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is a
Disease affecting
Arterial Blood Vessel s. It is a chronic inflammatory response in the walls of arteries, in large part to the deposition of
Lipoproteins (plasma proteins that carry cholesterol and
Triglycerides ). It is commonly referred to as a "hardening" or "furring" of the arteries. It is caused by the formation of multiple
Plaques within the
Arteries .
Pathologically , the is divided into three distinct components:
# The ''
Atheroma '' ("lump of porridge", from ''Athera'',
Porridge in Greek,) is the nodular accumulation of a soft, flaky, yellowish material at the center of large plaques, composed of
Macrophage s nearest the
Lumen of the artery.
# Underlying areas of
Cholesterol crystals.
# 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, arteriolosclerosis and atherosclerosis. is a general term describing any hardening (and loss of elasticity) of medium or large arteries (in Greek, "Arterio" meaning artery and "sclerosis" meaning hardening), '''arteriolosclerosis''' is arteriosclerosis mainly affecting the
Arteriole s (small arteries), '''atherosclerosis''' is a hardening of an artery specifically due to an atheromatous plaque. Therefore, atherosclerosis is a form of arteriosclerosis.
Atherosclerosis causes two main problems. First, the
Atheromatous Plaques , though long compensated for by artery enlargement, see
IMT , eventually lead to plaque ruptures and ''stenosis'' (narrowing) of the artery and, therefore, an insufficient blood supply to the organ it feeds. Alternatively, if the compensating artery enlargement process is excessive, then a net
Aneurysm results.
These complications are chronic, slowly progressing and cumulative. Most commonly, soft plaque suddenly ''ruptures'' (see
Vulnerable Plaque ), causing the formation of a thrombus that will rapidly slow or stop blood flow, e.g. 5 minutes, leading to death of the tissues fed by the artery. This catastrophic event is called an ''
Infarction ''. One of the most common recognized scenarios is called
Coronary Thrombosis of a
Coronary Artery causing
Myocardial Infarction (a heart attack). Another common scenario in very advanced disease is ''
Claudication '' from insufficient blood supply to the legs, typically due to a combination of both stenosis and aneurysmal segments narrowed with
Clots . Since atherosclerosis is a body wide process, similar events also occur in the arteries to the brain, intestines, kidneys, legs, etc.
Atherosclerosis typically begins in early adolescence, and is usually found in most major
Arteries , yet is asymptomatic and not detected by most diagnostic methods during life. Autopsies of healthy young men who died during the Korean and Vietnam Wars showed evidence of the disease. It most commonly becomes seriously symptomatic when interfering with the
Coronary Circulation supplying the
Heart or
Cerebral Circulation supplying the
Brain , and is considered the most important underlying cause of
Strokes ,
Heart Attack s, various
Heart Disease s including
Congestive Heart Failure and most
Cardiovascular Disease s in general. Atheroma in arm or more often leg arteries and producing decreased blood flow is called
Peripheral Artery Occlusive Disease (PAOD).
According to United States data for the year 2004, for about 65% of men and 47% of women, the first
Symptom of atherosclerotic
Cardiovascular Disease is
Heart Attack or
Sudden Cardiac Death (death within one hour of onset of the symptom).
Most artery flow disrupting events occur at locations with less than 50% 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 ing, traditionally the most commonly performed non-invasive testing method for blood flow limitations generally only detects
Lumen narrowing of ~75% or greater, although some physicians advocate that nuclear stress methods can detect as little as 50%.
''Atherogenesis'' is the developmental process of atheromatous plaques. It is characterized by a remodeling of
Arteries 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 of the artery lumen in cardiac muscle. The ensuing
Inflammation leads to formation of ''atheromatous plaques'' in the arterial
Tunica Intima , a region of the vessel wall located between the
Endothelium and the
Tunica Media and
Tunica Adventitia . The bulk of these lesions are made of excess fat,
Collagen , and
Elastin . Initially, as the plaques grow only
Wall Thickening occurs without any narrowing, stenosis of the artery opening, called the lumen;
Stenosis is a late event which may never occur and is often the result of repeated plaque rupture and healing responses, not the just atherosclerosis process by itself.
The first step of atherogenesis is the development of
Fatty Streak s, small subendothelial deposits of lipid. The exact cause for this process is unknown, and fatty streaks may appear and disappear.
