Coronary Sclerosis
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Atherosclerosis is a pattern of the disease
arteriosclerosis Arteriosclerosis, literally meaning "hardening of the arteries", is an umbrella term for a vascular disorder characterized by abnormal thickening, hardening, and loss of elasticity of the walls of arteries; this process gradually restricts th ...
, characterized by development of abnormalities called
lesion A lesion is any damage or abnormal change in the tissue of an organism, usually caused by injury or diseases. The term ''Lesion'' is derived from the Latin meaning "injury". Lesions may occur in both plants and animals. Types There is no de ...
s in walls of
arteries An artery () is a blood vessel in humans and most other animals that takes oxygenated blood away from the heart in the systemic circulation to one or more parts of the body. Exceptions that carry deoxygenated blood are the pulmonary arteries in ...
. This is a chronic inflammatory disease involving many different cell types and is driven by elevated blood levels of cholesterol. These lesions may lead to narrowing of the arterial walls due to buildup of
atheromatous plaque An atheroma, or atheromatous plaque, is an abnormal 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 of fibrous conne ...
s. At the onset, there are usually no symptoms, but if they develop, symptoms generally begin around
middle age Middle age (or middle adulthood) is the age range of the years halfway between childhood and old age. The exact range is subject to public debate, but the term is commonly used to denote the age range from 45 to 65 years. Overall This time span ...
. In severe cases, it can result in
coronary artery disease Coronary artery disease (CAD), also called coronary heart disease (CHD), or ischemic heart disease (IHD), is a type of cardiovascular disease, heart disease involving Ischemia, the reduction of blood flow to the cardiac muscle due to a build-up ...
,
stroke Stroke is a medical condition in which poor cerebral circulation, blood flow to a part of the brain causes cell death. There are two main types of stroke: brain ischemia, ischemic, due to lack of blood flow, and intracranial hemorrhage, hemor ...
,
peripheral artery disease Peripheral artery disease (PAD) is a vascular disorder that causes abnormal narrowing of arteries other than those that supply the heart or brain. PAD can happen in any blood vessel, but it is more common in the legs than the arms. When narr ...
, or
kidney disorder Kidney disease, or renal disease, technically referred to as nephropathy, is damage to or disease of a kidney. Nephritis is an inflammatory kidney disease and has several types according to the location of the inflammation. Inflammation can b ...
s, depending on which body part(s) the affected arteries are located in the body. The exact cause of atherosclerosis is unknown and is proposed to be multifactorial. Risk factors include abnormal cholesterol levels, elevated levels of
inflammatory biomarker Acute-phase proteins (APPs) are a class of proteins whose concentrations in blood plasma either increase (positive acute-phase proteins) or decrease (negative acute-phase proteins) in response to inflammation. This response is called the ''acute-p ...
s,
high blood pressure Hypertension, also known as high blood pressure, 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 itself. It is, however, a major ri ...
,
diabetes Diabetes mellitus, commonly known as diabetes, is a group of common endocrine diseases characterized by sustained high blood sugar levels. Diabetes is due to either the pancreas not producing enough of the hormone insulin, or the cells of th ...
,
smoking Smoking is a practice in which a substance is combusted, and the resulting smoke is typically inhaled to be tasted and absorbed into the bloodstream of a person. Most commonly, the substance used is the dried leaves of the tobacco plant, whi ...
(both active and
passive smoking Passive smoking is the inhalation of tobacco smoke, called passive smoke, secondhand smoke (SHS) or environmental tobacco smoke (ETS), by individuals other than the active Tobacco smoking, smoker. It occurs when tobacco smoke diffuses into the ...
),
obesity Obesity is a medical condition, considered by multiple organizations to be a disease, in which excess Adipose tissue, body fat has accumulated to such an extent that it can potentially have negative effects on health. People are classifi ...
, genetic factors, family history, lifestyle habits, and an unhealthy diet. Plaque is made up of fat,
cholesterol Cholesterol is the principal sterol of all higher animals, distributed in body Tissue (biology), tissues, especially the brain and spinal cord, and in Animal fat, animal fats and oils. Cholesterol is biosynthesis, biosynthesized by all anima ...
, immune cells,
calcium Calcium is a chemical element; it has 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 to it ...
, 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 is com ...
. The narrowing of
arteries An artery () is a blood vessel in humans and most other animals that takes oxygenated blood away from the heart in the systemic circulation to one or more parts of the body. Exceptions that carry deoxygenated blood are the pulmonary arteries in ...
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 guidelines include 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 body weight. Treatment of established atherosclerotic disease may include medications to lower
cholesterol Cholesterol is the principal sterol of all higher animals, distributed in body Tissue (biology), tissues, especially the brain and spinal cord, and in Animal fat, animal fats and oils. Cholesterol is biosynthesis, biosynthesized by all anima ...
such as
statin Statins (or HMG-CoA reductase inhibitors) are a class of medications that lower cholesterol. They are prescribed typically to people who are at high risk of cardiovascular disease. Low-density lipoprotein (LDL) carriers of cholesterol play ...
s, blood pressure medication, and anticoagulant therapies to reduce the risk of blood clot formation. As the disease state progresses, more invasive strategies are applied, such as
percutaneous coronary intervention Percutaneous coronary intervention (PCI) is a minimally invasive non-surgical procedure used to treat stenosis, narrowing of the coronary artery, coronary arteries of the heart found in coronary artery disease. The procedure is used to place and ...
, coronary artery bypass graft, or
carotid endarterectomy Carotid endarterectomy is a surgical procedure used to reduce the risk of stroke from carotid artery stenosis (narrowing the internal carotid artery). In an endarterectomy, the surgeon opens the artery and removes the plaque. The plaque forms ...
. Genetic factors are also strongly implicated in the disease process; it is unlikely to be entirely based on lifestyle choices. 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 the 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. In rare cases, an ...
and
disability Disability is the experience of any condition that makes it more difficult for a person to do certain activities or have equitable access within a given society. Disabilities may be Cognitive disability, cognitive, Developmental disability, d ...
in
developed countries A developed country, or advanced country, is a sovereign state that has a high quality of life, developed economy, and advanced technological infrastructure relative to other less industrialized nations. Most commonly, the criteria for eval ...
. Though it was first described in 1575, there is evidence suggesting that this disease state is genetically inherent in the broader human population, with its origins tracing back to CMAH genetic mutations that may have occurred more than two million years ago during the evolution of hominin ancestors of modern human beings.


