Atherosclerosis is a pattern of the disease arteriosclerosis in which the wall of the artery develops abnormalities, called

lesion A lesion is any damage or abnormal change in the tissue of an organism, usually caused by disease or trauma. ''Lesion'' is derived from the Latin "injury". Lesions may occur in plants as well as animals. Types There is no designated classif ...

s. These

s may lead to narrowing due to the buildup of atheromatous plaque. At onset there are usually no symptoms, but if they develop, symptoms generally begin around middle age. When severe, it can result in coronary artery disease,

stroke A stroke is a medical condition in which poor blood flow to the brain causes cell death. There are two main types of stroke: ischemic, due to lack of blood flow, and hemorrhagic, due to bleeding. Both cause parts of the brain to stop funct ...

peripheral artery disease Peripheral artery disease (PAD) is an abnormal narrowing of arteries other than those that supply the heart or brain. When narrowing occurs in the heart, it is called coronary artery disease, and in the brain, it is called cerebrovascular dise ...

, or kidney problems, depending on which

arteries An artery (plural arteries) () is a blood vessel in humans and most animals that takes blood away from the heart to one or more parts of the body (tissues, lungs, brain etc.). Most arteries carry oxygenated blood; the two exceptions are the pu ...

are affected. The exact cause is not known and is proposed to be multifactorial. Risk factors include abnormal cholesterol levels, elevated levels of inflammatory markers, high blood pressure, diabetes, smoking,

obesity Obesity is a medical condition, sometimes considered a disease, in which excess body fat has accumulated to such an extent that it may negatively affect health. People are classified as obese when their body mass index (BMI)—a person's ...

, family history, genetic, and an unhealthy diet. Plaque is made up of fat,

cholesterol Cholesterol is any of a class of certain organic molecules called lipids. It is a sterol (or modified steroid), a type of lipid. Cholesterol is biosynthesized by all animal cells and is an essential structural component of animal cell mem ...

calcium Calcium is a chemical element with the symbol Ca and atomic number 20. As an alkaline earth metal, calcium is a reactive metal that forms a dark oxide-nitride layer when exposed to air. Its physical and chemical properties are most similar ...

, and other substances found in the

blood Blood is a body fluid in the circulatory system of humans and other vertebrates that delivers necessary substances such as nutrients and oxygen to the cells, and transports metabolic waste products away from those same cells. Blood in th ...

. The narrowing of

limits the flow of oxygen-rich blood to parts of the body. Diagnosis is based upon a physical exam, electrocardiogram, and exercise stress test, among others. Prevention is generally by eating a

healthy diet A healthy diet is a diet that maintains or improves overall health. A healthy diet provides the body with essential nutrition: fluid, macronutrients such as protein, micronutrients such as vitamins, and adequate fibre and food energy. A he ...

, exercising, not smoking, and maintaining a

normal weight Body mass index (BMI) is a value derived from the mass ( weight) and height of a person. The BMI is defined as the body mass divided by the square of the body height, and is expressed in units of kg/m2, resulting from mass in kilograms and ...

. Treatment of established disease may include medications to lower

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 Coronary artery bypass surgery, also known as coronary artery bypass graft (CABG, pronounced "cabbage") is a surgical procedure to treat coronary artery disease (CAD), the buildup of plaques in the arteries of the heart. It can relieve chest pa ...

, or carotid endarterectomy. Atherosclerosis generally starts when a person is young and worsens with age. Almost all people are affected to some degree by the age of 65. It is the number one

cause of death In law, medicine, and statistics, cause of death is an official determination of conditions resulting in a human's death, which may be recorded on a death certificate. A cause of death is determined by a medical examiner. The cause of death i ...

and disability in the

developed world A developed country (or industrialized country, high-income country, more economically developed country (MEDC), advanced country) is a sovereign state that has a high quality of life, developed economy and advanced technological infrastr ...

. Though it was first described in 1575, there is evidence that the condition occurred in people more than 5,000 years ago.

