Atheroma/ja

アテローム
Other names	atheromata (複数形), atheromas (複数形), atheromatous plaque, plaque
頸動脈内膜剥離術標本のアテローム性動脈硬化プラーク。これは共通が内と外側頸動脈に分かれていることを示している。
Complications	Thrombosis/ja, embolism/ja, atherosclerosis/ja, arteriosclerosis/ja
Causes	高脂血症, hypertriglyceridemia/ja, hypercholesterolemia/ja

アテロームまたはアテローム性プラークは、動脈壁の内層に異常な物質が蓄積したものである。

この物質は主にマクロファージ細胞、または脂質、カルシウム、および可変量の線維性結合組織を含む残骸から成る。蓄積した物質は動脈壁に腫脹を形成し、動脈の内腔に侵入して狭窄し、血流を制限する。アテロームは動脈硬化症のサブタイプであるアテローム性動脈硬化症の病理学的基礎である。

Signs and symptoms

For most people, the first symptoms result from atheroma progression within the heart arteries, most commonly resulting in a heart attack and ensuing debility. The heart arteries are difficult to track because they are small (from about 5 mm down to microscopic), they are hidden deep within the chest and they never stop moving. Additionally, all mass-applied clinical strategies focus on both minimal cost and the overall safety of the procedure. Therefore, existing diagnostic strategies for detecting atheroma and tracking response to treatment have been extremely limited. The methods most commonly relied upon, patient symptoms and cardiac stress testing, do not detect any symptoms of the problem until atheromatous disease is very advanced because arteries enlarge, not constrict, in response to increasing atheroma. It is plaque ruptures, producing debris and clots which obstruct blood flow downstream, sometimes also locally (as seen on angiograms), which reduce/stop blood flow. Yet these events occur suddenly and are not revealed in advance by either stress tests

Mechanism

The healthy epicardial coronary artery consists of three layers, the tunica intima, media, and adventitia. Atheroma and changes in the artery wall usually result in small aneurysms (enlargements) just large enough to compensate for the extra wall thickness with no change in the lumen diameter. However, eventually, typically as a result of rupture of vulnerable plaques and clots within the lumen over the plaque, stenosis (narrowing) of the vessel develops in some areas. Less frequently, the artery enlarges so much that a gross aneurysmal enlargement of the artery results. All three results are often observed, at different locations, within the same individual.

Stenosis and closure

Over time, atheromata usually progress in size and thickness and induce the surrounding muscular central region (the media) of the artery to stretch out, which is termed remodeling. Typically, remodeling occurs just enough to compensate for the atheroma's size such that the calibre of the artery opening (lumen) remains unchanged, until about 50% of the artery wall cross-sectional area consists of atheromatous tissue.

Narrowed arterial blood vessel blocked with an atheroma (artist's conception).

If the muscular wall enlargement eventually fails to keep up with the enlargement of the atheroma volume, or a clot forms and organizes over the plaque, then the lumen of the artery becomes narrowed as a result of repeated ruptures, clots and fibrosis over the tissues separating the atheroma from the blood stream. This narrowing becomes more common after decades of living, increasingly more common after people are in their 30s to 40s.

The endothelium (the cell monolayer on the inside of the vessel) and covering tissue, termed fibrous cap, separate atheroma from the blood in the lumen. If a rupture (see vulnerable plaque) of the endothelium and fibrous cap occurs, then both a shower of debris from the plaque (debris larger than 5 micrometres are too large to pass through capillaries) combined with a platelet and clotting response (an injury/repair response to both the debris and at the rupture site) begins within fractions of a second, eventually resulting in narrowing or sometimes closure of the lumen. Eventually downstream tissue damage occurs due to closure or obstruction of downstream microvessels and/or closure of the lumen at the rupture, both resulting in loss of blood flow to downstream tissues. This is the principal mechanism of myocardial infarction, stroke or other related cardiovascular disease problems.

While clots at the rupture site typically shrink in volume over time, some of the clot may become organized into fibrotic tissue resulting in narrowing of the artery lumen; the narrowings sometimes seen on angiography examinations, if severe enough. Since angiography methods can only reveal larger lumens, typically larger than 200 micrometres, angiography after a cardiovascular event commonly does not reveal what happened.