Signs and symptoms

Atherosclerosis is typically
asymptomatic Asymptomatic (or clinically silent) is an adjective categorising the medical conditions (i.e., injuries or diseases) that patients carry but without experiencing their symptoms, despite an explicit diagnosis (e.g., a positive medical test). P ...
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 happen 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
stroke Stroke is a medical condition in which poor cerebral circulation, blood flow to a part of the brain causes cell death. There are two main types of stroke: brain ischemia, ischemic, due to lack of blood flow, and intracranial hemorrhage, hemor ...
or
heart attack A myocardial infarction (MI), commonly known as a heart attack, occurs when Ischemia, blood flow decreases or stops in one of the coronary arteries of the heart, causing infarction (tissue death) to the heart muscle. The most common symptom ...
. These symptoms, however, still vary depending on which artery or organ is affected. Early atherosclerotic processes likely begin in childhood. Fibrous and gelatinous lesions have been observed in the
coronary arteries The coronary arteries are the arteries, arterial blood vessels of coronary circulation, which transport oxygenated blood to the Cardiac muscle, heart muscle. The heart requires a continuous supply of oxygen to function and survive, much like any ...
of children. Fatty streaks have been observed in the coronary arteries of juveniles. While
coronary artery disease Coronary artery disease (CAD), also called coronary heart disease (CHD), or ischemic heart disease (IHD), is a type of cardiovascular disease, heart disease involving Ischemia, the reduction of blood flow to the cardiac muscle due to a build-up ...
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 Angina, also known as angina pectoris, is chest pain or pressure, usually caused by insufficient blood flow to the heart muscle (myocardium). It is most commonly a symptom of coronary artery disease. Angina is typically the result of parti ...
and shortness of breath, sweating,
nausea Nausea is a diffuse sensation of unease and discomfort, sometimes perceived as an urge to vomit. It can be a debilitating symptom if prolonged and has been described as placing discomfort on the chest, abdomen, or back of the throat. Over 30 d ...
, dizziness or lightheadedness, breathlessness or
palpitations Palpitations occur when a person becomes aware of their heartbeat. The heartbeat may feel hard, fast, or uneven in their chest. Symptoms include a very fast or irregular heartbeat. Palpitations are a sensory symptom. They are often described as ...
. Abnormal heart rhythms called
arrhythmia Arrhythmias, also known as cardiac arrhythmias, are irregularities in the cardiac cycle, heartbeat, including when it is too fast or too slow. Essentially, this is anything but normal sinus rhythm. A resting heart rate that is too fast – ab ...
s—the heart beating either too slowly or too quickly—are another consequence of
ischemia Ischemia or ischaemia is a restriction in blood supply to any tissue, muscle group, or organ of the body, causing a shortage of oxygen that is needed for cellular metabolism (to keep tissue alive). Ischemia is generally caused by problems ...
.Arrhythmia. Heart and Stroke Foundation. (2011)
Carotid arteries In anatomy, the left and right common carotid arteries (carotids) () are arteries that supply the head and neck with oxygenated blood; they divide in the neck to form the external and internal carotid arteries. Structure The common carotid ...
supply blood to the brain and neck. 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 pain and numbness in the arms or legs. 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 Chronic kidney disease (CKD) is a type of long-term kidney disease, defined by the sustained presence of abnormal kidney function and/or abnormal kidney structure. To meet criteria for CKD, the abnormalities must be present for at least three mo ...
, which, like in all other areas, is typically asymptomatic until late stages. In 2004, US data indicated that in ~66% of men and ~47% of women, the first symptom of atherosclerotic cardiovascular disease was a
heart attack A myocardial infarction (MI), commonly known as a heart attack, occurs when Ischemia, blood flow decreases or stops in one of the coronary arteries of the heart, causing infarction (tissue death) to the heart muscle. The most common symptom ...
or
sudden cardiac death Cardiac arrest (also known as sudden cardiac arrest ''SCA is when the heart suddenly and unexpectedly stops beating. When the heart stops beating, blood cannot properly circulate around the body and the blood flow to the brain and other org ...
(defined as death within one hour of onset of the symptom). Case studies have included
autopsies An autopsy (also referred to as post-mortem examination, obduction, necropsy, or autopsia cadaverum) is a surgical procedure that consists of a thorough examination of a corpse by dissection to determine the cause, mode, and manner of death; ...
of U.S. soldiers killed in
World War II World War II or the Second World War (1 September 1939 – 2 September 1945) was a World war, global conflict between two coalitions: the Allies of World War II, Allies and the Axis powers. World War II by country, Nearly all of the wo ...
and the
Korean War The Korean War (25 June 1950 – 27 July 1953) was an armed conflict on the Korean Peninsula fought between North Korea (Democratic People's Republic of Korea; DPRK) and South Korea (Republic of Korea; ROK) and their allies. North Korea was s ...
. 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.