Signs and symptoms

Atherosclerosis is

asymptomatic In medicine, any disease is classified asymptomatic if a patient tests as carrier for a disease or infection but experiences no symptoms. Whenever a medical condition fails to show noticeable symptoms after a diagnosis it might be considered as ...

for decades because the arteries enlarge at all plaque locations, thus there is no effect on blood flow. Even most plaque ruptures do not produce symptoms until enough narrowing or closure of an artery, due to clots, occurs. Signs and symptoms only occur after severe narrowing or 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 cardiovascular disorders such as

or heart attack. These symptoms, however, still vary depending on which artery or organ is affected. Abnormalities associated with atherosclerosis begin in childhood. Fibrous and gelatinous lesions have been observed in the coronary arteries of children aged 6–10. Fatty streaks have been observed in the coronary arteries of juveniles aged 11–15, though they appear at a much younger age within the

aorta The aorta ( ) is the main and largest artery in the human body, originating from the left ventricle of the heart and extending down to the abdomen, where it splits into two smaller arteries (the common iliac arteries). The aorta distributes ox ...

. 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 chest pain of angina and shortness of breath, sweating,

nausea Nausea is a diffuse sensation of unease and discomfort, sometimes perceived as an urge to vomit. While not painful, it can be a debilitating symptom if prolonged and has been described as placing discomfort on the chest, abdomen, or back of th ...

, dizziness or light-headedness, breathlessness or

palpitations Palpitations are perceived abnormalities of the heartbeat characterized by awareness of cardiac muscle contractions in the chest, which is further characterized by the hard, fast and/or irregular beatings of the heart. Symptoms include a rapi ...

. Abnormal heart rhythms called arrhythmias—the heart beating either too slowly or too quickly—are another consequence of ischemia.Arrhythmia. Heart and Stroke Foundation. (2011)

Carotid arteries In anatomy, the left and right common carotid arteries (carotids) (Entry "carotid"
in
Marked narrowing of the carotid arteries can present with symptoms such as: a feeling of weakness; being unable to think straight; difficulty speaking; dizziness; difficulty in walking or standing up straight; blurred vision; numbness of the face, arms and legs; severe headache; and loss of consciousness. These symptoms are also related to stroke (death of brain cells). Stroke is caused by marked narrowing or closure of arteries going to the brain; lack of adequate blood supply leads to the death of the cells of the affected tissue. Peripheral arteries, which supply blood to the legs, arms and pelvis, also experience marked narrowing due to plaque rupture and clots. Symptoms of the narrowing are numbness within the arms or legs, as well as pain. Another significant location for plaque formation is the renal arteries, which supply blood to the kidneys. Plaque occurrence and accumulation lead to decreased kidney blood flow and chronic kidney disease, which, like in all other areas, is 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 U.S. soldiers killed in

World War II World War II or the Second World War, often abbreviated as WWII or WW2, was a world war that lasted from 1939 to 1945. It involved the vast majority of the world's countries—including all of the great powers—forming two opposing ...

and the

Korean War {{Infobox military conflict , conflict = Korean War , partof = the Cold War and the Korean conflict , image = Korean War Montage 2.png , image_size = 300px , caption = Clockwise from top:{ ...

. A much-cited report involved the autopsies of 300 U.S. soldiers killed in Korea. Although the average age of the men was 22.1 years, 77.3 percent had "gross evidence of coronary arteriosclerosis". The average age was calculated from the ages of 200 of the soldiers. No age was recorded in nearly 100 of the men. Other studies done of soldiers in the

Vietnam War The Vietnam War (also known by other names) was a conflict in Vietnam, Laos, and Cambodia from 1 November 1955 to the fall of Saigon on 30 April 1975. It was the second of the Indochina Wars and was officially fought between North Vietna ...

showed similar results, although often worse than the ones from the earlier wars. Theories include high rates of tobacco use and (in the case of the Vietnam soldiers) the advent of processed foods after World War II.

