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Atherosclerosis

Atherosclerosis

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Atherosclerosis (also known as Arteriosclerotic Vascular Disease or ASVD) is the condition in which an artery wall thickens as the result of a build-up of fatty materials such as cholesterol
Cholesterol
Cholesterol is a lipidic, waxy steroid found in the cell membranes and transported in the blood plasma of all animals. It is an essential component of mammalian cell membranes, where it is required to establish proper membrane permeability and fluidity...

. It is a syndrome
Syndrome
In medicine and psychology, the term syndrome refers to the association of several clinically recognizable features, signs , symptoms , phenomena or characteristics that often occur together, so that the presence of one feature alerts the physician to the presence of the others...

 affecting arterial
Artery
Arteries are blood vessels that carry blood away from the heart. All arteries, with the exception of the pulmonary and umbilical arteries, carry oxygenated blood.The circulatory system is extremely important for sustaining life...

 blood vessel
Blood vessel
The blood vessels are the part of the circulatory system that transport blood throughout the body. There are three major types of blood vessels: the arteries, which carry the blood away from the heart, the capillaries, which enable the actual exchange of water and chemicals between the blood and...

s, a chronic inflammatory response in the walls of arteries, in large part due to the accumulation of macrophage
Macrophage
Macrophages are white blood cells within tissues, produced by the division of monocytes. Human macrophages are about in diameter...

 white blood cells and promoted by low density (especially small particle) lipoproteins (plasma proteins that carry cholesterol
Cholesterol
Cholesterol is a lipidic, waxy steroid found in the cell membranes and transported in the blood plasma of all animals. It is an essential component of mammalian cell membranes, where it is required to establish proper membrane permeability and fluidity...

 and triglycerides) without adequate removal of fats and cholesterol from the macrophages by functional high density lipoprotein
High density lipoprotein
High-density lipoprotein is one of the five major groups of lipoproteins that enable lipids like cholesterol and triglycerides to be transported within the water-based bloodstream...

s (HDL), (see apoA-1 Milano
ApoA-1 Milano
ApoA-1 Milano is a naturally occurring mutated variant of the apolipoprotein A1 protein found in human HDL, the lipoprotein particle that carries cholesterol from tissues to the liver and is associated with protection against cardiovascular disease...

). It is commonly referred to as a hardening or furring of the arteries. It is caused by the formation of multiple plaques
Atheroma
In pathology, an atheroma is an accumulation and swelling in artery walls that is made up of cells , or cell debris, that contain lipids , calcium and a variable amount of fibrous connective tissue. In the context of heart or artery matters, atheromata are commonly referred to as atheromatous...

 within the arteries.

The atheromatous plaque
Atheroma
In pathology, an atheroma is an accumulation and swelling in artery walls that is made up of cells , or cell debris, that contain lipids , calcium and a variable amount of fibrous connective tissue. In the context of heart or artery matters, atheromata are commonly referred to as atheromatous...

is divided into three distinct components:
  1. The atheroma
    Atheroma
    In pathology, an atheroma is an accumulation and swelling in artery walls that is made up of cells , or cell debris, that contain lipids , calcium and a variable amount of fibrous connective tissue. In the context of heart or artery matters, atheromata are commonly referred to as atheromatous...

     ("lump of wax", from Athera, wax
    Wax
    Wax refers to beeswax or another substance with similar properties. The traditional meaning, beeswax, refers to a substance secreted by bees and used by them in constructing their honeycombs...

     in Greek,), which is the nodular accumulation of a soft, flaky, yellowish material at the center of large plaques, composed of macrophage
    Macrophage
    Macrophages are white blood cells within tissues, produced by the division of monocytes. Human macrophages are about in diameter...

    s nearest the lumen
    Lumen (anatomy)
    A lumen in biology is the inside space of a tubular structure, such as an artery or intestine...

     of the artery
  2. Underlying areas of cholesterol
    Cholesterol
    Cholesterol is a lipidic, waxy steroid found in the cell membranes and transported in the blood plasma of all animals. It is an essential component of mammalian cell membranes, where it is required to establish proper membrane permeability and fluidity...

     crystals
  3. Calcification at the outer base of older/more advanced lesions.


The following terms are similar, yet distinct, in both spelling and meaning, and can be easily confused: arteriosclerosis
Arteriosclerosis
Arteriosclerosis refers to a stiffening of arteries.Arteriosclerosis is a general term describing any hardening of medium or large arteries...

, arteriolosclerosis, and atherosclerosis. Arteriosclerosis is a general term describing any hardening (and loss of elasticity) of medium or large arteries (from the Greek Arterio, meaning artery, and sclerosis, meaning hardening); arteriolosclerosis is any hardening (and loss of elasticity) of arteriole
Arteriole
An arteriole is a small diameter blood vessel in the microcirculation that extends and branches out from an artery and leads to capillaries. Arterioles have thin muscular walls and are the primary site of vascular resistance...

s (small arteries); atherosclerosis is a hardening of an artery specifically due to an atheromatous plaque. Therefore, atherosclerosis is a form of arteriosclerosis.

Atherosclerosis, though typically asymptomatic for decades, eventually produces two main problems: First, the atheromatous plaques
Atheroma
In pathology, an atheroma is an accumulation and swelling in artery walls that is made up of cells , or cell debris, that contain lipids , calcium and a variable amount of fibrous connective tissue. In the context of heart or artery matters, atheromata are commonly referred to as atheromatous...

, though long compensated for by artery enlargement (see IMT
Intima-media thickness
Intima-media thickness , also called intimal medial thickness, is a measurement of the thickness of artery walls, usually by external ultrasound, occasionally by internal, invasive ultrasound catheters, see IVUS, to both detect the presence and to track the progression of atherosclerotic disease in...

), eventually lead to plaque ruptures
Vulnerable plaque
A vulnerable plaque is an atheromatous plaque, an unstable collection of white blood cells and lipids in the wall of an artery which is particularly prone to produce sudden major problems, such as a heart attack or stroke.In many cases, a vulnerable plaque has a thin fibrous cap and a large and...

 and clots inside the artery lumen
Lumen (anatomy)
A lumen in biology is the inside space of a tubular structure, such as an artery or intestine...

 over the ruptures. The clots heal and usually shrink but leave behind stenosis
Stenosis
A stenosis is an abnormal narrowing in a blood vessel or other tubular organ or structure.It is also sometimes called a "stricture" ....

 (narrowing) of the artery (both locally and in smaller downstream branches), or worse, complete closure, and, therefore, an insufficient blood supply to the tissues and organ it feeds. Second, if the compensating artery enlargement process is excessive, then a net aneurysm
Aneurysm
An aneurysm or aneurism , is a localized, blood-filled dilation of a blood vessel caused by disease or weakening of the vessel wall....

 results.

These complications of advanced atherosclerosis are chronic, slowly progressive and cumulative. Most commonly, soft plaque suddenly ruptures (see vulnerable plaque
Vulnerable plaque
A vulnerable plaque is an atheromatous plaque, an unstable collection of white blood cells and lipids in the wall of an artery which is particularly prone to produce sudden major problems, such as a heart attack or stroke.In many cases, a vulnerable plaque has a thin fibrous cap and a large and...

), causing the formation of a thrombus
Thrombus
A thrombus , or blood clot, is the final product of the blood coagulation step in hemostasis. It is achieved via the aggregation of platelets that form a platelet plug, and the activation of the humoral coagulation system...

 that will rapidly slow or stop blood flow, leading to death of the tissues fed by the artery in approximately 5 minutes. This catastrophic event is called an infarction
Infarction
In medicine, an infarction is the process of tissue death caused by blockage of the tissue's blood supply. The supplying artery may be blocked by an obstruction , may be mechanically compressed , ruptured by trauma , or vasoconstricted In medicine, an infarction is the process of tissue death...

. One of the most common recognized scenarios is called coronary thrombosis
Coronary thrombosis
Coronary thrombosis is a form of thrombosis affecting the coronary circulation. It is associated with stenosis subsequent to clotting. The condition is considered as a type of ischaemic heart disease.It can lead to a myocardial infarction...

 of a coronary artery, causing myocardial infarction
Myocardial infarction
Myocardial infarction or acute myocardial infarction , commonly known as a heart attack, is the interruption of blood supply to part of the heart, causing some heart cells to die...

 (a heart attack). Even worse is the same process in an artery to the brain, commonly called stroke
Stroke
A stroke is the rapidly developing loss of brain function due to disturbance in the blood supply to the brain. This can be due to ischemia caused by thrombosis or embolism or due to a hemorrhage...

. Another common scenario in very advanced disease is claudication
Claudication
Claudication, literally 'limping' , is used as a medical term to indicate impairment in walking.- Intermittent vascular claudication :...

 from insufficient blood supply to the legs, typically due to a combination of both stenosis and aneurysmal segments narrowed with clots
Thrombus
A thrombus , or blood clot, is the final product of the blood coagulation step in hemostasis. It is achieved via the aggregation of platelets that form a platelet plug, and the activation of the humoral coagulation system...

. Since atherosclerosis is a body-wide process, similar events occur also in the arteries to the brain, intestines, kidneys, legs, etc.

Yet, many infarctions involve only very small amounts of tissue and are termed clinically silent, because the person having the infarction does not notice the problem, does not seek medical help or when they do, physicians do not recognize what has happened.

Causes


Atherosclerosis develops from low-density lipoprotein molecules (LDL) becoming oxidized (ldl-ox) by free radicals, particularly oxygen free radicals (ROS). When oxidized LDL comes in contact with an artery wall, a series of reactions occur to repair the damage to the artery wall caused by oxidized LDL. The LDL molecule is globular shaped with a hollow core to carry cholesterol throughout the body to generate brain tissues, vitamin D, and so on. Cholesterol does not dissolve in water. Blood is 70% water. Cholesterol can move in the bloodstream only by being transported by LDL.

The body's immune system responds to the damage to the artery wall caused by oxidized LDL by sending specialized white blood cells (macrophages and T-lymphocytes) to absorb the oxidized-LDL forming specialized foam cells
Foam cells
Foam cells are cells in an atheroma derived from both macrophages and smooth muscle cells which have accumulated low density lipoproteins, LDLs, by endocytosis. The LDL has crossed the endothelial barrier and has been oxidized by reactive oxygen species produced by the endothelial cells...

. Unfortunately, these white blood cells are not able to process the oxidized-LDL, and ultimately grow then rupture, depositing a greater amount of oxidized cholesterol into the artery wall. This triggers more white blood cells, continuing the cycle.

Eventually, the artery becomes inflamed. The cholesterol plaque causes the muscle cells to enlarge and form a hard cover over the affected area. This hard cover is what causes a narrowing of the artery, reduces the blood flow and increases blood pressure.

Some researchers believe that atherosclerosis may be caused by an infection of the vascular smooth muscle cells. Chickens, for example, develop atherosclerosis when infected with the Marek's disease
Marek's disease
Marek's disease is a highly contagious viral neoplastic disease in chickens. Occasionally misdiagnosed as an abtissue pathology it is caused by an alphaherpesvirus known as Marek's disease virus or gallid herpesvirus 2 . The disease is characterized by presence of T cell lymphoma as well as...

 herpesvirus. Herpesvirus infection of arterial smooth muscle cells has been shown to cause cholesteryl ester (CE) accumulation. Cholesteryl ester
Cholesteryl ester
A cholesteryl ester is, as its name would imply, an ester of cholesterol. The ester bond is formed between the carboxylate group of a fatty acid and the hydroxyl group of cholesterol. Cholesteryl Esters have a lower solubility in water than Cholesterol...

 accumulation is associated with atherosclerosis.