Risk factors

The atherosclerotic process is not well understood. Atherosclerosis is associated with inflammatory processes in the
endothelial cells The endothelium (: endothelia) 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 res ...
of the vessel wall associated with retained
low-density lipoprotein Low-density lipoprotein (LDL) is one of the five major groups of lipoprotein that transport all fat molecules around the body in extracellular water. These groups, from least dense to most dense, are chylomicrons (aka ULDL by the overall density ...
(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 A muscle cell, also known as a myocyte, is a mature contractile cell in the muscle of an animal. In humans and other vertebrates there are three types: skeletal, smooth, and cardiac (cardiomyocytes). A skeletal muscle cell is long and threadli ...
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 The Western pattern diet is a modern dietary pattern originating in the industrialized West which is generally characterized by high intakes of pre-packaged foods, refined grains, red and processed meat, high-sugar drinks, candy and swee ...
*
Abdominal obesity Abdominal obesity, also known as central obesity and truncal obesity, is the human condition of an excessive concentration of visceral fat around the stomach and abdomen to such an extent that it is likely to harm its bearer's health. Abdominal ...
*
Diabetes Diabetes mellitus, commonly known as diabetes, is a group of common endocrine diseases characterized by sustained high blood sugar levels. Diabetes is due to either the pancreas not producing enough of the hormone insulin, or the cells of th ...
*
Dyslipidemia Dyslipidemia is a metabolic disorder characterized by abnormally high or low amounts of any or all lipids (e.g. fats, triglycerides, cholesterol, phospholipids) or lipoproteins in the blood. Dyslipidemia is a risk factor for the development of ...
* High blood cholesterol *
Hypertension Hypertension, also known as high blood pressure, is a Chronic condition, long-term Disease, medical condition in which the blood pressure in the artery, arteries is persistently elevated. High blood pressure usually does not cause symptoms i ...
* Elevated
low-density lipoprotein Low-density lipoprotein (LDL) is one of the five major groups of lipoprotein that transport all fat molecules around the body in extracellular water. These groups, from least dense to most dense, are chylomicrons (aka ULDL by the overall density ...
(LDL) *High
saturated fat A saturated fat is a type of fat in which the fatty acid chains have all single bonds between the carbon atoms. A fat known as a glyceride is made of two kinds of smaller molecules: a short glycerol backbone, and fatty acids that each cont ...
diet *
Trans fat Trans fat is a type of unsaturated fat that occurs in foods. Small amounts of trans fats occur naturally, but large amounts are found in some processed foods made with partially hydrogenated oils. Because consumption of trans fats is associated ...
*
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 released from the mouth, as is generally done with pipes and cigars. The practice is believed to hav ...
*
Bacterial infections Pathogenic bacteria are bacteria that can cause disease. This article focuses on the bacteria that are pathogenic to humans. Most species of bacteria are harmless and many are beneficial but others can cause infectious diseases. The number of t ...
*
HIV/AIDS The HIV, human immunodeficiency virus (HIV) is a retrovirus that attacks the immune system. Without treatment, it can lead to a spectrum of conditions including acquired immunodeficiency syndrome (AIDS). It is a Preventive healthcare, pr ...
*
Psychological stress In psychology, stress is a feeling of emotional strain and pressure. Stress is a form of psychological and mental discomfort. Small amounts of stress may be beneficial, as it can improve athletic performance, motivation and reaction to the envi ...
*
Sedentary lifestyle Sedentary lifestyle is a Lifestyle (social sciences), 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 enga ...


Nonmodifiable

* Biological sex *
South Asian South Asia is the southern Subregion#Asia, subregion of Asia that is defined in both geographical and Ethnicity, ethnic-Culture, cultural terms. South Asia, with a population of 2.04 billion, contains a quarter (25%) of the world's populatio ...
descentIndian Heart Association Why South Asians Facts Web. 30 April 2015. http://indianheartassociation.org/why-indians-why-south-asians/overview/ * Advanced age * Genetic abnormalities * 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 ...
* Elevated
triglycerides A triglyceride (from ''wikt:tri-#Prefix, tri-'' and ''glyceride''; also TG, triacylglycerol, TAG, or triacylglyceride) is an ester derived from glycerol and three fatty acids. Triglycerides are the main constituents of body fat in humans and oth ...
* Systemic inflammation * 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 (medicine), chronic ...
*
Air pollution Air pollution is the presence of substances in the Atmosphere of Earth, air that are harmful to humans, other living beings or the environment. Pollutants can be Gas, gases like Ground-level ozone, ozone or nitrogen oxides or small particles li ...
*
Arsenic poisoning Arsenic poisoning (or arsenicosis) is a medical condition that occurs due to elevated levels of arsenic in the body. If arsenic poisoning occurs over a brief period of time, symptoms may include vomiting, abdominal pain, encephalopathy, and water ...
*
Hypothyroidism Hypothyroidism is an endocrine disease in which the thyroid gland does not produce enough thyroid hormones. It can cause a number of symptoms, such as cold intolerance, poor ability to tolerate cold, fatigue, extreme fatigue, muscle aches, co ...
*
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 c ...