Risk factors

The atherosclerotic process is not well understood. Atherosclerosis is associated with inflammatory processes in the

endothelial cells The endothelium is a single layer of squamous endothelial cells that line the interior surface of blood vessels and lymphatic vessels. The endothelium forms an interface between circulating blood or lymph in the lumen and the rest of the ve ...

of the vessel wall associated with retained low-density lipoprotein (LDL) particles. This retention may be a cause, an effect, or both, of the underlying inflammatory process. The presence of the plaque induces the muscle cells of the blood vessel to stretch, compensating for the additional bulk. The endothelial lining then thickens, increasing the separation between the plaque and lumen. The thickening somewhat offsets the narrowing caused by the growth of the plaque, but moreover, it causes the wall to stiffen and become less compliant to stretching with each heartbeat.

Modifiable

* Western pattern diet * Abdominal obesity *

Insulin resistance Insulin resistance (IR) is a pathological condition in which cells fail to respond normally to the hormone insulin. Insulin is a hormone that facilitates the transport of glucose from blood into cells, thereby reducing blood glucose (blood sug ...

* Diabetes *

Dyslipidemia Dyslipidemia is an abnormal amount of lipids (e.g. triglycerides, cholesterol and/or fat phospholipids) in the blood. Dyslipidemia is a risk factor for the development of atherosclerotic cardiovascular disease ( ASCVD). ASCVD includes coronary ar ...

Hypertension Hypertension (HTN or HT), also known as high blood pressure (HBP), is a long-term medical condition in which the blood pressure in the arteries is persistently elevated. High blood pressure usually does not cause symptoms. Long-term high bl ...

Trans fat Trans fat, also called trans-unsaturated fatty acids, or trans fatty acids, is a type of unsaturated fat that naturally occurs in small amounts in meat and milk fat. It became widely produced as an unintentional byproduct in the industrial p ...

Tobacco smoking Tobacco smoking is the practice of burning tobacco and ingesting the resulting smoke. The smoke may be inhaled, as is done with cigarettes, or simply released from the mouth, as is generally done with pipes and cigars. The practice is believ ...

* Bacterial infections *

HIV/AIDS Human immunodeficiency virus infection and acquired immunodeficiency syndrome (HIV/AIDS) is a spectrum of conditions caused by infection with the human immunodeficiency virus (HIV), a retrovirus. Following initial infection an individual ...

Nonmodifiable

South Asian South Asia is the southern subregion of Asia, which is defined in both geographical and ethno-cultural terms. The region consists of the countries of Afghanistan, Bangladesh, Bhutan, India, Maldives, Nepal, Pakistan, and Sri Lanka.;;;;;;; ...

descentIndian Heart Association Why South Asians Facts Web. 30 April 2015. http://indianheartassociation.org/why-indians-why-south-asians/overview/ * Advanced age *

Genetic abnormalities A genetic disorder is a health problem caused by one or more abnormalities in the genome. It can be caused by a mutation in a single gene (monogenic) or multiple genes (polygenic) or by a chromosomal abnormality. Although polygenic disorde ...

* Family history * Coronary anatomy and branch pattern

Lesser or uncertain

Thrombophilia Thrombophilia (sometimes called hypercoagulability or a prothrombotic state) is an abnormality of blood coagulation that increases the risk of thrombosis (blood clots in blood vessels). Such abnormalities can be identified in 50% of people who ...

* Saturated fat * Excessive

carbohydrate In organic chemistry, a carbohydrate () is a biomolecule consisting of carbon (C), hydrogen (H) and oxygen (O) atoms, usually with a hydrogen–oxygen atom ratio of 2:1 (as in water) and thus with the empirical formula (where ''m'' may or ma ...

s * Elevated triglycerides *

Systemic inflammation Chronic systemic inflammation (SI) is the result of release of pro-inflammatory cytokines from immune-related cells and the chronic activation of the innate immune system. It can contribute to the development or progression of certain conditions ...

* Hyperinsulinemia *

Sleep deprivation Sleep deprivation, also known as sleep insufficiency or sleeplessness, is the condition of not having adequate duration and/or quality of sleep to support decent alertness, performance, and health. It can be either chronic or acute and may vary ...

Air pollution Air pollution is the contamination of air due to the presence of substances in the atmosphere that are harmful to the health of humans and other living beings, or cause damage to the climate or to materials. There are many different types ...