Also, cytomegalovirus
Cytomegalovirus
Cytomegalovirus is a herpes viral genus of the Herpesviruses group: in humans it is commonly known as HCMV or Human Herpesvirus 5 . CMV belongs to the Betaherpesvirinae subfamily of Herpesviridae, which also includes Roseolovirus...

 (CMV) infection is associated with cardiovascular diseases.

Symptoms


Atherosclerosis typically begins in early adolescence, and is usually found in most major arteries
Artery
Arteries are blood vessels that carry blood away from the heart. All arteries, with the exception of the pulmonary and umbilical arteries, carry oxygenated blood.The circulatory system is extremely important for sustaining life...

, yet is asymptomatic and not detected by most diagnostic methods during life. Atheroma in arm, or more often in leg arteries, which produces decreased blood flow is called peripheral artery occlusive disease
Peripheral artery occlusive disease
Peripheral vascular disease , also known as peripheral artery disease or peripheral artery occlusive disease , includes all diseases caused by the obstruction of large arteries in the arms and legs. PVD can result from atherosclerosis, inflammatory processes leading to stenosis, an embolism or...

 (PAOD).

According to United States data for the year 2004, for about 65% of men and 47% of women, the first symptom
Symptom
A symptom is a departure from normal function or feeling which is noticed by a patient, indicating the presence of disease or abnormality...

 of atherosclerotic cardiovascular disease
Cardiovascular disease
Cardiovascular disease or cardiovascular diseases is the class of diseases that involve the heart or blood vessels ....

 is heart attack
Myocardial infarction
Myocardial infarction or acute myocardial infarction , commonly known as a heart attack, is the interruption of blood supply to part of the heart, causing some heart cells to die...

 or sudden cardiac death
Sudden Cardiac Death
The term sudden cardiac death refers to natural death from cardiac causes, heralded by abrupt loss of consciousness within one hour of the onset of acute symptoms. Other forms of sudden death may be noncardiac in origin...

 (death within one hour of onset of the symptom).

Most artery flow disrupting events occur at locations with less than 50% lumen
Lumen (anatomy)
A lumen in biology is the inside space of a tubular structure, such as an artery or intestine...

 narrowing (~20% stenosis
Stenosis
A stenosis is an abnormal narrowing in a blood vessel or other tubular organ or structure.It is also sometimes called a "stricture" ....

 is average). [The reader might reflect that the illustration above, like most illustrations of arterial disease, overemphasizes lumen narrowing, as opposed to compensatory external diameter enlargement (at least within smaller arteries, e.g., heart arteries) typical of the atherosclerosis process as it progresses, see Glagov and the ASTEROID trial, the IVUS photographs on page 8, as examples for a more accurate understanding. The relative geometry error within the illustration is common to many older illustrations, an error slowly being more commonly recognized within the last decade.]

Cardiac stress test
Cardiac stress test
A cardiac stress test is a medical test that indirectly reflects arterial blood flow to the heart during physical exercise. When compared to blood flow during rest, the test reflects imbalances of blood flow to the heart's left ventricular muscle tissue – the part of the heart that performs the...

ing, traditionally the most commonly performed non-invasive testing method for blood flow limitations, in general, detects only lumen
Lumen (anatomy)
A lumen in biology is the inside space of a tubular structure, such as an artery or intestine...

 narrowing of ~75% or greater, although some physicians claim that nuclear stress methods can detect as little as 50%.

Atherogenesis


Atherogenesis is the developmental process of atheromatous plaques. It is characterized by a remodeling of arteries
Artery
Arteries are blood vessels that carry blood away from the heart. All arteries, with the exception of the pulmonary and umbilical arteries, carry oxygenated blood.The circulatory system is extremely important for sustaining life...

 involving the concomitant accumulation of fatty substances called plaques. One recent theory suggests that, for unknown reasons, leukocytes, such as monocytes or basophils, begin to attack the endothelium
Endothelium
The endothelium is the thin layer of cells that line the interior surface of blood vessels, forming an interface between circulating blood in the lumen and the rest of the vessel wall. Endothelial cells line the entire circulatory system, from the heart to the smallest capillary...

 of the artery lumen in cardiac muscle
Cardiac muscle
Cardiac muscle is a type of involuntary striated muscle found in the walls of the heart, specifically the myocardium. Cardiac muscle cells are known as cardiac myocytes . Cardiac muscle is one of three major types of muscle, the others being skeletal and smooth muscle...

. The ensuing inflammation
Inflammation
Inflammation is the complex biological response of vascular tissues to harmful stimuli, such as pathogens, damaged cells, or irritants. Inflammation is a protective attempt by the organism to remove the injurious stimuli as well as initiate the healing process for the tissue. Inflammation is not a...

 leads to formation of atheromatous plaques in the arterial tunica intima
Tunica intima
The tunica intima is the innermost layer of an artery or vein. It is made up of one layer of endothelial cells and is supported by an internal elastic lamina...

, a region of the vessel wall located between the endothelium
Endothelium
The endothelium is the thin layer of cells that line the interior surface of blood vessels, forming an interface between circulating blood in the lumen and the rest of the vessel wall. Endothelial cells line the entire circulatory system, from the heart to the smallest capillary...

 and the tunica media
Tunica media
The tunica media is the middle layer of an artery or vein.-Artery:It is made up of smooth muscle cells and elastic tissue...

. The bulk of these lesions is made of excess fat, collagen
Collagen
Collagen is the main protein of connective tissue in animals and the most abundant protein in mammals, making up about 25% to 35% of the whole-body protein content. It is naturally found exclusively in metazoa, including sponges. In muscle tissue it serves as a major component of endomysium...

, and elastin
Elastin
Elastin is a protein in connective tissue that is elastic and allows many tissues in the body to resume their shape after stretching or contracting. Elastin helps skin to return to its original position when it is poked or pinched...

. At first, as the plaques grow, only wall thickening
Intima-media thickness
Intima-media thickness , also called intimal medial thickness, is a measurement of the thickness of artery walls, usually by external ultrasound, occasionally by internal, invasive ultrasound catheters, see IVUS, to both detect the presence and to track the progression of atherosclerotic disease in...

 occurs without any narrowing, stenosis of the artery opening, called the lumen; stenosis
Stenosis
A stenosis is an abnormal narrowing in a blood vessel or other tubular organ or structure.It is also sometimes called a "stricture" ....

 is a late event, which may never occur and is often the result of repeated plaque rupture and healing responses, not just the atherosclerosis process by itself.

A 4 minute animation of the atherosclerosis process, entitled "Pathogenesis of Acute MI", commissioned by Paul M. Ridker, MD, MPH, FACC, FAHA, at the Harvard Medical School, can be viewed at pri-med.com http://www.pri-med.com/pmo/Home.aspx. While the animation contains a few technical errors, partly due to the great difficulty/complexity of making a truly accurate presentation, it is better than most and correctly illustrates the principal issues.

Cellular



The first step of atherogenesis is the development of so called "fatty streak
Fatty streak
Fatty streak, though composed of macrophage white blood cells, not fat, is the term generally given to the earliest stages of atheroma, as viewed at autopsy, looking at the inner surface of arteries, without magnification....

"s, which are small sub-endothelial deposits of monocyte-derived macrophages. The primary documented driver of this process is oxidized Lipoprotein particles within the wall, beneath the endothelial
Endothelium
The endothelium is the thin layer of cells that line the interior surface of blood vessels, forming an interface between circulating blood in the lumen and the rest of the vessel wall. Endothelial cells line the entire circulatory system, from the heart to the smallest capillary...

 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 particles in blood plasma, when they invade the endothelium
Endothelium
The endothelium is the thin layer of cells that line the interior surface of blood vessels, forming an interface between circulating blood in the lumen and the rest of the vessel wall. Endothelial cells line the entire circulatory system, from the heart to the smallest capillary...

 and become oxidized creates a risk for cardiovascular disease
Cardiovascular disease
Cardiovascular disease or cardiovascular diseases is the class of diseases that involve the heart or blood vessels ....

. A complex set of biochemical reactions regulates the oxidation of LDL, chiefly stimulated by presence of enzymes, e.g. Lp-LpA2
Lp-LpA2
Lipoprotein Associated Phospholipase A2 has been identified and verified in multiple human trials as an enzymatic activity which is an independent predictor of atherosclotic disease progression and events in humans, including coronary heart disease, because it promotes oxidation of lipoproteins and...

 and free radicals in the endothelium
Endothelium
The endothelium is the thin layer of cells that line the interior surface of blood vessels, forming an interface between circulating blood in the lumen and the rest of the vessel wall. Endothelial cells line the entire circulatory system, from the heart to the smallest capillary...

 or blood vessel lining.

The initial damage to the blood vessel wall results in a "call for help," an inflammatory response. Monocyte
Monocyte
Monocyte is a type of white blood cell, part of the human body's immune system. Monocytes have two main functions in the immune system: replenish resident macrophages and dendritic cells under normal states, and in response to inflammation signals, monocytes can move quickly Monocyte is a type of...

s (a type of white blood cell
White blood cell
White blood cells , or leukocytes , are cells of the immune system defending the body against both infectious disease and foreign materials. Five different and diverse types of leukocytes exist, but they are all produced and derived from a multipotent cell in the bone marrow known as a...

) enter the artery wall from the bloodstream, with platelets adhering to the area of insult. This may be promoted by redox signaling
Redox signaling
Redox signaling is the process wherein free radicals, reactive oxygen species , and other electronically-activated species act as messengers in biological systems.-History:...

 induction of factors such as VCAM-1
VCAM-1
VCAM-1 , also known as CD106, is the name of both a human gene and its protein product which have a considerable role in the human immune system.-Structure:...

, which recruit circulating monocytes. The monocyte
Monocyte
Monocyte is a type of white blood cell, part of the human body's immune system. Monocytes have two main functions in the immune system: replenish resident macrophages and dendritic cells under normal states, and in response to inflammation signals, monocytes can move quickly Monocyte is a type of...

s differentiate macrophage
Macrophage
Macrophages are white blood cells within tissues, produced by the division of monocytes. Human macrophages are about in diameter...

s, which ingest oxidized LDL, slowly turning into large "foam cells" – so-described because of their changed appearance resulting from the numerous internal cytoplasmic vesicle
Vesicle (biology)
A vesicle is a bubble of liquid within a cell. More technically, a vesicle is a small, intracellular, membrane-enclosed sac that stores or transports substances within a cell. Vesicles form naturally because of the properties of lipid membranes ...

s and resulting high lipid
Lipid
Lipids are a broad group of naturally-occurring molecules which includes fats, waxes, sterols, fat-soluble vitamins , monoglycerides, diglycerides, phospholipids, and others...

 content. Under the microscope, the lesion now appears as a fatty streak. Foam cells eventually die, and further propagate the inflammatory process.
There is also smooth muscle proliferation and migration from tunica media to intima responding to cytokines secreted by damaged endothelial cells. This would cause the formation of a fibrous capsule covering the fatty streak.