Dietary

The relation between dietary fat and atherosclerosis is controversial. The
USDA The United States Department of Agriculture (USDA) is an United States federal executive departments, executive department of the Federal government of the United States, United States federal government that aims to meet the needs of commerc ...
, in its food pyramid, promotes a diet of about 64%
carbohydrate A carbohydrate () is a biomolecule composed of carbon (C), hydrogen (H), and oxygen (O) atoms. The typical hydrogen-to-oxygen atomic ratio is 2:1, analogous to that of water, and is represented by the empirical formula (where ''m'' and ''n'' ...
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 Heart, cardiac care in an effort to reduce disability ...
, 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 diabetes ...
, 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 The Nurses Health Study is a series of prospective studies that examine epidemiology and the long-term effects of nutrition, hormones, environment, and nurses' work-life on health and disease development. The studies have been among the largest i ...
) recommends much higher levels of fat, especially of monounsaturated and
polyunsaturated fat In biochemistry and nutrition, a polyunsaturated fat is a fat that contains a polyunsaturated fatty acid (abbreviated PUFA), which is a subclass of fatty acid characterized by a backbone with two or more carbon–carbon double bonds. Some polyunsa ...
. These dietary recommendations reach a consensus, though, against consumption of
trans fat Trans fat is a type of unsaturated fat that occurs in foods. Small amounts of trans fats occur naturally, but large amounts are found in some processed foods made with partially hydrogenated oils. Because consumption of trans fats is associated ...
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 Chemical compound, compounds that inhibit Redox, oxidation, a chemical reaction that can produce Radical (chemistry), free radicals. Autoxidation leads to degradation of organic compounds, including living matter. Antioxidants ...
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 phospholipids typ ...
hydroperoxide Hydroperoxides or peroxols are Chemical compound, compounds of the form ROOH, where R stands for any group, typically Organic compound, organic, which contain the hydroperoxy functional group (). Hydroperoxide also refers to the hydroperoxide anio ...
in their blood, livers and kidneys. Rancid fats and oils taste very unpleasant in even small amounts, so people avoid eating them. Measuring or estimating the actual human consumption of these substances is challenging. 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 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 several years through a complex series of cellular events occurring within the arterial wall and in response to several local vascular circulating factors. One recent hypothesis suggests that, for unknown reasons,
leukocytes White blood cells (scientific name leukocytes), also called immune cells or immunocytes, are cells of the immune system that are involved in protecting the body against both infectious disease and foreign entities. White blood cells are genera ...
, 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 monocyte-derived dendritic cells. As a part of the vertebrate innate immune system monocytes also i ...
or basophils, begin to attack the
endothelium The endothelium (: endothelia) 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 r ...
of the artery lumen in
cardiac muscle Cardiac muscle (also called heart muscle or myocardium) is one of three types of vertebrate muscle tissues, the others being skeletal muscle and smooth muscle. It is an involuntary, striated muscle that constitutes the main tissue of the wall o ...
. The ensuing
inflammation Inflammation (from ) is part of the biological response of body tissues to harmful stimuli, such as pathogens, damaged cells, or irritants. The five cardinal signs are heat, pain, redness, swelling, and loss of function (Latin ''calor'', '' ...
leads to the formation of atheromatous plaques in the arterial
tunica intima The tunica intima (Neo-Latin "inner coat"), or intima for short, is the innermost tunica (biology), tunica (layer) of an artery or vein. It is made up of one layer of endothelium, endothelial cells (and macrophages in areas of disturbed blood flo ...
, a region of the vessel wall located between the
endothelium The endothelium (: endothelia) 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 r ...
and the
tunica media The tunica media (Neo-Latin "middle coat"), or media for short, is the middle tunica (layer) of an artery or vein. It lies between the internal elastic lamina of the tunica intima on the inside and the tunica externa on the outside. Artery The ...
. Chronic inflammation within the arterial wall, driven by immune cells like macrophages, accelerates atherosclerotic plaque instability by promoting collagen breakdown and thinning the fibrous cap, which increases the likelihood of rupture and thrombosis. The bulk of these lesions is made of excess fat,
collagen Collagen () is the main structural protein in the extracellular matrix of the connective tissues of many animals. It is the most abundant protein in mammals, making up 25% to 35% of protein content. Amino acids are bound together to form a trip ...
, and
elastin Elastin is a protein encoded by the ''ELN'' gene in humans and several other animals. Elastin is a key component in the extracellular matrix of gnathostomes (jawed vertebrates). It is highly Elasticity (physics), elastic and present in connective ...
. At first, as the plaques grow, only wall thickening occurs without narrowing.
Stenosis Stenosis () is the abnormal narrowing of a blood vessel or other tubular organ or structure such as foramina and canals. It is also sometimes called a stricture (as in urethral stricture). ''Stricture'' as a term is usually used when narrowing ...
is a late event, which may never happen and is often the result of repeated plaque rupture and healing responses, not just the atherosclerotic process. Autopsy studies have shown that the prevalence of coronary artery atherosclerosis in males from the United States, with an average age of 22.1 years, who died in war, ranges from 45% to 77.3%.