Sedentary lifestyle Sedentary lifestyle is a lifestyle type, in which one is physically inactive and does little or no physical movement and or exercise. A person living a sedentary lifestyle is often sitting or lying down while engaged in an activity like soci ...

* Arsenic poisoning *

Alcohol Alcohol most commonly refers to: * Alcohol (chemistry), an organic compound in which a hydroxyl group is bound to a carbon atom * Alcohol (drug), an intoxicant found in alcoholic drinks Alcohol may also refer to: Chemicals * Ethanol, one of se ...

Chronic stress Chronic stress is the physiological or psychological response induced by a long-term internal or external stressor. The stressor, either physically present or recollected, will produce the same effect and trigger a chronic stress response. There is ...

Hypothyroidism Hypothyroidism (also called ''underactive thyroid'', ''low thyroid'' or ''hypothyreosis'') is a disorder of the endocrine system in which the thyroid gland does not produce enough thyroid hormone. It can cause a number of symptoms, such as p ...

Periodontal disease Periodontal disease, also known as gum disease, is a set of inflammatory conditions affecting the tissues surrounding the teeth. In its early stage, called gingivitis, the gums become swollen and red and may bleed. It is considered the main cau ...

Dietary

The relation between dietary fat and atherosclerosis is controversial. The USDA, in its food pyramid, promotes a diet of about 64%

s from total calories. The

American Heart Association The American Heart Association (AHA) is a nonprofit organization in the United States that funds cardiovascular medical research, educates consumers on healthy living and fosters appropriate cardiac care in an effort to reduce disability and death ...

, the

American Diabetes Association The American Diabetes Association (ADA) is a United States-based nonprofit that seeks to educate the public about diabetes and to help those affected by it through funding research to manage, cure and prevent diabetes (including type 1 diabete ...

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 of fat, especially of monounsaturated and polyunsaturated fat. These dietary recommendations reach a consensus, though, against consumption of

trans fat Trans fat, also called trans-unsaturated fatty acids, or trans fatty acids, is a type of unsaturated fat that naturally occurs in small amounts in meat and milk fat. It became widely produced as an unintentional byproduct in the industrial p ...

s. The role of eating oxidized fats ( rancid fats) in humans is not clear. Rabbits fed rancid fats develop atherosclerosis faster. Rats fed DHA-containing oils experienced marked disruptions to their

antioxidant Antioxidants are compounds that inhibit oxidation, a chemical reaction that can produce free radicals. This can lead to polymerization and other chain reactions. They are frequently added to industrial products, such as fuels and lubric ...

systems, and accumulated significant amounts of

phospholipid Phospholipids, are a class of lipids whose molecule has a hydrophilic "head" containing a phosphate group and two hydrophobic "tails" derived from fatty acids, joined by an alcohol residue (usually a glycerol molecule). Marine phospholipi ...

hydroperoxide in their blood, livers and kidneys. 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 An atheroma, or atheromatous plaque, is an abnormal and reversible accumulation of material in the inner layer of an arterial wall. The material consists of mostly macrophage cells, or debris, containing lipids, calcium and a variable amount o ...

. 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 White blood cells, also called leukocytes or leucocytes, are the cells of the immune system that are involved in protecting the body against both infectious disease and foreign invaders. All white blood cells are produced and derived from mu ...

, such as

monocytes Monocytes are a type of leukocyte or white blood cell. They are the largest type of leukocyte in blood and can differentiate into macrophages and conventional dendritic cells. As a part of the vertebrate innate immune system monocytes also ...

basophils Basophils are a type of white blood cell. Basophils are the least common type of granulocyte, representing about 0.5% to 1% of circulating white blood cells. However, they are the largest type of granulocyte. They are responsible for inflammat ...

, begin to attack the

endothelium The endothelium is a single layer of squamous endothelial cells that line the interior surface of blood vessels and lymphatic vessels. The endothelium forms an interface between circulating blood or lymph in the lumen and the rest of the vess ...

of the artery lumen in

cardiac muscle Cardiac muscle (also called heart muscle, myocardium, cardiomyocytes and cardiac myocytes) is one of three types of vertebrate muscle tissues, with the other two being skeletal muscle and smooth muscle. It is an involuntary, striated muscle t ...

