, and myeloid cell differentiation. It was found in rodents that the inhibition of miR-33 will raise HDL level and the expression of miR-33 is down-regulated in humans 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 Apolipoprotein-1 and it is also important in the reverse cholesterol transport pathway, where cholesterol is delivered 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.

The sugar, cyclodextrin, removed cholesterol that had built up in the arteries of mice fed a high-fat diet.

DNA損傷

加齢は心血管障害の最も重要な危険因子である。 他の危険因子とは別に、加齢がその影響を媒介する原因的基盤はまだ明らかにされていない。 血管の老化においてDNA損傷が重要な役割を果たすという証拠がレビューされている。8-oxoGは、DNAにおける酸化的損傷の一般的なタイプであり、プラーク血管平滑筋細胞、マクロファージ、内皮細胞に蓄積することが分かっており、DNA損傷とプラーク形成が関連している。DNA鎖切断もアテローム性動脈硬化プラークで増加している。 ウェルナー症候群（WS）は、ヒトの早老症である。 WSは、DNAから損傷を除去するいくつかの修復プロセスに関与するRecQヘリカーゼの遺伝子欠損によって引き起こされる。 WS患者は、冠動脈および大動脈にかなりの動脈硬化性プラークを生じ、大動脈弁の石灰化も頻繁に観察される。 大動脈弁の石灰化もしばしば観察される。これらの所見は、修復されない過剰なDNA損傷と早期老化および早期のアテローム性動脈硬化プラーク発生とを結びつけている（老化のDNA損傷説を参照）。

微生物

体内にある全ての微生物からなる細菌叢は、様々な方法で動脈硬化に寄与する可能性がある: 免疫系の調節、代謝の変化、栄養素の処理、そして血液循環に入る特定の代謝産物の生成など。そうした代謝産物の一つに、腸内細菌が生成するトリメチルアミンN-オキシド(TMAO)がある。 TMOAの濃度レベルは、ヒトの研究において動脈硬化と関連があることが示されており、動物実験では因果関係がある可能性が示唆されている。 TMAOの生成に関与する酵素であるトリメチルアミンリアーゼをコードする細菌遺伝子とアテローム性動脈硬化症との関連も指摘されている。

血管平滑筋細胞

血管平滑筋細胞はアテローム形成において重要な役割を果たし、歴史的には、保護線維性被膜を形成し、強度を与える細胞外マトリックス成分を合成することによって、プラークの安定性に有益であると考えられてきた。しかしながら、線維性被膜に加えて、血管平滑筋細胞はプラークコア内に見られる多くの細胞タイプを生み出し、プラークの安定性を促進したり低下させたりするためにその表現型を変化させることができる。血管平滑筋細胞はアテローム性動脈硬化プラーク内で顕著な可塑性を示し、マクロファージ、筋線維芽細胞、間葉系幹細胞、骨軟骨細胞などの様々な他の細胞型に類似するように遺伝子発現プロファイルを変化させることができる。重要なことは、遺伝子系統追跡実験によって、プラーク常在細胞の40-90％が血管平滑筋細胞由来であることが明確に示されたことである。したがって、新しい治療標的を同定するためには、動脈硬化における血管平滑筋細胞の役割を研究することが重要である。

外部リンク

• Quotations related to Atherosclerosis at Wikiquote
• Atherosclerosis/ja at Curlie
• Atherosclerosis pathophysiology-stages and types