Cellular

Early atherogenesis is characterized by the adherence of blood circulating
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 monocyte-derived dendritic cells. As a part of the vertebrate innate immune system monocytes also i ...
(a type of
white blood cell White blood cells (scientific name leukocytes), also called immune cells or immunocytes, are cells of the immune system that are involved in protecting the body against both infectious disease and foreign entities. White blood cells are genera ...
) to the vascular bed lining, the
endothelium The endothelium (: endothelia) 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 r ...
, then by their migration to the sub-endothelial space, and further activation into monocyte-derived
macrophage Macrophages (; abbreviated MPhi, φ, MΦ or MP) are a type of white blood cell of the innate immune system that engulf and digest pathogens, such as cancer cells, microbes, cellular debris and foreign substances, which do not have proteins that ...
s. The primary documented driver of this process is oxidized lipoprotein particles within the wall, beneath the
endothelial The endothelium (: endothelia) 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 res ...
cells, though upper normal or elevated concentrations of
blood glucose The blood sugar level, blood sugar concentration, blood glucose level, or glycemia is the measure of glucose concentrated in the blood. The body tightly blood sugar regulation, regulates blood glucose levels as a part of metabolic homeostasis ...
also plays a major role and not all factors are fully understood. Fatty streaks may appear and disappear.
Low-density lipoprotein Low-density lipoprotein (LDL) is one of the five major groups of lipoprotein that transport all fat molecules around the body in extracellular water. These groups, from least dense to most dense, are chylomicrons (aka ULDL by the overall density ...
(LDL) particles in blood plasma invade the
endothelium The endothelium (: endothelia) 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 r ...
and become oxidized, creating risk of
cardiovascular disease Cardiovascular disease (CVD) is any disease involving the heart or blood vessels. CVDs constitute a class of diseases that includes: coronary artery diseases (e.g. angina, heart attack), heart failure, hypertensive heart disease, rheumati ...
. A complex set of biochemical reactions regulates the oxidation of LDL, involving enzymes (such as Lp-LpA2) and
free radical A daughter category of ''Ageing'', this category deals only with the biological aspects of ageing. Ageing Biogerontology Biological processes Causes of death Cellular processes Gerontology Life extension Metabolic disorders Metabolism ...
s in the endothelium. Initial damage to the endothelium results in an inflammatory response. Monocytes enter the artery wall from the bloodstream, with
platelet Platelets or thrombocytes () are a part of blood whose function (along with the coagulation#Coagulation factors, coagulation factors) is to react to bleeding from blood vessel injury by clumping to form a thrombus, blood clot. Platelets have no ...
s 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 messenger ...
induction of factors such as VCAM-1, which recruits circulating monocytes, and M-CSF, which is selectively required for the differentiation of monocytes to macrophages. The monocytes differentiate into
macrophage Macrophages (; abbreviated MPhi, φ, MΦ or MP) are a type of white blood cell of the innate immune system that engulf and digest pathogens, such as cancer cells, microbes, cellular debris and foreign substances, which do not have proteins that ...
s, 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 Lipids are a broad group of organic compounds which include fats, waxes, sterols, fat-soluble vitamins (such as vitamins A, D, E and K), monoglycerides, diglycerides, phospholipids, and others. The functions of lipids include storing ...
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 one of the three major types of vertebrate muscle tissue, the others being skeletal and cardiac muscle. It can also be found in invertebrates and is controlled by the autonomic nervous system. It is non- striated, so-called bec ...
proliferation and migration from the
tunica media The tunica media (Neo-Latin "middle coat"), or media for short, is the middle tunica (layer) of an artery or vein. It lies between the internal elastic lamina of the tunica intima on the inside and the tunica externa on the outside. Artery The ...
into the intima in response to
cytokine Cytokines () are a broad and loose category of small proteins (~5–25 kDa) important in cell signaling. Cytokines are produced by a broad range of cells, including immune cells like macrophages, B cell, B lymphocytes, T cell, T lymphocytes ...
s 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, nitrogen monooxide, 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 den ...
.


Calcification and lipids

Calcification Calcification is the accumulation of calcium salts in a body tissue. It normally occurs in the formation of bone, but calcium can be deposited abnormally in soft tissue,Miller, J. D. Cardiovascular calcification: Orbicular origins. ''Nature M ...
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 v ...
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 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 Low-density lipoprotein (LDL) is one of the five major groups of lipoprotein that transport all fat molecules around the body in extracellular water. These groups, from least dense to most dense, are chylomicrons (aka ULDL by the overall density ...
(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 t ...
(HDL), the lipoprotein particle that removes cholesterol from tissues and carries it back to the liver. The foam cells and
platelet Platelets or thrombocytes () are a part of blood whose function (along with the coagulation#Coagulation factors, coagulation factors) is to react to bleeding from blood vessel injury by clumping to form a thrombus, blood clot. Platelets have no ...
s encourage the migration and proliferation of
smooth muscle Smooth muscle is one of the three major types of vertebrate muscle tissue, the others being skeletal and cardiac muscle. It can also be found in invertebrates and is controlled by the autonomic nervous system. It is non- striated, so-called bec ...
cells, which in turn ingest lipids, become replaced by
collagen Collagen () is the main structural protein in the extracellular matrix of the connective tissues of many animals. It is the most abundant protein in mammals, making up 25% to 35% of protein content. Amino acids are bound together to form a trip ...
, 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 Stenosis () is the abnormal narrowing of a blood vessel or other tubular organ or structure such as foramina and canals. It is also sometimes called a stricture (as in urethral stricture). ''Stricture'' as a term is usually used when narrowing ...
") of the opening ("lumen") occurs. The artery expands with an egg-shaped cross-section, still with a circular opening. If the enlargement is beyond proportion to the atheroma thickness, then an
aneurysm An aneurysm is an outward :wikt:bulge, bulging, likened to a bubble or balloon, caused by a localized, abnormal, weak spot on a blood vessel wall. Aneurysms may be a result of a hereditary condition or an acquired disease. Aneurysms can also b ...
is created.