. The ensuing

inflammation Inflammation (from la, inflammatio) is part of the complex biological response of body tissues to harmful stimuli, such as pathogens, damaged cells, or irritants, and is a protective response involving immune cells, blood vessels, and molec ...

leads to the formation of atheromatous plaques in the arterial

tunica intima The tunica intima (New Latin "inner coat"), or intima for short, is the innermost tunica (layer) of an artery or vein. It is made up of one layer of endothelial cells and is supported by an internal elastic lamina. The endothelial cells are in ...

, a region of the vessel wall located between the

and the

tunica media The tunica media ( New Latin "middle coat"), or media for short, is the middle tunica (layer) of an artery or vein. It lies between the tunica intima on the inside and the tunica externa on the outside. Artery Tunica media is made up of smoo ...

. The bulk of these lesions is made of excess fat,

collagen Collagen () is the main structural protein in the extracellular matrix found in the body's various connective tissues. As the main component of connective tissue, it is the most abundant protein in mammals, making up from 25% to 35% of the whol ...

, and

elastin Elastin is a protein that in humans is encoded by the ''ELN'' gene. Elastin is a key component of the extracellular matrix in gnathostomes (jawed vertebrates). It is highly elastic and present in connective tissue allowing many tissues in the ...

. 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

Early atherogenesis is characterized by the adherence of blood circulating

(a type of

white blood cell White blood cells, also called leukocytes or leucocytes, are the cells of the immune system that are involved in protecting the body against both infectious disease and foreign invaders. All white blood cells are produced and derived from mult ...

) to the vascular bed lining, the

, then by their migration to the sub-endothelial space, and further activation into monocyte-derived

macrophage Macrophages (abbreviated as M φ, MΦ or MP) ( el, large eaters, from Greek ''μακρός'' (') = large, ''φαγεῖν'' (') = to eat) are a type of white blood cell of the immune system that engulfs and digests pathogens, such as cancer ce ...

s. 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

and become oxidized, creating risk of

cardiovascular disease Cardiovascular disease (CVD) is a class of diseases that involve the heart or blood vessels. CVD includes coronary artery diseases (CAD) such as angina and myocardial infarction (commonly known as a heart attack). Other CVDs include stroke, ...

. 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 ''Antioxidants & Redox Signaling '' is a peer-reviewed scientific journal covering reduction–oxidation (redox) signaling and antioxidant research. It covers topics such as reactive oxygen species/reactive nitrogen species (ROS/RNS) as messeng ...

induction of factors such as

VCAM-1 Vascular cell adhesion protein 1 also known as vascular cell adhesion molecule 1 (VCAM-1) or cluster of differentiation 106 (CD106) is a protein that in humans is encoded by the ''VCAM1'' gene. VCAM-1 functions as a cell adhesion molecule. St ...

, which recruit circulating monocytes, and M-CSF, which is selectively required for the differentiation of monocytes to macrophages. The monocytes differentiate into

s, which proliferate locally, ingest oxidized LDL, slowly turning into large "

foam cell Foam cells, also called lipid-laden macrophages, are a type of cell that contain cholesterol. These can form a plaque that can lead to atherosclerosis and trigger heart attacks and stroke. Foam cells are fat-laden cells with a M2 macrophage-l ...

s" – so-called because of their changed appearance resulting from the numerous internal cytoplasmic vesicles and resulting high

lipid Lipids are a broad group of naturally-occurring molecules which includes fats, waxes, sterols, fat-soluble vitamins (such as vitamins A, D, E and K), monoglycerides, diglycerides, phospholipids, and others. The functions of lipids includ ...

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 Smooth muscle is an involuntary non-striated muscle, so-called because it has no sarcomeres and therefore no striations (''bands'' or ''stripes''). It is divided into two subgroups, single-unit and multiunit smooth muscle. Within single-unit mu ...

proliferation and migration from the

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 Nitric oxide (nitrogen oxide or nitrogen monoxide) is a colorless gas with the formula . It is one of the principal oxides of nitrogen. Nitric oxide is a free radical: it has an unpaired electron, which is sometimes denoted by a dot in its ...