Artery enlargement

If the muscular wall enlargement is overdone over time, then a gross enlargement of the artery results, usually over decades of living. This is a less common outcome. Atheroma within aneurysmal enlargement (vessel bulging) can also rupture and shower debris of atheroma and clot downstream. If the arterial enlargement continues to 2 to 3 times the usual diameter, the walls often become weak enough that with just the stress of the pulse, a loss of wall integrity may occur leading to sudden hemorrhage (bleeding), major symptoms and debility; often rapid death. The main stimulus for aneurysm formation is pressure atrophy of the structural support of the muscle layers. The main structural proteins are collagen and elastin. This causes thinning and the wall balloons allowing gross enlargement to occur, as is common in the abdominal region of the aorta.

Histology

The accumulation (swelling) is always in the tunica intima, between the endothelium lining and the smooth muscle middle layer of the artery wall. While the early stages, based on gross appearance, have traditionally been termed fatty streaks by pathologists, they are not composed of fat cells but of accumulations of white blood cells, especially macrophages, that have taken up oxidized low-density lipoprotein (LDL).

After they accumulate large amounts of cytoplasmic membranes (with associated high cholesterol content) they are called foam cells. When foam cells die, their contents are released, which attracts more macrophages and creates an extracellular lipid core near the centre to inner surface of each atherosclerotic plaque.

Conversely, the outer, older portions of the plaque become more calcified, less metabolically active and more physically stiff over time.

Veins do not develop atheromata, because they are not subjected to the same haemodynamic pressure that arteries are, unless surgically moved to function as an artery, as in bypass surgery.

Diagnosis

Illustration comparing a normal blood vessel and partially blocked vessel due to atherosclerotic plaque. Notice the enlargement & absence of much luminal narrowing.

Because artery walls enlarge at locations with atheroma, detecting atheroma before death and autopsy has long been problematic at best. Most methods have focused on the openings of arteries; while these methods are highly relevant, they totally miss the atheroma within the arterial lumen.

Historically, arterial wall fixation, staining and thin section has been the gold standard for detection and description of atheroma, after death and autopsy. With special stains and examination, micro calcifications can be detected, typically within smooth muscle cells of the arterial media near the fatty streaks within a year or two of fatty streaks forming.

Interventional and non-interventional methods to detect atherosclerosis, specifically vulnerable plaque (non-occlusive or soft plaque), are widely used in research and clinical practice today.

Carotid Intima-media thickness Scan (CIMT can be measured by B-mode ultrasonography) measurement has been recommended by the American Heart Association as the most useful method to identify atherosclerosis and may now very well be the gold standard for detection.

Intravascular ultrasound is the current most sensitive method detecting and measuring more advanced atheroma within living individuals, but has had limited applications due to cost and body invasiveness.

CT scans using state of the art higher resolution spiral, or the higher speed EBT, machines have been the most effective method for detecting calcification present in plaque. However, the atheroma have to be advanced enough to have relatively large areas of calcification within them to create large enough regions of ~130 Hounsfield units which a CT scanner's software can recognize as distinct from the other surrounding tissues. Typically, such regions start occurring within the heart arteries about 2–3 decades after atheroma start developing. The presence of smaller, spotty plaques may actually be more dangerous for progressing to acute myocardial infarction.

Arterial ultrasound, especially of the carotid arteries, with measurement of the thickness of the artery wall, offers a way to partially track the disease progression. As of 2006, the thickness, commonly referred to as IMT for intimal-medial thickness, is not measured clinically though it has been used by some researchers since the mid-1990s to track changes in arterial walls. Traditionally, clinical carotid ultrasounds have only estimated the degree of blood lumen restriction, stenosis, a result of very advanced disease. The National Institute of Health did a five-year $5 million study, headed by medical researcher Kenneth Ouriel, to study intravascular ultrasound techniques regarding atherosclerotic plaque. More progressive clinicians have begun using IMT measurement as a way to quantify and track disease progression or stability within individual patients.