Calcification and lipids


Intracellular microcalcifications
Calcification
Calcification is the process in which calcium salts build up in soft tissue, causing it to harden. Calcifications may be classified on whether there is mineral balance or not, and the location of the calcification.-Mineral balance:...

 form within vascular smooth muscle
Vascular smooth muscle
Vascular smooth muscle refers to the particular type of smooth muscle found within, and composing the majority of the wall of blood vessels.Vascular smooth muscle contracts or relaxes to both change the volume of blood vessels and the local blood pressure, a mechanism that is responsible for the...

 cells of the surrounding muscular layer, specifically in the muscle cells adjacent to the atheromas. In time, as cells die, this leads to extracellular calcium deposits between the muscular wall and outer portion of the atheromatous plaques. A similar form of an intramural calcification, presenting the picture of an early phase of arteriosclerosis, appears to be induced by a number of drugs that have an antiproliferative mechanism of action (Rainer Liedtke
Rainer Liedtke
Rainer K. Liedtke is a German physician, scientist and entrepreneur. Theory and practice of biomedical information systems and medical innovation...

 2008).

Cholesterol is delivered into the vessel wall by cholesterol-containing low-density lipoprotein (LDL) particles. To attract and stimulate macrophages, the cholesterol must be released from the LDL particles and oxidized, a key step in the ongoing inflammatory process. The process is worsened if there is insufficient high-density lipoprotein (HDL), the lipoprotein particle that removes cholesterol from tissues and carries it back to the liver.

The foam cells and platelets encourage the migration and proliferation of smooth muscle
Smooth muscle
Smooth muscle is an involuntary non-striated muscle, found within the tunica media layer of large and small arteries and veins, the bladder, uterus, male and female reproductive tracts, gastrointestinal tract, respiratory tract, arrector pili of skin, the ciliary muscle, and iris of...

 cells, which in turn ingest lipids, become replaced by collagen and transform into foam cells themselves. A protective fibrous cap normally forms between the fatty deposits and the artery lining (the intima
Endothelium
The endothelium is the thin layer of cells that line the interior surface of blood vessels, forming an interface between circulating blood in the lumen and the rest of the vessel wall. Endothelial cells line the entire circulatory system, from the heart to the smallest capillary...

).

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
A stenosis is an abnormal narrowing in a blood vessel or other tubular organ or structure.It is also sometimes called a "stricture" ....

") 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
Aneurysm
An aneurysm or aneurism , is a localized, blood-filled dilation of a blood vessel caused by disease or weakening of the vessel wall....

 is created.

Visible features



Although arteries are not typically studied microscopically, two plaque types can be distinguishedhttp://www.pathologyatlas.ro/coronary-atherosclerosis-fibrous-plaque.php:
  1. The fibro-lipid (fibro-fatty) plaque is characterized by an accumulation of lipid-laden cells underneath the intima of the arteries, typically without narrowing the lumen due to compensatory expansion of the bounding muscular layer of the artery wall. Beneath the endothelium there is a "fibrous cap" covering the atheromatous "core" of the plaque. The core consists of lipid-laden cells (macrophages and smooth muscle cells) with elevated tissue cholesterol and cholesterol ester content, fibrin, proteoglycans, collagen, elastin, and cellular debris. In advanced plaques, the central core of the plaque usually contains extracellular cholesterol deposits (released from dead cells), which form areas of cholesterol crystals with empty, needle-like clefts. At the periphery of the plaque are younger "foamy" cells and capillaries. These plaques usually produce the most damage to the individual when they rupture.
  2. The fibrous plaque is also localized under the intima, within the wall of the artery resulting in thickening and expansion of the wall and, sometimes, spotty localized narrowing of the lumen with some atrophy of the muscular layer. The fibrous plaque contains collagen fibers (eosinophilic), precipitates of calcium (hematoxylinophilic) and, rarely, lipid-laden cells.


In effect, the muscular portion of the artery wall forms small aneurysm
Aneurysm
An aneurysm or aneurism , is a localized, blood-filled dilation of a blood vessel caused by disease or weakening of the vessel wall....

s just large enough to hold the atheroma
Atheroma
In pathology, an atheroma is an accumulation and swelling in artery walls that is made up of cells , or cell debris, that contain lipids , calcium and a variable amount of fibrous connective tissue. In the context of heart or artery matters, atheromata are commonly referred to as atheromatous...

 that are present. The muscular portion of artery walls usually remain strong, even after they have remodeled to compensate for the atheroma
Atheroma
In pathology, an atheroma is an accumulation and swelling in artery walls that is made up of cells , or cell debris, that contain lipids , calcium and a variable amount of fibrous connective tissue. In the context of heart or artery matters, atheromata are commonly referred to as atheromatous...

tous plaques.

However, atheroma
Atheroma
In pathology, an atheroma is an accumulation and swelling in artery walls that is made up of cells , or cell debris, that contain lipids , calcium and a variable amount of fibrous connective tissue. In the context of heart or artery matters, atheromata are commonly referred to as atheromatous...

s 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
Computed tomography
Computed tomography is a medical imaging method employing tomography created by computer processing. Digital geometry processing is used to generate a three-dimensional image of the inside of an object from a large series of two-dimensional X-ray images taken around a single axis of rotation.CT...

 or electron beam tomography
Electron beam tomography
Electron beam tomography is a specific form of computed tomography in which the X-ray tube is not mechanically spun in order to rotate the source of X-ray photons...

 (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
Hounsfield scale
The Hounsfield scale, named after Sir Godfrey Newbold Hounsfield, is a quantitative scale for describing radiodensity.-Definition:The Hounsfield unit scale is a linear transformation of the original linear attenuation coefficient measurement in one in which the radiodensity of distilled water at...

 (some argue for 90 units) has been the radiographic density usually accepted as clearly representing tissue calcification within arteries. These deposits demonstrate unequivocal evidence of the disease, relatively advanced, even though the lumen of the artery is often still normal by angiographic or intravascular ultrasound
Intravascular ultrasound
Intravascular ultrasound is a medical imaging methodology using a specially designed catheter with a miniaturized ultrasound probe attached to the distal end of the catheter. The proximal end of the catheter is attached to computerized ultrasound equipment...

.

Rupture and stenosis


Although the disease process tends to be slowly progressive over decades, it usually remains asymptomatic until an atheroma ulcerates which leads to immediate blood clotting at the site of atheroma ulcer. This triggers a cascade of events that leads to clot enlargement which may quickly obstruct the lumen (opening) of the artery itself. 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
A stenosis is an abnormal narrowing in a blood vessel or other tubular organ or structure.It is also sometimes called a "stricture" ....

 or closure of the lumen, or over time and after repeated ruptures, resulting in a persistent, usually localized stenosis or blockage of the artery lumen. Stenoses can be slowly progressive, whereas plaque ulceration is a sudden event that occurs specifically in atheromas with thinner/weaker fibrous caps that have become "unstable."

Repeated plaque ruptures, ones not resulting in total lumen closure, combined with the clot patch over the rupture and healing response to stabilize the clot, is the process that produces most stenoses over time. The stenotic areas tend to become more stable, despite increased flow velocities at these narrowings. Most major blood-flow-stopping events occur at large plaques, which, prior to their rupture, produced very little if any stenosis.

From clinical trials, 20% is the average stenosis at plaques that subsequently rupture with resulting complete artery closure. Most severe clinical events do not occur at plaques that produce high-grade stenosis. From clinical trials, only 14% of heart attacks occur from artery closure at plaques producing a 75% or greater stenosis prior to the vessel closing.

If the fibrous cap separating a soft atheroma from the bloodstream within the artery ruptures, tissue fragments are exposed and released, and blood enters the atheroma within the wall and sometimes results in a sudden expansion of the atheroma size. Tissue fragments are very clot-promoting, containing collagen
Collagen
Collagen is the main protein of connective tissue in animals and the most abundant protein in mammals, making up about 25% to 35% of the whole-body protein content. It is naturally found exclusively in metazoa, including sponges. In muscle tissue it serves as a major component of endomysium...

 and tissue factor
Tissue factor
Tissue factor, also called factor III or CD142 is a protein present in subendothelial tissue, platelets, and leukocytes necessary for the initiation of thrombin formation from the zymogen prothrombin. An incorrect synonym is thromboplastin. Historically, thromboplastin was a lab reagent, usually...

; they activate platelet
Platelet
Platelets, or thrombocytes , are small, irregularly-shaped anuclear cells , 2-3 µm in diameter, which are derived from fragmentation of precursor megakaryocytes.  The average lifespan of a platelet is between 8 and 12 days...

s and activate the system of coagulation
Coagulation
Coagulation is a complex process by which blood forms clots. It is an important part of hemostasis , wherein a damaged blood vessel wall is covered by a platelet and fibrin-containing clot to stop bleeding and begin repair of the damaged vessel...

. The result is the formation of a thrombus
Thrombus
A thrombus , or blood clot, is the final product of the blood coagulation step in hemostasis. It is achieved via the aggregation of platelets that form a platelet plug, and the activation of the humoral coagulation system...

 (blood clot) overlying the atheroma, which obstructs blood flow acutely. With the obstruction of blood flow, downstream tissues are starved of oxygen
Oxygen
Oxygen Oxygen Oxygen (acid, literally "sharp", from the taste of acids) and -γενής (-genēs) (producer, literally begetter) is the element with atomic number 8 and represented by the symbol O...

 and nutrients. If this is the myocardium (heart muscle), angina (cardiac chest pain) or myocardial infarction
Myocardial infarction
Myocardial infarction or acute myocardial infarction , commonly known as a heart attack, is the interruption of blood supply to part of the heart, causing some heart cells to die...

 (heart attack) develops.

Diagnosis of plaque-related disease



Areas of severe narrowing, stenosis
Stenosis
A stenosis is an abnormal narrowing in a blood vessel or other tubular organ or structure.It is also sometimes called a "stricture" ....

, detectable by angiography, and to a lesser extent "stress testing
Stress testing
Stress testing is a form of testing that is used to determine the stability of a given system or entity. It involves testing beyond normal operational capacity, often to a breaking point, in order to observe the results...

" have long been the focus of human diagnostic techniques for cardiovascular disease
Cardiovascular disease
Cardiovascular disease or cardiovascular diseases is the class of diseases that involve the heart or blood vessels ....

, in general. However, these methods focus on detecting only severe narrowing
Stenosis
A stenosis is an abnormal narrowing in a blood vessel or other tubular organ or structure.It is also sometimes called a "stricture" ....

, 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
Stenosis
A stenosis is an abnormal narrowing in a blood vessel or other tubular organ or structure.It is also sometimes called a "stricture" ....

 present before debilitating events suddenly occur. Plaque rupture can lead to artery lumen occlusion within seconds to minutes, and potential permanent debility and sometimes sudden death.