Calcification and lipids

Calcification forms among

vascular smooth muscle Vascular smooth muscle is the type of smooth muscle that makes up most of the walls of blood vessels. Structure Vascular smooth muscle refers to the particular type of smooth muscle found within, and composing the majority of the wall of blood ...

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 High-density lipoprotein (HDL) is one of the five major groups of lipoproteins. Lipoproteins are complex particles composed of multiple proteins which transport all fat molecules ( lipids) around the body within the water outside cells. They are ...

(HDL), the lipoprotein particle that removes cholesterol from tissues and carries it back to the liver. The

s and platelets encourage the migration and proliferation of

cells, which in turn ingest lipids, become replaced by

, 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

Atherosclerosis, aorta, gross pathology PHIL 846 lores

Although arteries are not typically studied microscopically, two plaque types can be distinguished: # 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 Fibrin (also called Factor Ia) is a fibrous, non-globular protein involved in the clotting of blood. It is formed by the action of the protease thrombin on fibrinogen, which causes it to polymerize. The polymerized fibrin, together with ...

proteoglycan Proteoglycans are proteins that are heavily glycosylated. The basic proteoglycan unit consists of a "core protein" with one or more covalently attached glycosaminoglycan (GAG) chain(s). The point of attachment is a serine (Ser) residue to whi ...

, 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. # 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 The Hounsfield scale , named after Sir Godfrey Hounsfield, is a quantitative scale for describing radiodensity. It is frequently used in CT scans, where its value is also termed CT number. Definition The Hounsfield unit (HU) scale is a linear tr ...

(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

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 A myocardial infarction (MI), commonly known as a heart attack, occurs when blood flow decreases or stops to the coronary artery of the heart, causing damage to the heart muscle. The most common symptom is chest pain or discomfort which may ...

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

and tissue factor; they activate platelets and activate the system of coagulation. The result is the formation of a

thrombus A thrombus (plural thrombi), colloquially called a blood clot, is the final product of the blood coagulation step in hemostasis. There are two components to a thrombus: aggregated platelets and red blood cells that form a plug, and a mesh of ...

(blood clot) overlying the atheroma, which obstructs blood flow acutely. With the obstruction of blood flow, downstream tissues are starved of

oxygen Oxygen is the chemical element with the symbol O and atomic number 8. It is a member of the chalcogen group in the periodic table, a highly reactive nonmetal, and an oxidizing agent that readily forms oxides with most elements as ...

and nutrients. If this is the

myocardium Cardiac muscle (also called heart muscle, myocardium, cardiomyocytes and cardiac myocytes) is one of three types of vertebrate muscle tissues, with the other two being skeletal muscle and smooth muscle. It is an involuntary, striated muscle t ...

(heart muscle) angina (cardiac chest pain) or

(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: # The atheroma ("lump of 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 # Underlying areas of cholesterol crystals # 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 In biology, the extracellular matrix (ECM), also called intercellular matrix, is a three-dimensional network consisting of extracellular macromolecules and minerals, such as collagen, enzymes, glycoproteins and hydroxyapatite that provide ...

and smooth muscle cells. On the other hand, unstable plaques are rich in macrophages and

s, 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

, to the circulation and eventually induce

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 Infarction is tissue death ( necrosis) due to inadequate blood supply to the affected area. It may be caused by artery blockages, rupture, mechanical compression, or vasoconstriction. The resulting lesion is referred to as an infarct (from the ...

Diagnosis

CT image of atherosclerosis of the abdominal aorta

Areas of severe narrowing, stenosis, detectable by

angiography Angiography or arteriography is a medical imaging technique used to visualize the inside, or lumen, of blood vessels and organs of the body, with particular interest in the arteries, veins, and the heart chambers. Modern angiography is perform ...

, and to a lesser extent " stress testing" have long been the focus of human diagnostic techniques for

, 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

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

, will trigger

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

supply to nearby cells, resulting in

necrosis Necrosis () is a form of cell injury which results in the premature death of cells in living tissue by autolysis. Necrosis is caused by factors external to the cell or tissue, such as infection, or trauma which result in the unregulated dig ...