Angiography, since the 1960s, has been the traditional way of evaluating for atheroma. However, angiography is only motion or still images of dye mixed with the blood within the arterial lumen and never show atheroma; the wall of arteries, including atheroma within the arterial wall remain invisible. The limited exception to this rule is that with very advanced atheroma, with extensive calcification within the wall, a halo-like ring of radiodensity can be seen in most older humans, especially when arterial lumens are visualized end-on. On cine-floro, cardiologists and radiologists typically look for these calcification shadows to recognize arteries before they inject any contrast agent during angiograms.

Classification of lesions

• Type I: Isolated macrophage foam cells
• Type II: Multiple foam cell layers
• Type III: Preatheroma, intermediate lesion
• Type IV: Atheroma
• Type V: Fibroatheroma
• Type VI: Fissured, ulcerated, hemorrhagic, thrombotic lesion
• Type VII: Calcific lesion
• Type VIII: Fibrotic lesion

Treatment

Many approaches have been promoted as methods to reduce or reverse atheroma progression:

• eating a diet of raw fruits, vegetables, nuts, beans, berries, and grains;
• consuming foods containing omega−3 fatty acids such as fish, fish-derived supplements, as well as flax seed oil, borage oil, and other non-animal-based oils;
• abdominal fat reduction;
• aerobic exercise;
• inhibitors of cholesterol synthesis (known as statins);
• low normal blood glucose levels (glycated hemoglobin, also called HbA1c);
• micronutrient (vitamins, potassium, and magnesium) consumption;
• maintaining normal, or healthy, blood pressure levels;
• aspirin supplement
• mouse studies indicated that subcutaneous administration of oligosaccharide 2-hydroxypropyl-β-cyclodextrin (2HPβCD) can solubilize cholesterol, removing it from plaques. However, later work concluded that "treatment with 2HPβCD is ineffective in inducing atherosclerosis regression".

研究の歴史

先進国では、公衆衛生の改善、感染制御、寿命の延長に伴い、アテローム過程は社会にとってますます重要な問題と負担となっている。 アテロームは、1960年代初頭から徐々に改善する傾向にあるにもかかわらず、障害や死亡の主な基礎となっている（患者の年齢で調整）。そのため、この問題をよりよく理解し、治療し、予防するための取り組みが増え続けている。

2004年の米国のデータによると、男性の約65％、女性の約47％において、心血管疾患の最初の症状は心筋梗塞（心臓発作）または突然死（症状発現から1時間以内の死亡）である。

動脈血流障害事象のかなりの割合が50％未満の内腔狭窄部位で起こる。伝統的に血流制限の非侵襲的検査法として最も一般的に行われている心臓負荷試験では、一般的に約75％以上の内腔狭窄しか検出されないが、時には50％以下でも検出できる核負荷試験を提唱する医師もいる。

既存の粥腫、脆弱プラーク（非閉塞性プラークまたはソフトプラーク）の合併症の突然の性質は、1950年代以降、集中治療室や複雑な内科的・外科的介入の開発につながった。狭窄を可視化したり間接的に検出したりするために血管造影やその後の心臓負荷試験が始まった。次にバイパス手術が行われるようになり、移植された静脈、時には動脈を狭窄部の周囲に配管し、最近では血管形成術が行われるようになった。

しかし、このような医療の進歩にもかかわらず、狭心症や血流低下の症状を軽減することに成功したにもかかわらず、アテローム破裂は依然として大きな問題であり、今日どこでも利用可能な最も迅速で大規模かつ熟練した医療・外科的介入にもかかわらず、突然の障害や死に至ることがある。いくつかの臨床試験によると、バイパス手術や血管形成術は、全生存率を改善する効果があったとしても、せいぜいごくわずかである。通常、バイパス手術の死亡率は1～4％、血管形成術の死亡率は1～1.5％である。

加えて、これらの血管インターベンションは、病気が原因で症状が現れ、多くの場合、すでに部分的に障害が残ってから行われることが多い。血管形成術もバイパス術も、将来の心臓発作を予防するものではないことも明らかである。

第二次世界大戦前に遡る、粥腫を理解するための古い方法は、剖検データに依存していた。剖検データは長い間、小児期後半に脂肪縞が発生し、数十年にわたってゆっくりと無症状に進行することを示してきた。