Plaques that have ruptured are called complicated plaques. The lipid matrix breaks through the thinning collagen
Collagen
Collagen is the main protein of connective tissue in animals and the most abundant protein in mammals, making up about 25% to 35% of the whole-body protein content. It is naturally found exclusively in metazoa, including sponges. In muscle tissue it serves as a major component of endomysium...

 gap and when the lipids come in contact with the blood, clotting occurs. After rupture the platelet adhesion causes the clotting cascade to contact with the lipid pool causing a thrombus
Thrombus
A thrombus , or blood clot, is the final product of the blood coagulation step in hemostasis. It is achieved via the aggregation of platelets that form a platelet plug, and the activation of the humoral coagulation system...

 to form. This thrombus will eventually grow and travel throughout the body. The thrombus
Thrombus
A thrombus , or blood clot, is the final product of the blood coagulation step in hemostasis. It is achieved via the aggregation of platelets that form a platelet plug, and the activation of the humoral coagulation system...

 will travel through different arteries and veins and eventually become lodged in an area that narrows. Once the area is blocked, blood and oxygen
Oxygen
Oxygen Oxygen Oxygen (acid, literally "sharp", from the taste of acids) and -γενής (-genēs) (producer, literally begetter) is the element with atomic number 8 and represented by the symbol O...

 will not be able to supply the vessels and will cause death of cells and lead to necrosis
Necrosis
Necrosis is the premature death of cells and living tissue. Necrosis is caused by external factors, such as infection, toxins , or trauma. This is in contrast to apoptosis, which is a naturally occurring cause of cellular death...

 and poisoning. Serious complicated plaques can cause death of organ tissues, causing serious complications to that organ system.

Greater than 75% lumen stenosis
Stenosis
A stenosis is an abnormal narrowing in a blood vessel or other tubular organ or structure.It is also sometimes called a "stricture" ....

 used to be considered by cardiologists as the hallmark of clinically significant disease because it is typically only at this severity of narrowing of the larger heart arteries that recurring episodes of angina and detectable abnormalities by stress test
Stress test
Stress test may refer to:*Stress Test , an episode of Brandy and Mr Whiskers*Stress testing, a form of testing that is used to determine the stability of a given system or entity*Stress testing , determines the robustness of software...

ing methods are seen.
However, clinical trials have shown that only about 14% of clinically-debilitating events occur at locations with this, or greater severity of narrowing
Stenosis
A stenosis is an abnormal narrowing in a blood vessel or other tubular organ or structure.It is also sometimes called a "stricture" ....

.
The majority of events occur due to atheroma plaque rupture at areas without narrowing
Stenosis
A stenosis is an abnormal narrowing in a blood vessel or other tubular organ or structure.It is also sometimes called a "stricture" ....

 sufficient enough to produce any angina or stress test
Stress test
Stress test may refer to:*Stress Test , an episode of Brandy and Mr Whiskers*Stress testing, a form of testing that is used to determine the stability of a given system or entity*Stress testing , determines the robustness of software...

 abnormalities.
Thus, since the later-1990s, greater attention is being focused on the "vulnerable plaque."

Though any artery in the body can be involved, usually only severe narrowing
Stenosis
A stenosis is an abnormal narrowing in a blood vessel or other tubular organ or structure.It is also sometimes called a "stricture" ....

 or obstruction of some arteries, those that supply more critically-important organs are recognized. Obstruction of arteries supplying the heart muscle result in a heart attack
Myocardial infarction
Myocardial infarction or acute myocardial infarction , commonly known as a heart attack, is the interruption of blood supply to part of the heart, causing some heart cells to die...

. Obstruction of arteries supplying the brain result in a stroke
Stroke
A stroke is the rapidly developing loss of brain function due to disturbance in the blood supply to the brain. This can be due to ischemia caused by thrombosis or embolism or due to a hemorrhage...

. These events are life-changing, and often result in irreversible loss of function because lost heart muscle and brain cells do not grow back to any significant extent, typically less than 2%.

Over the last couple of decades, methods other than angiography and stress-testing have been increasingly developed as ways to better detect atherosclerotic disease before it becomes symptomatic. These have included both (a) anatomic detection methods and (b) physiologic measurement methods.

Examples of anatomic methods include: (1) coronary calcium scoring by CT, (2) carotid IMT (intimal media thickness
Intima-media thickness
Intima-media thickness , also called intimal medial thickness, is a measurement of the thickness of artery walls, usually by external ultrasound, occasionally by internal, invasive ultrasound catheters, see IVUS, to both detect the presence and to track the progression of atherosclerotic disease in...

) measurement by ultrasound, and (3) IVUS.

Examples of physiologic methods include: (1) lipoprotein subclass analysis, (2) HbA1c
Glycosylated hemoglobin
Glycated hemoglobin is a form of hemoglobin used primarily to identify the average plasma glucose concentration over prolonged periods of time. It is formed in a non-enzymatic pathway by hemoglobin's normal exposure to high plasma levels of glucose...

, (3) hs-CRP
C-reactive protein
C-reactive protein is a protein found in the blood, the levels of which rise in response to inflammation ....

, and (4) homocysteine
Homocysteine
Homocysteine is an amino acid with the formula HSCH2CH2CHCO2H. It is a homologue of the amino acid cysteine, differing by an additional methylene group. It is biosynthesized from methionine by the removal of its terminal Cε methyl group...

.

The example of the metabolic syndrome combines both anatomic (abdominal girth) and physiologic (blood pressure, elevated blood glucose) methods.

Advantages of these two approaches: The anatomic methods directly measure some aspect of the actual atherosclerotic disease process itself, thus offer potential for earlier detection, including before symptoms start, disease staging and tracking of disease progression. The physiologic methods are often less expensive and safer and changing them for the better may slow disease progression, in some cases with marked improvement.

Disadvantages of these two approaches: The anatomic methods are generally more expensive and several are invasive, such as IVUS. The physiologic methods do not quantify the current state of the disease or directly track progression. For both, clinicians and third party payers have been slow to accept the usefulness of these newer approaches.

Physiologic factors that increase risk


Various anatomic, physiological & behavioral risk factors for atherosclerosis are known.
These can be divided into various categories: congenital vs acquired, modifiable or not, classical or non-classical. The points labelled '+' in the following list form the core components of "metabolic syndrome
Metabolic syndrome
Metabolic syndrome is a combination of medical disorders that increase the risk of developing cardiovascular disease and diabetes. It affects one in five people, and prevalence increases with age...

".

Factors add to each other multiplicatively, with two factors increasing the risk of atherosclerosis fourfold. Hyperlipidemia, hypertension and cigarette smoking together increases the risk seven times.

Modifiable

  • Having diabetes or Impaired glucose tolerance
    Impaired glucose tolerance
    Impaired Glucose Tolerance is a pre-diabetic state of dysglycemia, that is associated with insulin resistance and increased risk of cardiovascular pathology. IGT may precede type 2 diabetes mellitus by many years...

     (IGT) +
  • Dyslipoproteinemia
    Lipoprotein
    A lipoprotein is a biochemical assembly that contains both proteins and lipids. The lipids or their derivatives may be covalently or non-covalently bound to the proteins. Many enzymes, transporters, structural proteins, antigens, adhesins and toxins are lipoproteins...

    (unhealthy patterns of serum proteins carrying fats & cholesterol
    Cholesterol
    Cholesterol is a lipidic, waxy steroid found in the cell membranes and transported in the blood plasma of all animals. It is an essential component of mammalian cell membranes, where it is required to establish proper membrane permeability and fluidity...

    ): +
    • High serum concentration of low-density lipoprotein (LDL, "bad if elevated concentrations and small"), and / or very low density lipoprotein
      Very low density lipoprotein
      Very-low-density lipoprotein is a type of lipoprotein made by the liver. VLDL is one of the five major groups of lipoproteins that enable fats and cholesterol to move within the water-based solution of the bloodstream...

       (VLDL) particles, i.e., "lipoprotein subclass analysis"
    • Low serum concentration of functioning high density lipoprotein
      High density lipoprotein
      High-density lipoprotein is one of the five major groups of lipoproteins that enable lipids like cholesterol and triglycerides to be transported within the water-based bloodstream...

       (HDL "protective if large and high enough" particles), i.e., "lipoprotein subclass analysis"
    • An LDL:HDL ratio greater than 3:1
  • Tobacco smoking
    Tobacco smoking
    Tobacco smoking is the practice where tobacco is burned and the vapors either tasted or inhaled. The practice began as early as 5000–3000 BC. Many civilizations burnt incense during religious rituals, which was later adopted for pleasure or as a social tool. Tobacco was introduced to the old world...

    , increases risk by 200% after several pack year
    Pack year
    -Definition:A way to measure the amount a person has smoked over a long period of time. It is calculated by multiplying the number of packs of cigarettes smoked per day by the number of years the person has smoked...

    s
  • Having high
    Hypertension
    Hypertension is a chronic medical condition in which the blood pressure is elevated. It is also referred to as high blood pressure or shortened to HT, HTN or HPN. The word "hypertension", by itself, normally refers to systemic, arterial hypertension.Hypertension can be classified as either...

     blood pressure
    Blood pressure
    Blood pressure is the pressure exerted by circulating blood on the walls of blood vessels, and is one of the principal vital signs. During each heartbeat, BP varies between a maximum and a minimum pressure...

    +, on its own increasing risk by 60%
  • Elevated serum C-reactive protein
    C-reactive protein
    C-reactive protein is a protein found in the blood, the levels of which rise in response to inflammation ....

     concentrations

Nonmodifiable

  • Advanced age
    Senescence
    Senescence refers to the biological changes which take place in organisms as they age. It encompasses all of the biological processes of a living organism's approaching an advanced age...

  • Male
    Male
    Male refers to the sex of an organism, or part of an organism, which produces small mobile gametes, called spermatozoa. Each spermatozoon can fuse with a larger female gamete or ovum, in the process of fertilization...

     sex
  • Having close relatives who have had some complication of atherosclerosis (eg. coronary heart disease
    Coronary heart disease
    Coronary artery disease is the end result of the accumulation of atheromatous plaques within the walls of the coronary arteries that supply the myocardium with oxygen and nutrients...

     or stroke
    Stroke
    A stroke is the rapidly developing loss of brain function due to disturbance in the blood supply to the brain. This can be due to ischemia caused by thrombosis or embolism or due to a hemorrhage...

    )
  • Genetic abnormalities, e.g. familial hypercholesterolemia
    Familial hypercholesterolemia
    Familial hypercholesterolemia is a genetic disorder characterized by high cholesterol levels, specifically very high low-density lipoprotein levels, in the blood and early cardiovascular disease...


Lesser or uncertain


The following factors are of relatively lesser importance, are uncertain or nonquantitated:
  • Being obese
    Obesity
    Obesity is a medical condition in which excess body fat has accumulated to the extent that it may have an adverse effect on health, leading to reduced life expectancy and/or increased health problems...

     (in particular central obesity
    Central obesity
    Abdominal obesity, colloquially known as belly fat or clinically as central obesity, is the accumulation of visceral fat resulting in an increase in waist size...

    , also referred to as abdominal or male-type obesity) +
  • A sedentary lifestyle
    Sedentary lifestyle
    Sedentary lifestyle is a medical term used to denote a type of lifestyle with a lack of physical exercise. It is commonly found in both the developed and developing world and characterized by sitting, reading, watching television and computer use for much of the day with little or no vigorous...

  • Postmenopausal estrogen deficiency
  • High carbohydrate intake
  • Intake of trans fat
    Trans fat
    Trans fat is the common name for unsaturated fat with trans-isomer fatty acid. Trans fats may be monounsaturated or polyunsaturated but never saturated.Unsaturated fat is a fat molecule, containing one or more double bonds between the carbon atoms...

  • Elevated serum levels of triglycerides +
  • Elevated serum levels of homocysteine
    Homocysteine
    Homocysteine is an amino acid with the formula HSCH2CH2CHCO2H. It is a homologue of the amino acid cysteine, differing by an additional methylene group. It is biosynthesized from methionine by the removal of its terminal Cε methyl group...