. 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

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

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 Glycated hemoglobin, also known as HbA1c, glycohemoglobin, hemoglobin A1c, A1C, is a form of hemoglobin (Hb) that is chemically linked to a sugar. Most monosaccharides, including glucose, galactose and fructose, spontaneously (i.e. non-enzymat ...

, 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

. 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 Cholesterol is any of a class of certain organic molecules called lipids. It is a sterol (or modified steroid), a type of lipid. Cholesterol is biosynthesized by all animal cells and is an essential structural component of animal cell mem ...

and

blood pressure Blood pressure (BP) is the pressure of circulating blood against the walls of blood vessels. Most of this pressure results from the heart pumping blood through the circulatory system. When used without qualification, the term "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,

, 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 Hypercholesterolemia, also called high cholesterol, is the presence of high levels of cholesterol in the blood. It is a form of hyperlipidemia (high levels of lipids in the blood), hyperlipoproteinemia (high levels of lipoproteins in the blood) ...

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

, surgery may be indicated. Vascular bypass surgery can re-establish flow around the diseased segment of artery, and

angioplasty Angioplasty, is also known as balloon angioplasty and percutaneous transluminal angioplasty (PTA), is a minimally invasive endovascular procedure used to widen narrowed or obstructed arteries or veins, typically to treat arterial atheroscler ...

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 Warfarin, sold under the brand name Coumadin among others, is a medication that is used as an anticoagulant (blood thinner). It is commonly used to prevent blood clots such as deep vein thrombosis and pulmonary embolism, and to prevent ...

, which inhibit clot formation by interfering with

Vitamin K Vitamin K refers to structurally similar, fat-soluble vitamers found in foods and marketed as dietary supplements. The human body requires vitamin K for post-synthesis modification of certain proteins that are required for blood coagulat ...

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 Coronary () may, as shorthand in English, be used to mean: * Coronary circulation, the system of arteries and veins in mammals ** Coronary artery disease **Coronary occlusion ** A myocardial infarction, a heart attack As adjective * Referring to ...

fatty streaks beginning in

adolescence Adolescence () is a transitional stage of physical and psychological development that generally occurs during the period from puberty to adulthood (typically corresponding to the age of majority). Adolescence is usually associated with t ...

.Kumar, Vinay; Abbas, Abul K.; Fausto, Nelson; & Mitchell, Richard N. (2007). ''Robbins Basic Pathology'' (8th ed.). Saunders Elsevier. pp. 348-351 In 1953, a study was published which examined the results of 300 autopsies performed on U.S. soldiers who had died in the

. 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 1985–1995, 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 (); ''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 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

(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

s 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 Lipid peroxidation is the chain of reactions of oxidative degradation of lipids. It is the process in which free radicals "steal" electrons from the lipids in cell membranes, resulting in cell damage. This process proceeds by a free radical cha ...

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

MicroRNA MicroRNA (miRNA) are small, single-stranded, non-coding RNA molecules containing 21 to 23 nucleotides. Found in plants, animals and some viruses, miRNAs are involved in RNA silencing and post-transcriptional regulation of gene expression. mi ...

s (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 An intron is any nucleotide sequence within a gene that is not expressed or operative in the final RNA product. The word ''intron'' is derived from the term ''intragenic region'', i.e. a region inside a gene."The notion of the cistron .e., gene ...

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 Bile (from Latin ''bilis''), or gall, is a dark-green-to-yellowish-brown fluid produced by the liver of most vertebrates that aids the digestion of lipids in the small intestine. In humans, bile is produced continuously by the liver (liver b ...

or converted to

bile acid Bile acids are steroid acids found predominantly in the bile of mammals and other vertebrates. Diverse bile acids are synthesized in the liver. Bile acids are conjugated with taurine or glycine residues to give anions called bile salts. Prima ...

s 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 damage

Aging Ageing ( BE) or aging ( AE) is the process of becoming older. The term refers mainly to humans, many other animals, and fungi, whereas for example, bacteria, perennial plants and some simple animals are potentially biologically immortal. In ...

is the most important risk factor for cardiovascular problems. The causative basis by which aging mediates its impact, independently of other recognized risk factors, remains to be determined. Evidence has been reviewed for a key role of

DNA damage DNA repair is a collection of processes by which a cell identifies and corrects damage to the DNA molecules that encode its genome. In human cells, both normal metabolic activities and environmental factors such as radiation can cause DNA d ...

in vascular aging. 8-oxoG, a common type of oxidative damage in DNA, is found to accumulate in plaque

cells,

s and

, thus linking DNA damage to plaque formation. DNA strand breaks also increased in atherosclerotic plaques.