LDL in blood plasma poses a risk for
Cardiovascular Disease when it invades the
Endothelium and becomes
Oxidize d. A complex set of biochemical reactions regulates the oxidation of LDL, chiefly stimulated by presence of
Free Radicals in the
Endothelium or blood vessel lining.
The initial damage to the blood vessel wall results in a "call for help," an
Inflammation response.
Monocyte s (a type of
White Blood Cell ) enter the artery wall from the bloodstream, with platelets adhering to the area of insult. This may be promoted by
Redox Signaling induction of factors such as
VCAM-1 , which recruit circulating monocytes. The
Monocyte s differentiate into
Macrophage s, which ingest
Oxidize d
LDL , slowly turning into large "foam cells" – so-described because of their changed appearance resulting from the numerous internal cytoplasmic
Vesicle s and resulting high
Lipid content. Under the microscope, the lesion now appears as a fatty streak. Foam cells eventually die, and further propagate the inflammatory process.
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.
Intracellular
Microcalcifications form within
Vascular Smooth Muscle 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.
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 cells, which in turn ingest lipids, become replaced by collagen and transform into foam cells themselves. A protective fibrous cap normally forms between the fatty deposits and the artery lining (the
Intima ).
These capped fatty deposits (now called ''atheromas'') produce enzymes that cause the artery to enlarge over time. As long as the artery enlarges sufficiently to compensate for the extra thickness of the atheroma, then no narrowing,
Stenosis , of the opening, lumen, occurs. The artery becomes expanded with an egg-shaped cross-section, still with a circular opening. If the enlargement is beyond proportion to the atheroma thickness, then an
Aneurysm is created.Glagov S, Weisenberg E, Zarins CK, Stankunavicius R, Kolettis GJ. Compensatory enlargement of human atherosclerotic coronary arteries. ''
N Engl J Med '' 1987;316:131-1375. PMID
.
Autopsy specimen.]]
Although arteries are not typically studied microscopically, two plaque types can be distinguished
{Link without Title} :
# ''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.
# ''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 fibres (eosinophilic), precipitates of calcium (hematoxylinophilic) and, rarely, lipid-laden cells.
In effect, the muscular portion of the artery wall forms small
Aneurysm s just large enough to hold the
Atheroma that are present. The muscular portion of artery walls usually remain strong, even after they have remodeled to compensate for the
Atheroma tous plaques.
However,
Atheroma 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 or
Electron Beam Tomography (EBT) as rings of increased radiographic density, forming halos around the outer edges of the atheromatous plaques, within the artery wall. On CT, >130 units on the
Hounsfield Scale {some argue for 90 units) has been the radiographic density usually accepted as clearly representing tissue calcification within arteries. These deposits demonstrate unequivocal evidence of the disease, relatively advanced, even though the lumen of the artery is often still normal by angiographic or
Intravascular Ultrasound .
Although the disease process tends to be slowly progressive over decades, it usually remains asymptomatic until an atheroma obstructs the bloodstream in the artery. This is typically by rupture of an atheroma, clotting and fibrous organization of the clot within the lumen, covering the rupture but also producing
Stenosis , or over time and after repeated ruptures, resulting in a persistent, usually localized stenosis. Stenoses can be slowly progressive, while plaque rupture 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 and
Tissue Factor ; they activate
Platelet s and activate the
System Of Coagulation . The result is the formation of a
Thrombus (blood clot) overlying the atheroma, which obstructs blood flow acutely. With the obstruction of blood flow, downstream tissues are starved of
Oxygen and nutrients. If this is the
Myocardium (heart muscle),
Angina (cardiac chest pain) or
Myocardial Infarction (heart attack) develops.
Areas of severe narrowing,
Stenosis , detectable by angiography, and to a lesser extent "
Stress Testing " have long been the focus of human diagnostic techniques for
Cardiovascular Disease , in general. However, these methods focus on detecting only severe
Narrowing , not the underlying atherosclerosis disease. As demonstrated by human clinical studies, most severe events occur in locations with heavy plaque, yet little or no lumen
Narrowing present before debilitating events suddenly occur. Plaque rupture can lead to artery lumen occlusion within seconds to minutes, and potential permanent debility and sometimes sudden death.
Greater than 75% lumen
Stenosis 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 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 . The majority of events occur due to atheroma plaque rupture at areas without
Narrowing sufficient enough to produce any
Angina or
Stress Test 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 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 . Obstruction of arteries supplying the brain result in a
Stroke . 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 medial thickness) measurement by ultrasound, and (3) IVUS.