  • Elevated serum levels of uric acid
    Uric acid
    Uric acid is an organic compound of carbon, nitrogen, oxygen and hydrogen with the formula C5H4N4O3.-Biology:...

     (also responsible for gout)
  • Elevated serum fibrinogen concentrations
  • Elevated serum lipoprotein(a)
    Lipoprotein(a)
    Lipoprotein is a lipoprotein subclass. Studies have identified Lp as a putative risk factor for atherosclerotic diseases such as coronary heart disease and stroke....

     concentrations
  • Chronic systemic inflammation
    Inflammation
    Inflammation is the complex biological response of vascular tissues to harmful stimuli, such as pathogens, damaged cells, or irritants. Inflammation is a protective attempt by the organism to remove the injurious stimuli as well as initiate the healing process for the tissue. Inflammation is not a...

     as reflected by upper normal WBC concentrations, elevated hs-CRP and many other blood chemistry markers, most only research level at present, not clinically done.
  • Stress
    Stress (medicine)
    Stress is a biological term for the consequences of the failure of a human or animal to respond appropriately to emotional or physical threats to the organism, whether actual or imagined....

     or symptoms of clinical depression
    Clinical depression
    Major depressive disorder is a mental disorder characterized by an all-encompassing low mood accompanied by low self-esteem, and loss of interest or pleasure in normally enjoyable activities...

  • Hyperthyroidism
    Hyperthyroidism
    Hyperthyroidism is the term for overactive tissue within the thyroid gland,resulting in overproduction and thus an excess of circulating free thyroid hormones: thyroxine , triiodothyronine , or both...

     (an over-active thyroid
    Thyroid
    The thyroid is one of the largest endocrine glands in the body. This gland is found in the neck inferior to the thyroid cartilage and at approximately the same level as the cricoid cartilage...

    )
  • Elevated serum insulin levels +
  • Short sleep duration
  • Chlamydia pneumoniae infection

Dietary risk factors


The relation between dietary fat and atherosclerosis is a contentious field.
The USDA
United States Department of Agriculture
The United States Department of Agriculture is the United States federal executive department responsible for developing and executing U.S. federal government policy on farming, agriculture, and food...

, in its food pyramid
Food pyramid
Food pyramid may refer to:*Food guide pyramid, a core concept in nutritional guides around the world.**MyPyramid, the USDA's 2005 version of the food guide pyramid.*Ecological pyramid or trophic pyramid, a representation of a food chain....

, promotes a low-fat diet, based largely on its view that fat in the diet is atherogenic.
The American Heart Association
American Heart Association
The American Heart Association is a non-profit organization in the United States that fosters appropriate cardiac care in an effort to reduce disability and deaths caused by cardiovascular disease and stroke. It is headquartered in Dallas, Texas...

, the American Diabetes Association
American Diabetes Association
The American Diabetes Association is the leading national association working to fight the deadly consequences of diabetes and to help those affected by diabetes...

 and the National Cholesterol Education Program
National Cholesterol Education Program
The National Cholesterol Education Program is a program managed by the National Heart, Lung and Blood Institute, a division of the National Institutes of Health. Its goal is to reduce increased cardiovascular disease rates due to hypercholesterolemia in the United States of America...

 make similar recommendations.
In contrast, Prof Walter Willett
Walter Willett
Dr. Walter Willett, MD, DrPH., is an American physician and nutrition researcher.Currently, Dr. Willett is the Fredrick John Stare Professor of Epidemiology and Nutrition in the Department of Nutrition and Epidemiology at Harvard School of Public Health, and is a Professor of Medicine at Harvard...

 (Harvard School of Public Health, PI
Principal investigator
A principal investigator is the lead scientist for a particular well-defined science project, such as an astronomical observing campaign, laboratory study or clinical trial....

 of the second Nurses' Health Study
Nurses' Health Study
The Nurses' Health Study, established in 1976 by Dr. Frank Speizer, and the Nurses' Health Study II, established in 1989 by Dr. Walter Willett, are the most definitive long-term epidemiological studies conducted to date on older women's health. The study has followed 121,700 female registered...

) recommends much higher levels, especially of monounsaturated
Monounsaturated fat
In biochemistry and nutrition, monounsaturated fats are fatty acids that have a single double bond in the fatty acid chain and all of the remainder of the carbon atoms in the chain are single-bonded...

 and polyunsaturated fat
Polyunsaturated fat
In nutrition, polyunsaturated fat, or polyunsaturated fatty acid, are fatty acids in which more than one double bond exists within the representative molecule. That is, the molecule has two or more points on its structure capable of supporting hydrogen atoms not currently part of the structure...

.
Writing in Science
Science
Science is in its broadest sense to any systematic knowledge-base or prescriptive practice that is capable of resulting in a prediction or predictable type of outcome...

, Gary Taubes
Gary Taubes
Gary Taubes is an American science writer. He is the author of Nobel Dreams , Bad Science: The Short Life and Weird Times of Cold Fusion , and Good Calories, Bad Calories , which is titled The Diet Delusion in the UK...

 detailed that political considerations played into the recommendations of government bodies.
These differing views reach a consensus, though, against consumption of trans fat
Trans fat
Trans fat is the common name for unsaturated fat with trans-isomer fatty acid. Trans fats may be monounsaturated or polyunsaturated but never saturated.Unsaturated fat is a fat molecule, containing one or more double bonds between the carbon atoms...

s.

The role of dietary oxidized fats / lipid peroxidation
Lipid peroxidation
Lipid peroxidation refers to the oxidative degradation of lipids. It is the process whereby free radicals "steal" electrons from the lipids in cell membranes, resulting in cell damage. This process proceeds by a free radical chain reaction mechanism...

 (rancid fats
Rancidification
Rancidification is the chemical decomposition of fats, oils and other lipids. There are three basic types of rancidity. Hydrolytic rancidity occurs when water splits fatty acid chains away from the glycerol backbone in glycerides. Oxidative rancidity occurs when the double bonds of an unsaturated...

) in humans is not clear.
Laboratory animals fed rancid fats develop atherosclerosis. Rats fed DHA
Docosahexaenoic acid
Docosahexaenoic acid is an omega-3 fatty acid. In chemical structure, DHA is a carboxylic acid with a 22-carbon chain and six cis double bonds; the first double bond is located at the third carbon from the omega end...

-containing oils experienced marked disruptions to their antioxidant
Antioxidant
An antioxidant is a molecule capable of slowing or preventing the oxidation of other molecules. Oxidation is a chemical reaction that transfers electrons from a substance to an oxidizing agent. Oxidation reactions can produce free radicals, which start chain reactions that damage cells...

 systems, as well as accumulated significant amounts of peroxide in their blood, livers and kidneys.
In another study, rabbits fed atherogenic diets containing various oils were found to undergo the greatest amount of oxidative susceptibility of LDL via polyunsaturated oils. In a study involving rabbits fed heated soybean oil, "grossly induced atherosclerosis and marked liver damage were histologically and clinically demonstrated".

Rancid fats and oils taste very bad even in small amounts; people avoid eating them.
It is very difficult to measure or estimate the actual human consumption of these substances. In addition, the majority of oils consumed in the United States are refined, bleached, deodorized and degummed by manufacturers. The resultant oils are colorless, odorless, tasteless and have a longer shelf life than their unrefined counterparts. This extensive processing serves to make peroxidated, rancid oils much more elusive to detection via the various human senses than the unprocessed alternatives.

The French paradox
French paradox
The French paradox is the observation that the French suffer a relatively low incidence of coronary heart disease, despite having a diet relatively rich in saturated fats. The term French paradox was coined by Dr...

 is the observation that despite having a diet similar to those United States in terms of fat intake, rates of heart disease are lower in France
France
France , officially the French Republic , is a country located in Western Europe, with several overseas islands and territories located on other continents. Metropolitan France extends from the Mediterranean Sea to the English Channel and the North Sea, and from the Rhine to the Atlantic Ocean...

. There is evidence to suggest the French paradox is due to underestimation of the rates of heart disease in France.

Prognosis


Lipoprotein imbalances
Dyslipidemia
Dyslipidemia is a disruption in the amount of lipids in the blood.In western societies, most dyslipidemias are hyperlipidemias; that is, an elevation of lipids in the blood, often due to diet and lifestyle. The prolonged elevation of insulin levels can lead to dyslipidemia...

, upper normal and especially elevated blood sugar, i.e., diabetes and high blood pressure are risk factors for atherosclerosis; homocysteine
Homocysteine
Homocysteine is an amino acid with the formula HSCH2CH2CHCO2H. It is a homologue of the amino acid cysteine, differing by an additional methylene group. It is biosynthesized from methionine by the removal of its terminal Cε methyl group...

, stopping smoking, taking anticoagulant
Anticoagulant
An anticoagulant is a substance that prevents coagulation; that is, it stops blood from clotting. A group of pharmaceuticals called anticoagulants can be used in vivo as a medication for thrombotic disorders...

s (anti-clotting agents), which target clotting factors, taking omega-3 oils from fatty fish or plant oils such as flax or canola oils, exercising and losing weight are the usual focus of treatments that have proven to be helpful in clinical trials. The target serum cholesterol level is ideally equal or less than 4 mmol/L (160 mg/dL), and triglycerides equal or less than 2 mmol/L (180 mg/dL).

Evidence has increased that people with diabetes, despite their not having clinically-detectable atherosclotic disease, have more severe debility from atherosclerotic events over time than even non-diabetics that have already suffered atherosclerotic events. Thus diabetes has been upgraded to be viewed as an advanced atherosclerotic disease equivalent.

Treatment


If atherosclerosis leads to symptoms, some symptoms such as angina pectoris can be treated. Non-pharmaceutical means are usually the first method of treatment, such as cessation of 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. However, medicines are criticized for their expense, patented control and occasional undesired effects.

Statins


In general, the group of medications referred to as statins has been the most popular and are widely prescribed for treating atherosclerosis. They have relatively few short-term or longer-term undesirable side-effects, and multiple comparative treatment/placebo trials
Placebo-controlled studies
A Placebo-controlled study is a way of testing a medical therapy in which, in addition to a group of subjects that receives the treatment to be evaluated, a separate control group receives a sham "placebo" treatment which is specifically designed to have no real effect...

 have fairly consistently shown strong effects in reducing atherosclerotic disease 'events' and generally ~25% comparative mortality reduction in clinical trials, although one study design, ALLHAT, was less strongly favorable.

The newest statin, rosuvastatin
Rosuvastatin
Rosuvastatin is a member of the drug class of statins, used to treat high cholesterol and related conditions, and to prevent cardiovascular disease. Shionogi developed the product and the pharmaceutical company AstraZeneca markets it as Crestor...

, has been the first to demonstrate regression of atherosclerotic plaque within the coronary arteries by IVUS (intravascular ultrasound evaluation). The study was set up to demonstrate effect primarily on atherosclerosis volume within a 2 year time-frame in people with active/symptomatic disease (angina frequency also declined markedly) but not global clinical outcomes, which was expected to require longer trial time periods; these longer trials remain in progress.