Visible features

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 protein, fibrous, non-globular protein involved in the Coagulation, clotting of blood. It is formed by the action of the protease thrombin on fibrinogen, which causes it to polymerization, polymerize. ...
,
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 w ...
s,
collagen Collagen () is the main structural protein in the extracellular matrix of the connective tissues of many animals. It is the most abundant protein in mammals, making up 25% to 35% of protein content. Amino acids are bound together to form a trip ...
,
elastin Elastin is a protein encoded by the ''ELN'' gene in humans and several other animals. Elastin is a key component in the extracellular matrix of gnathostomes (jawed vertebrates). It is highly Elasticity (physics), elastic and present in connective ...
, 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 arterial wall, 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 Eosinophilic (Greek suffix '' -phil'', meaning ''eosin-loving'') describes the staining of tissues, cells, or organelles after they have been washed with eosin, a dye commonly used in histological staining. Eosin is an acidic dye for stainin ...
), precipitates of calcium (hematoxylinophilic), and rarely, lipid-laden cells. In effect, the muscular portion of the artery wall forms small
aneurysm An aneurysm is an outward :wikt:bulge, bulging, likened to a bubble or balloon, caused by a localized, abnormal, weak spot on a blood vessel wall. Aneurysms may be a result of a hereditary condition or an acquired disease. Aneurysms can also b ...
s just large enough to hold the
atheroma An atheroma, or atheromatous plaque, is an abnormal accumulation of material in the tunica intima, inner layer of an arterial wall. The material consists of mostly macrophage, macrophage cells, or debris, containing lipids, calcium and a variabl ...
that are present. The muscular portion of artery walls usually remains strong, even after they have been 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 A computed tomography scan (CT scan), formerly called computed axial tomography scan (CAT scan), is a medical imaging technique used to obtain detailed internal images of the body. The personnel that perform CT scans are called radiographers or ...
or
electron beam tomography Electron beam computed tomography (EBCT) is a fifth generation computed tomography (CT) scanner in which the X-ray tube is not mechanically spun in order to rotate the source of X-ray photons. This different design was explicitly developed to ...
(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 t ...
(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 wikt:ulcer, 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 blood flow. 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 Stenosis () is the abnormal narrowing of a blood vessel or other tubular organ or structure such as foramina and canals. It is also sometimes called a stricture (as in urethral stricture). ''Stricture'' as a term is usually used when narrowing ...
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 often 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 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 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 Collagen () is the main structural protein in the extracellular matrix of the connective tissues of many animals. It is the most abundant protein in mammals, making up 25% to 35% of protein content. Amino acids are bound together to form a trip ...
and tissue factor; they activate
platelet Platelets or thrombocytes () are a part of blood whose function (along with the coagulation#Coagulation factors, coagulation factors) is to react to bleeding from blood vessel injury by clumping to form a thrombus, blood clot. Platelets have no ...
s and activate the coagulation, system of coagulation. The result is the formation of a thrombus (blood clot) overlying the atheroma, which obstructs blood flow acutely. With the obstruction of blood flow, downstream tissues are starved of oxygen and nutrients. If this is the myocardium (heart muscle) Angina pectoris, angina (cardiac chest pain) or myocardial infarction (heart attack) develops.


Accelerated growth of plaques

The distribution of atherosclerotic plaques in a part of the 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 age spots on the skin. Misrepair-accumulation aging theory suggests that misrepair mechanisms play an important role in the focal development of atherosclerosis. The development of a plaque is a result of the repair of the injured endothelium. Because of the infusion of lipids into the sub-endothelium, the repair has to end up with altered remodeling of the local endothelium. This is the manifestation of a misrepair. This altered remodeling increases the susceptibility of the local endothelium to damage and reduces its repair efficiency. Consequently, this part of the endothelium has an increased risk of being injured and improperly repaired. Thus, the accumulation of misrepairs of the endothelium is focalized and self-accelerating. In this way, the growth 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 An atheroma, or atheromatous plaque, is an abnormal accumulation of material in the tunica intima, inner layer of an arterial wall. The material consists of mostly macrophage, macrophage cells, or debris, containing lipids, calcium and a variabl ...
("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 (anatomy), 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 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 Collagen () is the main structural protein in the extracellular matrix of the connective tissues of many animals. It is the most abundant protein in mammals, making up 25% to 35% of protein content. Amino acids are bound together to form a trip ...
, 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 the lumen
stenosis Stenosis () is the abnormal narrowing of a blood vessel or other tubular organ or structure such as foramina and canals. It is also sometimes called a stricture (as in urethral stricture). ''Stricture'' as a term is usually used when narrowing ...
is so severe (usually over 80%) that blood supply to downstream tissue(s) is insufficient, resulting in
ischemia Ischemia or ischaemia is a restriction in blood supply to any tissue, muscle group, or organ of the body, causing a shortage of oxygen that is needed for cellular metabolism (to keep tissue alive). Ischemia is generally caused by problems ...
. 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