Examples of physiologic methods include: (1) lipoprotein subclass analysis, (2) HbA1c, (3) hs-CRP, and (4) homocysteine.
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.
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 ":
- Advanced Age
- Male sex
- Having Diabetes or Impaired Glucose Tolerance (IGT) +
- Dyslipoproteinemia (unhealthy patterns of serum proteins carrying fats & Cholesterol ): +
- --- High serum concentration of Low Density Lipoprotein (LDL, "bad if elevated concentrations and small"), Lipoprotein(a) (a variant of LDL), and / or Very Low Density Lipoprotein (VLDL) particles, i.e. "lipoprotein subclass analysis"
- --- Low serum concentration of functioning High Density Lipoprotein (HDL "protective if large and high enough" particles), i.e. "lipoprotein subclass analysis"
- Tobacco Smoking
- Having High Blood Pressure +
- Being Obese (in particular Central Obesity , also referred to as ''abdominal'' or ''male-type'' obesity) +
- A Sedentary Lifestyle
- Having close relatives who have had some complication of atherosclerosis (eg. Coronary Heart Disease or Stroke )
- Elevated serum levels of Homocysteine
- Elevated serum levels of Uric Acid (also responsible for gout)
- Elevated serum Fibrinogen concentrations +
- Chronic systemic Inflammation 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. Deepak L. Bhatt, MD; Eric J. Topol, MD ''Need to Test the Arterial Inflammation Hypothesis'', 2002, referenced on 4/1/06
- Stress or symptoms of Clinical Depression
- Hypothyroidism (a slow-acting Thyroid )
- High intake of trans-fats and saturated fats in diet
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.
Lipoprotein Imbalances , upper normal and especially elevated blood sugar, i.e.
Diabetes , high blood pressure,
Homocysteine , stopping smoking, taking
Anticoagulant 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 which have proved to be helpful in clinical trials. The target serum cholesterol level is ideally equal or less than 4mmol/L (160 mg/dL) and triglycerides equal or less than 2mmol/L 180 (mg/dL).
In general, the group of medications referred to as statins has seen popularity yet they are not approved in most jurisdictions for treating atherosclerosis. They have relatively few short-term undesirable side-effects and have shown some effect in reducing atherosclerotic disease 'events' in some but not all studies such as
ALLHAT .
The newest statin, begin forming.
Lowering
Lipoprotein Little A , a genetic variant of LDL, can be achieved with large daily doses of vitamin B3, niacin. Niacin also tends to shift LDL particle distribution to larger particle size and improve HDL functioning. Work on increasing HDL particle concentration and function, beyond the niacin effect, perhaps even more important, is slowly advancing. Combinations of
Statin s,
Niacin , intestinal cholesterol absorption inhibiting supplements (
Ezetimibe and others, and to a much lesser extent
Fibrate s have been the most successful in changing
Dyslipidemia patterns and but, in the case of inhibitors and fibrates without improving clinical outcomes in secondary prevention. In primary prevention, cholesterol lowering agents have not reduced the mortality rates, for example the AFCAPS/TexCAPS and EXCEL trials and the 2 main trials with atorvastatin, Lipitor, as in the ASCOT and SPARCL studies. Dietary changes to achieve benefit have been more controversial, generally far less effective and less widely adhered to with success.
Evidence has increased that people with
Diabetes , despite not having clinically detectable atherosclotic disease, have more severe debility from atherosclerotic events over time than even non-diabetics who have already suffered atherosclerotic events. Thus
Diabetes has been upgraded to be viewed as an advanced atherosclerotic disease equivalent.
Lowering
Homocysteine levels, including within the normal range and 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 Controlled human clinical trials.
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.
Other physical treatments, helpful in the short term, include minimally invasive
Angioplasty procedures to physically expand narrowed arteries and major invasive surgery, such as
Bypass Surgery , to create additional blood supply connections which go around the more severely narrowed areas.
High dose supplements of vitamin E or C, with the goal of improving
Antioxidant protection, have failed to produce any beneficial trends in human, double blind, clinical research trials. However, these trials have consistently used lower doses than those claimed to be effective and have ignored the short half life of high intakes of
Vitamin C in the body.
On the other hand, the
Statin s, and some other medications have been shown to have
Antioxidant effects, possibly part of their basis for some of their therapeutic success in reducing cardiac 'events'.