However, for most people, changing their physiologic behaviors, from the usual high risk to greatly reduced risk, requires a combination of several compounds, taken on a daily basis and indefinitely. More and more human treatment trials have been done and are ongoing that demonstrate improved outcome for those people using more-complex and effective treatment regimens that change physiologic behaviour patterns to more closely resemble those that humans exhibit in childhood at a time before fatty streaks begin forming.

The statin
Statin
The statins are a class of drugs that lower cholesterol levels in people with or at risk of cardiovascular disease...

s, and some other medications, have been shown to have antioxidant
Antioxidant
An antioxidant is a molecule capable of slowing or preventing the oxidation of other molecules. Oxidation is a chemical reaction that transfers electrons from a substance to an oxidizing agent. Oxidation reactions can produce free radicals, which start chain reactions that damage cells...

 effects, possibly part of their basis for some of their therapeutic success in reducing cardiac 'events'.

The success of statin drugs in clinical trials is based on some reductions in mortality rates, however by trial design biased toward men and middle-age, the data is as, as yet, less strongly clear for women and people over the age of 70. For example, in the Scandinavian Simvastatin Survival Study (4S)
Scandinavian Simvastatin Survival Study
The Scandinavian Simvastatin Survival Study is a multicenter clinical trial that was performed in 1990s in Scandinavia....

, the first large placebo controlled, randomized clinical trial of a statin in people with advanced disease who had already suffered a heart attack, the overall mortality rate reduction for those taking the statin, vs. placebo, was 30%. For the subgroup of people in the trial that had Diabetes Mellitus, the mortality rate reduction between statin and placebo was 54%. 4S was a 5.4-year trial that started in 1989 and was published in 1995 after completion. There were 3 more dead women at trial's end on statin than in the group on placebo drug whether chance or some relation to the statin remains unclear. The ASTEROID trial has been the first to show actual disease volume regression (see page 8 of the paper, which shows cross-sectional areas of the total heart artery wall at start and 2 years of rosuvastatin 40 mg/day treatment); however, its design was not able to "prove" the mortality reduction issue since it did not include a placebo group, the individuals offered treatment within the trial had advanced disease and promoting a comparison placebo arm was judged to be unethical.

Primary and secondary prevention


Combinations of statin
Statin
The statins are a class of drugs that lower cholesterol levels in people with or at risk of cardiovascular disease...

s, niacin
Niacin
Niacin, also known as vitamin B3 or nicotinic acid, is a water-soluble vitamin. It is an organic compound with the molecular formula C6H5NO2. It is a derivative of pyridine, with a carboxyl group at the 3-position...

, intestinal cholesterol absorption-inhibiting supplements (ezetimibe
Ezetimibe
Ezetimibe is an anti-hyperlipidemic medication that is used to lower cholesterol levels. It acts by decreasing cholesterol absorption in the intestine. It may be used alone when other cholesterol-lowering medications are not tolerated, or together with statins Ezetimibe is an...

 and others, and to a much lesser extent fibrate
Fibrate
In pharmacology, the fibrates are a class of amphipathic carboxylic acids. They are used for a range of metabolic disorders, mainly hypercholesterolemia , and are therefore hypolipidemic agents.- Members :...

s) have been the most successful in changing common but sub-optimal lipoprotein
Lipoprotein
A lipoprotein is a biochemical assembly that contains both proteins and lipids. The lipids or their derivatives may be covalently or non-covalently bound to the proteins. Many enzymes, transporters, structural proteins, antigens, adhesins and toxins are lipoproteins...

 patterns and group outcomes.
In the many secondary prevention and several primary prevention trials, several classes of lipoprotein expression (less correctly termed "cholesterol-lowering") altering agents have consistently reduced not only heart attack, stroke and hospitalization but also all-cause mortality rates.
The first of the large secondary prevention comparative statin/placebo treatment trials was the Scandinavian Simvastatin Survival Study. (4S)
with over 15 more extending through the more recent ASTEROID
trial published in 2006.
The first primary prevention comparative treatment trial was AFCAPS/TexCAPS
with multiple later comparative statin/placebo treatment trials
including EXCEL.,
ASCOT
and SPARCL.

While the statin trials have all been clearly favorable for improved human outcomes, only ASTEROID showed evidence of atherosclerotic regression (slight). For both human and animal trials, those which have shown evidence of disease regression had all utilized more aggressive combination agent treatment strategies, nearly always including niacin.

Diet and dietary supplements


Vitamin B3, AKA niacin
Niacin
Niacin, also known as vitamin B3 or nicotinic acid, is a water-soluble vitamin. It is an organic compound with the molecular formula C6H5NO2. It is a derivative of pyridine, with a carboxyl group at the 3-position...

, in pharmacologic doses, (generally 1,000 to 3,000 mg/day), sold in many OTC and prescription formulations, tends to improve (a) HDL levels, size and function, (b) shift LDL particle distribution to larger particle size and (c) lower lipoprotein(a)
Lipoprotein(a)
Lipoprotein is a lipoprotein subclass. Studies have identified Lp as a putative risk factor for atherosclerotic diseases such as coronary heart disease and stroke....

, an atherosclerosis promoting genetic variant of LDL. Additionally, individual responses to daily niacin, while mostly evident after a month at effective doses, tends to continue to slowly improve further over time. (However, careful patient understanding of how to achieve this without nuisance symptoms is needed, though not often achieved.) Research work on increasing HDL particle concentration and function, beyond the usual niacin effect/response, even more important, is slowly advancing.

Dietary changes to achieve benefit have been more controversial, generally far less effective and less widely adhered to with success. One key reason for this is that most cholesterol, typically 80-90%, within the body is created and controlled by internal production by all cells in the body (true of all animals), with typically slightly greater relative production by hepatic/liver cells. (Cell structure relies on fat membranes to separate and organize intracellular water, proteins and nucleic acids and cholesterol is one of the components of all animal cell membranes.)

Caldwell B Esselstyn Jr. MD has had an article published in Preventive Cardiology 2001;4: 171-177 in which he has published angiograms showing regression of atherosclerosis brought about by a very low fat vegan diet in some cases with cholesterol lowering medications.

While the absolute production quantities vary with the individual, group averages for total human body content of cholesterol within the U.S. population commonly run about ~35,000 mg (assuming lean build; varies with body weight and build) and ~1,000 mg/day ongoing production. Dietary intake plays a smaller role, 200-300 mg/day being common values; for pure vegetarians, essentially 0 mg/day, but this typically does not change the situation very much because internal production increases to largely compensate for the reduced intake. For many, especially those with greater than optimal body mass and increased glucose levels, reducing carbohydrate (especially simple forms) intake, not fats or cholesterol, is often more effective for improving lipoprotein expression patterns, weight and blood glucose values. For this reason, medical authorities much less frequently promote the low dietary fat concepts than was commonly the case prior to about year 2005. However, evidence has increased that processed, particularly industrial non-enzymatic hydrogenation
Hydrogenation
Hydrogenation is the chemical reaction that results from the addition of hydrogen . The process is usually employed to reduce or saturate organic compounds. The process typically constitutes the addition of pairs of hydrogen atoms to a molecule. Catalysts are required for the reaction to be...

 produced trans fats, as opposed to the natural cis
Cis
Cis may have the following meanings:* "Cis-" as a prefix of Latin origin, meaning "on the same side [as]" or "on this side [of]", with several derived usages:** In chemistry, cis- refers to cis-trans isomerism...

-configured fats, which living cells primarily produce, is a significant health hazard.

Dietary supplements of Omega-3 oils, especially those from the muscle of some deep salt water living fish species, also have clinical evidence of significant protective effects as confirmed by 6 double blind placebo
Placebo
A placebo is a sham medical intervention. In one common placebo procedure, a patient is given an inert sugar pill, told that it may improve his/her condition, but not told that it is in fact inert...

 controlled
Scientific control
When an experiment is being conducted to investigate the effect of a single variable of interest on a particular system, a scientific control is used to minimize unintended influences on that system. Such unintended influences include researcher bias, environmental changes, and biological variation...

 human clinical trials.

There is also a variety of evidence, though less robust, that homocysteine
Homocysteine
Homocysteine is an amino acid with the formula HSCH2CH2CHCO2H. It is a homologue of the amino acid cysteine, differing by an additional methylene group. It is biosynthesized from methionine by the removal of its terminal Cε methyl group...

 and uric acid
Uric acid
Uric acid is an organic compound of carbon, nitrogen, oxygen and hydrogen with the formula C5H4N4O3.-Biology:...

 levels, including within the normal range promote atherosclerosis and that lowering these levels is helpful, up to a point.

In animals Vitamin C
Vitamin C
Vitamin C or L-ascorbic acid is an essential nutrient for humans, in which it functions as a vitamin. Ascorbate is required for a range of essential metabolic reactions in all animals and plants...

 deficiency has been confirmed as an important role in development of hypercholesterolemia
Hypercholesterolemia
Hypercholesterolemia is the presence of high levels of cholesterol in the blood. It is not a disease but a metabolic derangement that can be secondary to many diseases and can contribute to many forms of disease, most notably cardiovascular disease...

 and atherosclerosis, but due to ethical reasons placebo-controlled human studies are impossible to do.
Vitamin C
Vitamin C
Vitamin C or L-ascorbic acid is an essential nutrient for humans, in which it functions as a vitamin. Ascorbate is required for a range of essential metabolic reactions in all animals and plants...

 acts as an antioxidant
Antioxidant
An antioxidant is a molecule capable of slowing or preventing the oxidation of other molecules. Oxidation is a chemical reaction that transfers electrons from a substance to an oxidizing agent. Oxidation reactions can produce free radicals, which start chain reactions that damage cells...

 in vessels and inhibits inflammatory process. It has therapeutic properties on high blood pressure and its fluctuation, and arterial stiffness in diabetes. Vitamin C is also a natural regulator of cholesterol and higher doses (over 150 mg/kg daily) may confer significant protection against atherosclerosis even in the situation of elevated cholesterol levels.

The scale of vitamin C benefits on cardiovascular system led several authors to the theory, that vitamin C deficiency is the primary cause of cardiovascular diseases. The theory was unified by twice Nobel prize winner Linus Pauling
Linus Pauling
Linus Carl Pauling was an American chemist, peace activist, author, and educator. He was one of the most influential chemists in history and ranks among the most important scientists in any field of the 20th century. Pauling was among the first scientists to work in the fields of quantum...

 and Matthias Rath
Matthias Rath
Matthias Rath is a German businessman, medical doctor, and vitamin entrepreneur. He earned his MD degree in Germany. Rath claims that a program of nutritional supplements , including formulations that he sells, can treat or cure diabetes, cardiovascular disease, cancer, and HIV/AIDS. Rath runs the...

. They suggest, that clinical manifestations of cardiovascular diseases are merely overshoot of body defense mechanisms, that are involved in stabilisation of vascular wall, after it is weakened by the vitamin C deficiency and the subsequent collagen degradation. They discuss several metabolic and genetic predispositions and their pathomechanism.

Trials on Vitamin E
Vitamin E
Vitamin E is a generic term for tocopherols and tocotrienols. Vitamin E is a family of α-, β-, γ-, and δ-tocopherols and corresponding four tocotrienols. Vitamin E is a fat-soluble antioxidant that stops the production of reactive oxygen species formed when fat undergoes oxidation...

 have been done, but they have failed to find a beneficial effect, for various reasons, but for some patients at high risk for atherosclerosis there may be some benefits.