Areas of severe narrowing,
stenosis Stenosis () is the abnormal narrowing of a blood vessel or other tubular organ or structure such as foramina and canals. It is also sometimes called a stricture (as in urethral stricture). ''Stricture'' as a term is usually used when narrowing ...
, detectable by angiography, and to a lesser extent "Cardiac stress test, stress testing" have long been the focus of human diagnostic techniques for
cardiovascular disease Cardiovascular disease (CVD) is any disease involving the heart or blood vessels. CVDs constitute a class of diseases that includes: coronary artery diseases (e.g. angina, heart attack), heart failure, hypertensive heart disease, rheumati ...
, 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, potential permanent disability, 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 Collagen () is the main structural protein in the extracellular matrix of the connective tissues of many animals. It is the most abundant protein in mammals, making up 25% to 35% of protein content. Amino acids are bound together to form a trip ...
, 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 Endoscopic optical coherence tomography imaging, 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 A myocardial infarction (MI), commonly known as a heart attack, occurs when Ischemia, blood flow decreases or stops in one of the coronary arteries of the heart, causing infarction (tissue death) to the heart muscle. The most common symptom ...
, while the obstruction of arteries supplying the brain results in an ischaemic
stroke Stroke is a medical condition in which poor cerebral circulation, blood flow to a part of the brain causes cell death. There are two main types of stroke: brain ischemia, ischemic, due to lack of blood flow, and intracranial hemorrhage, hemor ...
. Lumen
stenosis Stenosis () is the abnormal narrowing of a blood vessel or other tubular organ or structure such as foramina and canals. It is also sometimes called a stricture (as in urethral stricture). ''Stricture'' as a term is usually used when narrowing ...
that is greater than 75% was considered the hallmark of clinically significant disease in the past because recurring episodes of Angina pectoris, angina and abnormalities in Cardiac stress test, 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. Most cardiovascular events that involve the sudden rupture of the atheroma plaque do not display any evident luminal narrowing. Thus, greater attention has been focused on "vulnerable plaque" since the late 1990s. 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 physiological measurement. Examples of anatomical detection methods include coronary calcium scoring by CT scan, CT, carotid IMT (Intima-media thickness, intimal media thickness) measurement by ultrasound, and intravascular imaging techniques, such as intravascular ultrasound (IVUS), and intravascular optical coherence tomography (OCT), allowing direct visualization of atherosclerotic plaques. Other methods include blood measurements, e.g., lipoprotein subclass analysis, Glycosylated hemoglobin, HbA1c, C-reactive protein, hs-CRP, and homocysteine. Both anatomic and physiologic methods allow early detection before symptoms appear, disease staging, and tracking of disease progression. In recent years, developments in Nuclear medicine, nuclear imaging techniques such as PET and SPECT have provided non-invasive 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 is generally achieved by eating a healthy diet, exercising, maintaining a normal weight, and not smoking.


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 Cardiovascular disease (CVD) is any disease involving the heart or blood vessels. CVDs constitute a class of diseases that includes: coronary artery diseases (e.g. angina, heart attack), heart failure, hypertensive heart disease, rheumati ...
. A diet rich 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). A 2024 review highlighted that bioactive compounds found in Mediterranean diet components (such as olive, grape, garlic, rosemary, and saffron) exhibit properties that may contribute to cardiovascular health and atherosclerosis prevention.


Exercise

A controlled exercise program combats atherosclerosis by improving the 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,
statin Statins (or HMG-CoA reductase inhibitors) are a class of medications that lower cholesterol. They are prescribed typically to people who are at high risk of cardiovascular disease. Low-density lipoprotein (LDL) carriers of cholesterol play ...
s help to lower cholesterol. Antiplatelet medications like aspirin help to prevent clots, and a variety of Antihypertensive drug, 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
statin Statins (or HMG-CoA reductase inhibitors) are a class of medications that lower cholesterol. They are prescribed typically to people who are at high risk of cardiovascular disease. Low-density lipoprotein (LDL) carriers of cholesterol play ...
s, blood pressure medication, or medications that decrease clotting, such as aspirin. Many procedures may also be carried out such as
percutaneous coronary intervention Percutaneous coronary intervention (PCI) is a minimally invasive non-surgical procedure used to treat stenosis, narrowing of the coronary artery, coronary arteries of the heart found in coronary artery disease. The procedure is used to place and ...
, coronary artery bypass graft, or
carotid endarterectomy Carotid endarterectomy is a surgical procedure used to reduce the risk of stroke from carotid artery stenosis (narrowing the internal carotid artery). In an endarterectomy, the surgeon opens the artery and removes the plaque. The plaque forms ...
. Medical treatments often focus on alleviating symptoms. However, measures that 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 more effective approaches is to combine 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 daily and indefinitely has generally produced better results, both before and especially after people are symptomatic.


Statins

Statin medications 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 a history of ASCVD (atherosclerotic cardiovascular disease) to prevent the 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. Inhibiting this rate-limiting enzyme reduces the body's ability to produce as much cholesterol endogenously, thereby reducing the level of LDL-cholesterol in the blood. 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-aged 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 Ischemia or ischaemia is a restriction in blood supply to any tissue, muscle group, or organ of the body, causing a shortage of oxygen that is needed for cellular metabolism (to keep tissue alive). Ischemia is generally caused by problems ...
, such as tissue loss in the case of
peripheral artery disease Peripheral artery disease (PAD) is a vascular disorder that causes abnormal narrowing of arteries other than those that supply the heart or brain. PAD can happen in any blood vessel, but it is more common in the legs than the arms. When narr ...
, surgery may be indicated. Vascular bypass, Vascular bypass surgery can re-establish flow around the diseased segment of the artery, and angioplasty with or without stenting can reopen narrowed arteries and improve blood flow. Coronary artery bypass surgery, 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 promote arterial calcification in the long term despite reducing clot formation in the short term. Also, small molecules such as 3-Hydroxybenzaldehyde, 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 country, developed countries have Aorta, aortic fatty streaks, with Coronary circulation, coronary fatty streaks beginning in adolescence.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 that examined the results of 300 autopsies performed on U.S. soldiers who had died in the
Korean War The Korean War (25 June 1950 – 27 July 1953) was an armed conflict on the Korean Peninsula fought between North Korea (Democratic People's Republic of Korea; DPRK) and South Korea (Republic of Korea; ROK) and their allies. North Korea was s ...
. 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 showed 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. A 2005 report of a study done between 1985 and 1995 found that around 87% of aortas and 30% of coronary arteries in the 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 Arteriosclerosis, literally meaning "hardening of the arteries", is an umbrella term for a vascular disorder characterized by abnormal thickening, hardening, and loss of elasticity of the walls of arteries; this process gradually restricts th ...
, 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 Atheroma, atheromatous plaque (). The term ''atherogenic'' is used for substances or processes that cause the formation of
atheroma An atheroma, or atheromatous plaque, is an abnormal accumulation of material in the tunica intima, inner layer of an arterial wall. The material consists of mostly macrophage, macrophage cells, or debris, containing lipids, calcium and a variabl ...
.