Werner syndrome Werner syndrome (WS) or Werner's syndrome, also known as "adult progeria",James, William; Berger, Timothy; Elston, Dirk (2005). ''Andrews' Diseases of the Skin: Clinical Dermatology''. (10th ed.). Saunders. . is a rare, autosomal recessive disorde ...

(WS) is a premature aging condition in humans. WS is caused by a genetic defect in a RecQ helicase that is employed in several repair processes that remove damages from DNA. WS patients develop a considerable burden of atherosclerotic plaques in their coronary arteries and

: calcification of the aortic valve is also frequently observed. These findings link excessive unrepaired DNA damage to premature aging and early atherosclerotic plaque development (see

DNA damage theory of aging The DNA damage theory of aging proposes that aging is a consequence of unrepaired accumulation of naturally occurring DNA damage. Damage in this context is a DNA alteration that has an abnormal structure. Although both mitochondrial and nuclear D ...

Microorganisms

The microbiota – all the

microorganism A microorganism, or microbe,, ''mikros'', "small") and ''organism'' from the el, ὀργανισμός, ''organismós'', "organism"). It is usually written as a single word but is sometimes hyphenated (''micro-organism''), especially in olde ...

s in the body, can contribute to atherosclerosis in many ways: modulation of the

immune system The immune system is a network of biological processes that protects an organism from diseases. It detects and responds to a wide variety of pathogens, from viruses to parasitic worms, as well as cancer cells and objects such as wood splint ...

, changes in

metabolism Metabolism (, from el, μεταβολή ''metabolē'', "change") is the set of life-sustaining chemical reactions in organisms. The three main functions of metabolism are: the conversion of the energy in food to energy available to run ...

, processing of nutrients and production of certain metabolites that can get into blood circulation. One such metabolite, produced by gut bacteria, is

trimethylamine N-oxide Trimethylamine ''N''-oxide (TMAO) is an organic compound with the formula (CH3)3NO. It is in the class of amine oxides. Although the anhydrous compound is known, trimethylamine ''N''-oxide is usually encountered as the dihydrate. Both the anhydr ...

(TMAO). Its levels have been associated with atherosclerosis in human studies and animal research suggest that there can be a causal relation. An association between the bacterial genes encoding trimethylamine lyases — the

enzyme Enzymes () are proteins that act as biological catalysts by accelerating chemical reactions. The molecules upon which enzymes may act are called substrates, and the enzyme converts the substrates into different molecules known as products. ...

s involved in TMAO generation — and atherosclerosis has been noted.

Vascular smooth muscle cells

Vascular smooth muscle cells play a key role in atherogenesis and were historically considered to be beneficial for plaque stability by forming a protective fibrous cap and synthesising strength-giving

components. However, in addition to the fibrous cap, vascular smooth muscle cells also give rise to many of the cell types found within the plaque core and can modulate their phenotype to both promote and reduce plaque stability. Vascular smooth muscle cells exhibit pronounced plasticity within atherosclerotic plaque and can modify their gene expression profile to resemble various other cell types, including

s, myofibroblasts,

mesenchymal stem cell Mesenchymal stem cells (MSCs) also known as mesenchymal stromal cells or medicinal signaling cells are multipotent stromal cells that can differentiate into a variety of cell types, including osteoblasts (bone cells), chondrocytes (cartilage c ...

s and osteochondrocytes. Importantly, genetic lineage‐tracing experiments have unequivocally shown that 40-90% of plaque-resident cells are vascular smooth muscle cell derived. Therefore, it is important to research the role of vascular smooth muscle cells in atherosclerosis to identify new therapeutic targets.

References

External links

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