One way to see atheroma is the very invasive and costly IVUS ultrasound technology; it gives us the precise volume of the inside intima plus the central media layers of about 25 mm (1 in) of artery length. Unfortunately, it gives no information about the structural strength of the artery. Angiography does not visualize atheroma; it only makes the blood flow within blood vessels visible. Alternative methods that are non or less physically invasive and less expensive per individual test have been used and are continuing to be developed, such as those using computed tomography (CT; led by the electron beam tomography form, given its greater speed) and magnetic resonance imaging (MRI). The most promising since the early 1990s has been EBT, detecting calcification within the atheroma before most individuals start having clinically recognized symptoms and debility. Statin therapy (to lower cholesterol) does not slow the speed of calcification as determined by CT scan. MRI coronary vessel wall imaging, although currently limited to research studies, has demonstrated the ability to detect vessel wall thickening in asymptomatic high risk individuals. As a non-invasive, ionising radiation free technique, MRI based techniques could have future uses in monitoring disease progression and regression. Most visualization techniques are used in research, they are not widely available to most patients, have significant technical limitations, have not been widely accepted and generally are not covered by medical insurance carriers.

From human clinical trials, it has become increasingly evident that a more effective focus of treatment is slowing, stopping and even partially reversing the atheroma growth process. There are several prospective epidemiologic studies including the Atherosclerosis Risk in Communities (ARIC) Study and the Cardiovascular Health Study (CHS), which have supported a direct correlation of Carotid Intima-media thickness (CIMT) with myocardial infarction and stroke risk in patients without cardiovascular disease history. The ARIC Study was conducted in 15,792 individuals between 5 and 65 years of age in four different regions of the US between 1987 and 1989. The baseline CIMT was measured and measurements were repeated at 4- to 7-year intervals by carotid B mode ultrasonography in this study. An increase in CIMT was correlated with an increased risk for CAD. The CHS was initiated in 1988, and the relationship of CIMT with risk of myocardial infarction and stroke was investigated in 4,476 subjects 65 years of age and below. At the end of approximately six years of follow-up, CIMT measurements were correlated with cardiovascular events.

Paroi artérielle et Risque Cardiovasculaire in Asia Africa/Middle East and Latin America (PARC-AALA) is another important large-scale study, in which 79 centres from countries in Asia, Africa, the Middle East, and Latin America participated, and the distribution of CIMT according to different ethnic groups and its association with the Framingham cardiovascular score was investigated. Multi-linear regression analysis revealed that an increased Framingham cardiovascular score was associated with CIMT, and carotid plaque independent of geographic differences.

Cahn et al. prospectively followed-up 152 patients with coronary artery disease for 6–11 months by carotid artery ultrasonography and noted 22 vascular events (myocardial infarction, transient ischemic attack, stroke, and coronary angioplasty) within this time period. They concluded that carotid atherosclerosis measured by this non-interventional method has prognostic significance in coronary artery patients.

In the Rotterdam Study, Bots et al. followed 7,983 patients >55 years of age for a mean period of 4.6 years, and reported 194 incident myocardial infarctions within this period. CIMT was significantly higher in the myocardial infarction group compared to the other group. Demircan et al. found that the CIMT of patients with acute coronary syndrome were significantly increased compared to patients with stable angina pectoris.

It has been reported in another study that a maximal CIMT value of 0.956 mm had 85.7% sensitivity and 85.1% specificity to predict angiographic CAD. The study group consisted of patients admitted to the cardiology outpatient clinic with symptoms of stable angina pectoris. The study showed CIMT was higher in patients with significant CAD than in patients with non-critical coronary lesions. Regression analysis revealed that thickening of the mean intima-media complex more than 1.0 was predictive of significant CAD our patients. There was incremental significant increase in CIMT with the number coronary vessel involved. In accordance with the literature, it was found that CIMT was significantly higher in the presence of CAD. Furthermore, CIMT was increased as the number of involved vessels increased and the highest CIMT values were noted in patients with left main coronary involvement. However, human clinical trials have been slow to provide clinical & medical evidence, partly because the asymptomatic nature of atheromata make them especially difficult to study. Promising results are found using carotid intima-media thickness scanning (CIMT can be measured by B-mode ultrasonography), B-vitamins that reduce a protein corrosive, homocysteine and that reduce neck carotid artery plaque volume and thickness, and stroke, even in late-stage disease.