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 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 t ...
(HDL) on atherosclerosis has been with the rare ApoA-1 Milano, Apo-A1 Milano human genetic variant of this High-density lipoprotein, HDL protein. A small short-term trial using bacterial-synthesized human ApoA-1 Milano, 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 reverse and remove 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
macrophage Macrophages (; abbreviated MPhi, φ, MΦ or MP) are a type of white blood cell of the innate immune system that engulf and digest pathogens, such as cancer cells, microbes, cellular debris and foreign substances, which do not have proteins that ...
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 chain reaction in atherogenesis triggered research on the protective role of the heavy isotope (Deuterated drug, 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, a model for human-like lipoprotein metabolism, adding D-PUFAs to the diet 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 signal transduction pathway, insulin signaling and Blood sugar regulation, glucose homeostatis, cell type progression and proliferation, and Myelocyte, myeloid cell differentiation. It was found in rodents that the inhibition of miR-33 will raise HDL-C levels, 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 (Sterol regulatory element-binding protein 2, SREBP2) gene on chromosome 22 and intron 17 of Sterol regulatory element-binding protein 1, SREBP1 gene on chromosome 17. miR-33a/b regulates cholesterol/lipid homeostasis by binding in the Three prime untranslated region, 3'UTRs of genes involved in cholesterol transport such as ATP-binding cassette transporter, ATP binding cassette (ABC) transporters and enhance or represses its expression. Studies have shown that ABCA1 mediates cholesterol transport from peripheral tissues to Apolipoprotein-1. 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 before excretion. Therefore, ABCA1 prevents cholesterol accumulation in macrophages. By enhancing miR-33 function, the level of ABCA1 is decreased, leading to decreased cellular cholesterol efflux to apoA-1. On the other hand, by inhibiting miR-33 function, the level of ABCA1 is increased, which increases the cholesterol efflux to Apolipoprotein A1, apoA-1. Suppression of miR-33 will lead to less cellular cholesterol and higher plasma HDL level through the regulation of ABCA1 expression.


DNA damage

Aging 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 (naturally occurring), DNA damage in vascular aging. 8-Oxoguanine, 8-oxoG, a common type of oxidative damage in DNA, is found to accumulate in plaque
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 v ...
cells,
macrophage Macrophages (; abbreviated MPhi, φ, MΦ or MP) are a type of white blood cell of the innate immune system that engulf and digest pathogens, such as cancer cells, microbes, cellular debris and foreign substances, which do not have proteins that ...
s and endothelium, endothelial cells, thus linking DNA damage to plaque formation. DNA strand breaks also increased in atherosclerotic plaques. Werner syndrome (WS) is a premature aging condition in humans. WS is caused by a genetic defect in a RecQ helicase that is employed in several DNA repair, repair processes that remove damages from DNA. WS patients develop a considerable burden of atherosclerotic plaques in their Coronary circulation, coronary arteries and aorta: 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).


Microorganisms

The human microbiota, microbiota – all the microorganisms in the body, can contribute to atherosclerosis in many ways: modulation of the immune system, changes in metabolism, processing of nutrients and production of certain metabolites that can get into blood circulation. One such metabolite, produced by gut flora, gut bacteria, is trimethylamine N-oxide (TMAO). Its levels have been associated with atherosclerosis in human studies, and animal research suggests that there may be a causal relation. An association between the bacterial genes encoding trimethylamine lyases — the enzymes involved in TMAO generation — and atherosclerosis has been noted.


Vascular smooth muscle cells

Vascular smooth muscle, Vascular smooth muscle cells play a crucial role in atherogenesis and were historically considered to be beneficial for plaque stability by forming a protective fibrous cap and synthesizing strength-giving extracellular matrix 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
macrophage Macrophages (; abbreviated MPhi, φ, MΦ or MP) are a type of white blood cell of the innate immune system that engulf and digest pathogens, such as cancer cells, microbes, cellular debris and foreign substances, which do not have proteins that ...
s, myofibroblasts, mesenchymal stem cells 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.


Treatment research

The sugar cyclodextrin (CD) removed cholesterol that had built up in the arteries of mice fed a high-fat diet. CD is absorbed into the mouse bloodstream. It increases the production of oxysterols in macrophages and plaques, which causes the activation of liver X receptor, LXR in macrophages. This, in turn, causes the macrophages to be more capable of cholesterol efflux and makes them more anti-inflammatory.


Presence in other species

Atherosclerosis primarily affects herbivorous species. Carnivorous animals such as dogs, cats, lions, and tigers can consume diets high in saturated fat and cholesterol without developing atherosclerotic plaques, as demonstrated in various studies. Atherosclerosis can be experimentally induced in carnivorous animals only by thyroidectomy. Removal of the thyroid gland appears to alter lipid metabolism, rendering saturated fat and cholesterol atherogenic in these species, similar to the effect observed in herbivores.


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External links

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