Menaquinone (Vitamin K2
Vitamin K
Vitamin K denotes a group of lipophilic, hydrophobic vitamins that are needed for the posttranslational modification of certain proteins, mostly required for blood coagulation...

), but not phylloquinone (Vitamin K1
Vitamin K
Vitamin K denotes a group of lipophilic, hydrophobic vitamins that are needed for the posttranslational modification of certain proteins, mostly required for blood coagulation...

), intake is associated with reduced risk of CHD mortality
Mortality rate
Mortality rate is a measure of the number of deaths in some population, scaled to the size of that population, per unit time. Mortality rate is typically expressed in units of deaths per 1000 individuals per year; thus, a mortality rate of 9.5 in a population of 100,000 would mean 950 deaths per...

, all-cause mortality
Mortality rate
Mortality rate is a measure of the number of deaths in some population, scaled to the size of that population, per unit time. Mortality rate is typically expressed in units of deaths per 1000 individuals per year; thus, a mortality rate of 9.5 in a population of 100,000 would mean 950 deaths per...

 and severe aortic calcification.

It has been suggested that excess iron
Iron
Iron is a metallic chemical element with the symbol Fe and atomic number 26. Iron is a group 8 and period 4 element and is therefore classified as a transition metal. Iron and iron alloys are by far the most common metals and the most common ferromagnetic materials in everyday use...

 may be involved in development of atherosclerosis, but one study found reducing body iron stores in patients with symptomatic peripheral artery disease
Peripheral artery occlusive disease
Peripheral vascular disease , also known as peripheral artery disease or peripheral artery occlusive disease , includes all diseases caused by the obstruction of large arteries in the arms and legs. PVD can result from atherosclerosis, inflammatory processes leading to stenosis, an embolism or...

 through phlebotomy
Phlebotomy
Phlebotomy may refer to:* Venipuncture, the practice of collecting blood samples* The main practice of a phlebotomist, an individual trained to draw blood* Bloodletting, the ancient medical practice* Phlebotomy...

 did not significantly decrease all-cause mortality or death plus nonfatal myocardial infarction and stroke. Further studies may be warranted.

Surgical intervention


Other physical treatments, helpful in the short term, include minimally invasive angioplasty
Angioplasty
Angioplasty is the technique of mechanically widening a narrowed or obstructed blood vessel; typically as a result of atherosclerosis. Tightly folded balloons are passed into the narrowed locations and then inflated to a fixed size using water pressures some 75 to 500 times normal blood pressure...

 procedures that may include stents to physically expand narrowed arteries and major invasive surgery, such as bypass surgery
Coronary artery bypass surgery
Coronary artery bypass surgery, also coronary artery bypass graft surgery, and colloquially heart bypass or bypass surgery is a surgical procedure performed to relieve angina and reduce the risk of death from coronary artery disease...

, to create additional blood supply connections that go around the more severely narrowed areas.

Prophylaxis


Patients at risk for atherosclerosis-related diseases are increasingly being treated prophylactically with low-dose aspirin
Aspirin
Aspirin , also known as acetylsalicylic acid , is a salicylate drug, often used as an analgesic to relieve minor aches and pains, as an antipyretic to reduce fever, and as an anti-inflammatory medication....

 and a statin
Statin
The statins are a class of drugs that lower cholesterol levels in people with or at risk of cardiovascular disease...

. The high incidence of cardiovascular disease led Wald and Law to propose a Polypill
Polypill
A polypill is a medication which contains a combination of active ingredients with the intention of reducing the number of tablets or capsules that need to be taken.-Origin:...

, a once-daily pill containing these two types of drugs in addition to an ACE inhibitor
ACE inhibitor
ACE inhibitors, or inhibitors of angiotensin-converting enzyme , are a group of pharmaceuticals that are used primarily in treatment of hypertension and congestive heart failure, in some cases as the drugs of first choice....

, diuretic
Diuretic
A diuretic is any drug that elevates the rate of urination and thus provides a means of forced diuresis. There are several categories of diuretics...

, beta blocker
Beta blocker
Beta blockers is a class of drugs used for various indications, but particularly for the management of cardiac arrhythmias, cardioprotection after myocardial infarction , and hypertension. Propranolol was the first clinically useful beta adrenergic receptor antagonist. Invented by Sir James W...

, and folic acid
Folic acid
Folic acid and folate , as well as pteroyl-L-glutamic acid and pteroyl-L-glutamate, are forms of the water-soluble vitamin B9...

. They maintain that high uptake by the general population by such a Polypill would reduce cardiovascular mortality by 80%. It must be emphasized however that this is purely theoretical, as the Polypill has never been tested in a clinical trial.

Medical treatments often focus predominantly on the symptoms. However, over time, the treatments which focus on decreasing the underlying atherosclerosis processes, as opposed to simply treating the symptoms resulting from the atherosclerosis, have been shown by clinical trials to be more effective.

In summary, the key to the more effective approaches has been better understanding of the widespread and insidious nature of the disease and to combine multiple different treatment strategies, not rely on just one or a few approaches. In addition, for those approaches, such as lipoprotein transport behaviors, which have been shown to produce the most success, adopting more aggressive combination treatment strategies has generally produced better results, both before and especially after people are symptomatic.

Because many blood thinners, particularly salicylates such as warfarin and aspirin thin the blood by interfering with Vitamin K, there is recent evidence that blood thinners which work by this mechanism, can actually worsen arterial calcification in the long term even though they thin the blood in the short term. http://lpi.oregonstate.edu/infocenter/vitamins/vitaminK/http://glycodocs.org/index.php?option=com_content&task=view&id=100&Itemid=52

Recent research


An indication of the role of HDL on atherosclerosis has been with the rare Apo-A1 Milano human genetic variant of this HDL protein. A small short-term trial using bacterial synthetized human Apo-A1 Milano
ApoA-1 Milano
ApoA-1 Milano is a naturally occurring mutated variant of the apolipoprotein A1 protein found in human HDL, the lipoprotein particle that carries cholesterol from tissues to the liver and is associated with protection against cardiovascular disease...

 HDL in people with unstable angina produced fairly dramatic reduction in measured coronary plaque volume in only 6 weeks vs. the usual increase in plaque volume in those randomized to placebo. The trial was published in JAMA in early 2006. Ongoing work starting in the 1990s may lead to human clinical trials—probably by about 2008. These may use synthesized Apo-A1 Milano HDL directly. Or they may use gene-transfer methods to pass the ability to synthesize the Apo-A1 Milano HDLipoprotein.

Methods to increase high-density lipoprotein (HDL) particle concentrations, which in some animal studies largely reverses and remove atheromas, are being developed and researched.

Niacin
Niacin
Niacin, also known as vitamin B3 or nicotinic acid, is a water-soluble vitamin. It is an organic compound with the molecular formula C6H5NO2. It is a derivative of pyridine, with a carboxyl group at the 3-position...

 has HDL raising effects (by 10 - 30%) and showed clinical trial benefit in the Coronary Drug Project and is commonly used in combination with other lipoprotein agents to improve efficacy of changing lipoprotein for the better. However most individuals have nuisance symptoms with short term flushing reactions, especially initially, and so working with a physician with a history of successful experience with niacin implementation, careful selection of brand, dosing strategy, etc. are usually critical to success.

However, increasing HDL by any means is not necessarily helpful. For example, the drug torcetrapib
Torcetrapib
Torcetrapib was a drug being developed to treat hypercholesterolemia and prevent cardiovascular disease...

 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 ERASE trial is a newer trial of an HDL booster which has shown promise.

The ASTEROID trial used a high-dose of rosuvastatin
Rosuvastatin
Rosuvastatin is a member of the drug class of statins, used to treat high cholesterol and related conditions, and to prevent cardiovascular disease. Shionogi developed the product and the pharmaceutical company AstraZeneca markets it as Crestor...

—the statin with typically the most potent dose/response correlation track record (both for LDLipoproteins and HDLipoproteins.)
It found plaque (intima + media volume) reduction.
Several additional rosuvastatin treatment/placebo trials for evaluating other clinical outcomes are in progress.

The actions of macrophages drive atherosclerotic plaque progression.
Immunomodulation of atherosclerosis is the term for techniques which modulate immune system function in order to suppress this macrophage action.
Immunomodulation has been pursued with considerable success in both mice and rabbits since about 2002.
Plans for human trials, hoped for by about 2008, are in progress.

Research on genetic expression and control mechanisms is progressing. Topics include
  • PPAR, known to be important in blood sugar and variants of lipoprotein production and function;
  • The multiple variants of the proteins that form the lipoprotein transport particles.


Some controversial research has suggested a link between atherosclerosis and the presence of several different nanobacteria
Nanobacterium
Nanobacteria is the name of a proposed class of living organisms; specifically cell-walled microorganisms with a size much smaller than the generally accepted lower limit size for life...

 in the arteries, e.g., Chlamydophila pneumoniae
Chlamydophila pneumoniae
Chlamydophila pneumoniae is a species of Chlamydophila bacteria that infects humans and is a major cause of pneumonia.Until recently it was known as "Chlamydia pneumoniae", and that name is used as an alternate in some sources. In some cases, to avoid confusion, both names are given.C...

, though trials of current antibiotic treatments known to be usually effective in suppressing growth or killing these bacteria have not been successful in improving outcomes.

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

The National Heart, Lung, and Blood Institute (NHLBI) and National Center for Complementary and Alternative Medicine (NCCAM) sponsored The Trial to Assess Chelation Therapy (TACT). The purpose of this study is to determine the safety and effectiveness of ethylene diamine tetra-acetic (EDTA) chelation therapy in individuals with coronary artery disease. EDTA chelation therapy involves repeated administrations of a synthetic amino acid to reduce atherosclerotic plaque and other mineral deposits throughout the cardiovascular system. The results of TACT will provide either a significant positive result or an informative null result upon which rational clinical decision-making and health policy can be based.

The Hemorheologic-Hemodynamic Theory


The theory of atherogenesis described above is presented largely as fact. While representing the mainstream view, this theory has several weaknesses. Aggressive reduction of serum LDL-cholesterol using high dose statin therapy still leaves significant risk of adverse cardiovascular events in high-risk patients. Despite lowering serum LDL-cholesterol to less than 100 mg/dL, the estimated risk of adverse events in patients with established coronary artery disease is estimated to be 9% per year. This, in conjunction with the failure of torcetrapib
Torcetrapib
Torcetrapib was a drug being developed to treat hypercholesterolemia and prevent cardiovascular disease...

 in clinical trials, should prompt reexamination of mainstream atherogenesis theory. Further, oxidized LDL is widely distributed in both arteries and veins, the latter of which do not develop atherosclerosis. The distribution of the putative precursor lesion, the fatty streak, correlates poorly with the distribution of fibrous plaques. The mainstream theory of atherogenesis does not explain the localization of fibrous plaques to the vicinity of changing arterial geometry, such as branches, curves, and dilatations. Mainstream theory provides no explanation for accelerated atherosclerosis associated with hypertension. Finally, mainstream theory cannot explain the presence of fibrous plaques in synthetic arteriovenous grafts.

The hemorheologic–hemodynamic theory holds that atherosclerosis is a disease of stasis of blood, which promotes the organization of a thrombus
Thrombus
A thrombus , or blood clot, is the final product of the blood coagulation step in hemostasis. It is achieved via the aggregation of platelets that form a platelet plug, and the activation of the humoral coagulation system...

 into an atherosclerotic plaque. Stasis of blood predisposes to thrombosis, as described in Virchow's triad
Virchow's triad
Virchow's triad the three broad categories of factors that are thought to contribute to thrombosis.*Hypercoagulability*Hemodynamic changes *Endothelial injury/dysfunctionIt is named for German physician Rudolf Virchow...