Additionally, understanding what drives atheroma development is complex with multiple factors involved, only some of which, such as lipoproteins, more importantly lipoprotein subclass analysis, blood sugar levels and hypertension are best known and researched. More recently, some of the complex immune system patterns that promote, or inhibit, the inherent inflammatory macrophage triggering processes involved in atheroma progression are slowly being better elucidated in animal models of atherosclerosis.

こちらも参照

• Angiogram/ja
• ApoA-1 Milano/ja
• アテローム性動脈硬化症
• Atherothrombosis/ja
• Coronary circulation/ja
• Coronary catheterization/ja
• EBT
• Hemorheologic-Hemodynamic Theory of Atherosclerosis/ja
• Lipoprotein/ja
• LDL/ja, HDL, IDL, VLDL/ja

さらに読む

• Ornish, D.; Brown, S.E.; Billings, J.H.; Scherwitz, L.W.; Armstrong, W.T.; Ports, T.A.; McLanahan, S.M.; Kirkeeide, R.L.; Gould, K.L.; Brand, R.J. (July 1990). "Can lifestyle changes reverse coronary heart disease?". The Lancet. 336 (8708): 129–133. doi:10.1016/0140-6736(90)91656-u. PMID 1973470. S2CID 4513736.
• Gould, K. Lance; Ornish, D; Scherwitz, L; Brown, S; Edens, RP; Hess, MJ; Mullani, N; Bolomey, L; Dobbs, F; Armstrong, WT (20 September 1995). "Changes in Myocardial Perfusion Abnormalities by Positron Emission Tomography After Long-term, Intense Risk Factor Modification". JAMA. 274 (11): 894–901. doi:10.1001/jama.1995.03530110056036. PMID 7674504.
• Ornish, Dean; Scherwitz, LW; Billings, JH; Brown, SE; Gould, KL; Merritt, TA; Sparler, S; Armstrong, WT; Ports, TA; Kirkeeide, RL; Hogeboom, C; Brand, RJ (16 December 1998). "Intensive Lifestyle Changes for Reversal of Coronary Heart Disease". JAMA. 280 (23): 2001–7. doi:10.1001/jama.280.23.2001. PMID 9863851. S2CID 21508600.
• Ornish, Dean (November 1998). "Avoiding revascularization with lifestyle changes: the multicenter lifestyle demonstration project". The American Journal of Cardiology. 82 (10): 72–76. doi:10.1016/s0002-9149(98)00744-9. PMID 9860380.
• Dod, Harvinder S.; Bhardwaj, Ravindra; Sajja, Venu; Weidner, Gerdi; Hobbs, Gerald R.; Konat, Gregory W.; Manivannan, Shanthi; Gharib, Wissam; Warden, Bradford E.; Nanda, Navin C.; Beto, Robert J.; Ornish, Dean; Jain, Abnash C. (February 2010). "Effect of Intensive Lifestyle Changes on Endothelial Function and on Inflammatory Markers of Atherosclerosis". The American Journal of Cardiology. 105 (3): 362–367. doi:10.1016/j.amjcard.2009.09.038. PMID 20102949.
• Silberman, Anna; Banthia, Rajni; Estay, Ivette S.; Kemp, Colleen; Studley, Joli; Hareras, Dennis; Ornish, Dean (March 2010). "The Effectiveness and Efficacy of an Intensive Cardiac Rehabilitation Program in 24 Sites". American Journal of Health Promotion. 24 (4): 260–266. doi:10.4278/ajhp.24.4.arb. PMID 20232608. S2CID 25915559.
• Glagov, Seymour; Weisenberg, Elliot; Zarins, Christopher K.; Stankunavicius, Regina; Kolettis, George J. (28 May 1987). "Compensatory Enlargement of Human Atherosclerotic Coronary Arteries". New England Journal of Medicine. 316 (22): 1371–1375. doi:10.1056/NEJM198705283162204. PMID 3574413.