. Risk factors for atherosclerosis create larger areas of decreased shear (flow) by increasing blood viscosity, arterial stiffness, or both. Both of these abnormalities are seen in association with aging, hypertension, diabetes mellitus, cigarette smoking, and obesity. The hemorheologic-hemodynamic theory posits that the same pathologic process, thrombosis, leads to both plaque development and its complication, superimposed thrombosis and infarction. The name reflects the fact that the interaction of hemorheologic, i.e., blood flow, and hemodynamic, i.e., blood velocity, pulsatility, and arterial geometry, factors lead to atherosclerosis.

Viscosity and localized stasis


In arteries during systole
Systole
Systole may refer to:*Systole , a term used to describe entry into the imagination in a text*Systole , a term describing the contraction of the heart*Systolic array, a term used in computer architecture...

, there is a gradient of blood velocity with the highest velocity in the center of the vessel and the lowest against the arterial wall. In areas of vascular branching, curving and dilatation, focal blood pooling occurs in the low shear environment against the arterial wall if blood velocity exceeds a critical value of Reynolds number
Reynolds number
In fluid mechanics, the Reynolds number is a dimensionless number that gives a measure of the ratio of inertial forces to viscous forces and consequently quantifies the relative importance of these two types of forces for given flow conditions...

 (see below). This phenomenon is seen in nature when rapidly flowing water encounters an obstruction, forming eddies and pools. Blood is a non-Newtonian fluid
Non-Newtonian fluid
A non-Newtonian fluid is a fluid whose flow properties are not described by a single constant value of viscosity. Many polymer solutions and molten polymers are non-Newtonian fluids, as are many commonly found substances such as ketchup, starch suspensions, paint, blood and shampoo...

, and its viscosity progressively increases with decreasing shear. In areas of pooling, a vicious cycle can develop in which increased viscosity leads to decreased flow, further increasing viscosity and decreasing flow, leading ultimately to stasis and thrombosis in the absence of adequate fibrinolytic activity. Decreased blood flow promotes thrombosis by decreasing influx of fibrinolytic molecules and decreasing efflux of activated clotting factors. Platelets activated by high shear in the central column of blood can be directed to the vicinity of the arterial wall by eddy currents. In these areas, decreased blood flow decreases endothelial production of molecules with antithrombotic activity such as nitric oxide
Nitric oxide
Nitric oxide or nitrogen monoxide is a chemical compound with chemical formula NO. This gas is an important signaling molecule in the body of mammals, including humans, and is an extremely important intermediate in the chemical industry...

 and prostacyclin
Prostacyclin
Prostacyclin is a member of the family of lipid molecules known as eicosanoids.As a drug, it is also known as "epoprostenol". The terms are sometimes used interchangeably. -History:During the 1960s a U.K...

, further promoting thrombosis. This is akin to endothelial dysfunction which in mainstream atherogensis theory is thought to be caused by putative cytopathic effects of oxidized low-density lipoprotein.

Arterial stiffening


Increased arterial stiffness accelerates atherosclerosis by increasing peak arterial blood velocity, thereby increasing Reynold's number, which indicates the propensity for a flowing fluid to develop pools and eddy currents in association with changing arterial geometry. In the normally compliant aorta, a portion of each stroke volume
Stroke volume
In cardiovascular physiology, stroke volume is the volume of blood pumped from one ventricle of the heart with each beat. It is calculated by subtracting the volume of blood in the ventricle at the end of a beat from the volume of blood just prior to the beat...

 is stored in systole and propelled with lower velocity in diastole, creating blood flow throughout most of the cardiac cycle
Cardiac cycle
Cardiac cycle is the term referring to all or any of the events related to the flow or blood pressure that occurs from the beginning of one heartbeat to the beginning of the next. The frequency of the cardiac cycle is the heart rate...

. An area of pooling created by high velocity would disappear during slow diastolic flow, and any accumulated microthrombus would be dispersed. In a perfectly stiff aorta, the entire stroke volume would be expelled in systole. Given constant stroke volume, conservation of mass requires increasing peak arterial blood velocity with increasing arterial stiffness. In addition, no low velocity diastolic flow will occur, so that a pool formed during high velocity systolic flow will persist throughout the cardiac cycle. This will allow the time necessary for thrombus growth and subsequent organization (see below). Additionly, increased peak arterial velocity will augment shear-mediated platelet activiation.

Organization of mural thrombi


J.B. Duguid promoted the idea that atherosclerotic plaques develop from organization of mural thrombi in the 1940s and 50's. Arterial thrombi tend to remain localized to the low shear environment of the arterial wall because of high blood velocity in the central portion of the artery. These thrombi are know as "mural" or "parietal." In veins, the velocity gradient between the center of the vessel and the vessel wall is small. Thus, thrombi in veins are more likely to become occlusive, as in deep venous thrombosis. This is why atherosclerosis is limited to arteries. If thrombi persist, whether in arteries or veins, they undergo organization, in which circulating fibrocyte
Fibrocyte
Fibrocyte is a very old term used to identify inactive mesenchymal cells, that is cells showing minimal cytoplasm,limited amounts of rough endoplasmic reticulum and lack of biochemical evidence of synthesis of proteins....

s colonize the thrombus and differentiate into cells capable of producing collagen and markers of smooth muscle differentiation, such as smooth muscle actin.

Role of lipoproteins in atherogenesis


The hemorheologic-hemodynamic theory predicts that low-density lipoprotein (LDL) should increase blood viscosity and high-density liporotein (HDL) should decrease blood viscosity, which has been demonstrated experimentally. Erythrocytes are separated by a minimum intercellular distance of approximately 15 nanometers caused by electrostatic repulsion due to sialic acid on the cell membrane surface. LDL has a particle diameter of 18 to 40 nanometers, large enough to simultaneously bind to two erythrocytes and form erythrocyte aggregates. Erythrocyte aggregates increase blood viscosity at low shear by increasing the inertia of the suspended particles. HDL, with a particle diameter of 8 to 12 nanometers, is too small to promote erythrocyte aggregation. Instead, by competing with LDL for binding to erythrocytes, it antagonizes erythrocyte aggregation and decreases blood viscosity. Erythrocyte aggregates are weak, and progressively distrupted with increasing shear. Given the relationship of LDL to blood viscosity, it is not surprising that hypercholesterolemia is a risk factor for both atherosclerosis and deep venous thrombosis.

Insights provided by the hemorheologic–hemodynamic theory


The hemorheologic-hemodynamic theory explains the significant remaining risk of adverse cardiovascular events in patients with established coronary artery disease despite aggressive lowering of LDL-cholesterol using high dose statin therapy. Despite lowering serum LDL-cholesterol to less than 100 mg/dL, the risk of major cardiovascular events in these patients is estimated to be 9% per year. Such therapy does not address the adverse consequences of arterial stiffening, or increased blood viscosity caused by other factors.

The hemorheologic-hemodynamic theory explains the existence of atherosclerotic plaques in synthetic arteriovenous grafts. These provide an extreme hemodynamic environment, where extremely high velocity blood flows through a curved vessel. These vessels are prone to thrombosis and development of atherosclerotic plaques despite anticoagulation. These vessels lack a tunica media, which received wisdom maintains is the origin of smooth muscle cells in atherosclerotic plaques via migration. The identification of the fibrocyte provides an alternative explanation for the origin of smooth muscle cells in atherosclerotic plaques. Being largely inanimate, the capacity of these vessels to respond to an injury with an inflammatory response, the inciting cause of atherosclerosis according to mainstream atherogenesis theory, would be very limited. Further, this theory explains the benefit of blood donation. and drinking large quantities of water. Both of these very low risk interventions reduce blood viscosity.

The hemorheologic-hemodynamic eliminates reliance on the fatty streak in atherogenesis. Fatty streaks routinely resolve without sequelae. This is acknowledged in by mainstream atherogenesis theory, which is unable to predict why a particular fatty streak progresses into an atherosclerotic plaque while the majority regress.

Increased HDL particle size and increased low-shear blood viscosity caused by torcetrapib
Torcetrapib
Torcetrapib was a drug being developed to treat hypercholesterolemia and prevent cardiovascular disease...

 therapy could account for the increased cardiovascular mortality seen in clinical trials.

Increased peak arterial blood velocity and arterial stiffening may also play a role in sudden cardiac death associated with physical exertion. Physical exertion results in increased cardiac output and increased blood pressure, both of which could increase peak arterial velocity, although the effect of increased cardiac output on peak arterial blood velocity in this situation has not been studied. Increased Reynolds number
Reynolds number
In fluid mechanics, the Reynolds number is a dimensionless number that gives a measure of the ratio of inertial forces to viscous forces and consequently quantifies the relative importance of these two types of forces for given flow conditions...

 could lead to acute coronary thrombosis as described above.

The future


Validation of the hemorheologic-hemodynamic theory will require a prospective study to determine if measuring blood viscosity and peak arterial blood velocity identifies subjects at high risk for symptomatic atherosclerosis better than routine markers such as lipid analysis.

See also

  • Angiogram
    Angiogram
    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. This is traditionally done by injecting a radio-opaque contrast agent into the blood...

  • Arterial stiffness
    Arterial stiffness
    Arteries stiffen as a consequence of age and atherosclerosis. The two leading causes of death in the developed world, myocardial infarction and stroke, are both a direct consequence of atherosclerosis. Increased arterial stiffness is associated with an increased risk of cardiovascular events...

  • Atheroma
    Atheroma
    In pathology, an atheroma is an accumulation and swelling in artery walls that is made up of cells , or cell debris, that contain lipids , calcium and a variable amount of fibrous connective tissue. In the context of heart or artery matters, atheromata are commonly referred to as atheromatous...

  • Chelation therapy
    Chelation therapy
    Chelation therapy is the administration of chelating agents to remove heavy metals from the body. For the most common forms of heavy metal intoxication—those involving lead, arsenic or mercury—the standard of care in the USA dictates the use of dimercaptosuccinic acid...

  • Coronary circulation
    Coronary circulation
    Coronary circulation is the circulation of blood in the blood vessels of the heart muscle. Although blood fills the chambers of the heart, the muscle tissue of the heart is so thick that it requires coronary blood vessels to deliver blood deep into it. The vessels that deliver oxygen-rich blood to...

  • Coronary catheterization
    Coronary catheterization
    A coronary catheterization is a minimally invasive procedure to access the coronary circulation and blood filled chambers of the heart using a catheter. It is performed for both diagnostic and interventional purposes....

  • Fatty streaks
  • Monckeberg's arteriosclerosis
    Monckeberg's arteriosclerosis
    Monckeberg's arteriosclerosis, also called medial calcific sclerosis, is a form of arteriosclerosis or vessel hardening, where calcium deposits form in the middle layer of the walls of medium sized vessels ....

  • Intravascular ultrasound
    Intravascular ultrasound
    Intravascular ultrasound is a medical imaging methodology using a specially designed catheter with a miniaturized ultrasound probe attached to the distal end of the catheter. The proximal end of the catheter is attached to computerized ultrasound equipment...