Atherosclerosis
Atherosclerosis (hardening of the arteries) is a disease affecting the arterial blood vessel. 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 atheromatous plaque comprises of the atheroma which is the nodular accumulation of a soft, flaky, yellowish material at the center of large plaques, composed of macrophages nearest the lumen of the artery, sometimes with underlying areas of cholesterol crystals, and possibly also calcification at the outer base of older/more advanced lesions.
Arteriosclerosis results from a deposition of tough, rigid collagen inside the vessel wall and around the atheroma. This increases the stiffness, decreases the elasticity of the artery wall. Arteriolosclerosis (hardening of small arteries called arterioles) is the result of collagen deposition. In many cases the thickening of the muscle wall is also caused by deposition of protein (hyaline). Calcification, sometimes even ossification (formation of complete bone tissue) occurs within the deepest and oldest layers of the sclerosed vessel wall.
Atherosclerosis causes two main problems. Firstly, the gradual deposition of the atheromatous plaques eventually leads to plaque ruptures and stenosis (narrowing) of the artery which in turn results in insufficient blood supply to the organ it feeds.
Alternatively, if the compensating artery enlargement process is excessive, then a net aneurysm is possible.
These complications are chronic, slowly progressing and cumulative. Most commonly, soft plaque suddenly ruptures; causing the formation of a blood clot (thrombus) that rapidly slows or stops blood flow, leading to death of the tissues fed by the artery. This 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 cases is claudication which occurs due to insufficient blood supply to body parts, typically due to a combination of both stenosis and aneurysmal segments narrowed with clots. This can effect the arteries to the brain, intestines, kidneys, legs, etc.
Atherosclerosis typically begins in early adolescence, yet is asymptomatic and not detected by most diagnostic methods during life. It most commonly becomes seriously symptomatic when interfering with the coronary circulation supplying the heart or cerebral circulation supplying the brain. It is considered the most important underlying cause of strokes, heart attacks, various heart diseases including congestive heart failure and most cardiovascular diseases in general. Atheroma in arm or more often leg arteries and producing decreased blood flow is called Peripheral artery occlusive disease (PAOD).
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%.
Atherogenesis
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 intima. The bulk of these lesions are made of excess fat, collagen, and elastin. The plaques initially grow without producing any narrowing, stenosis, of the artery opening, called the lumen.
Cellular
The first step of atherogenesis is the development of fatty streaks, small subendothelial deposits of lipid. The exact cause for this process is unknown, and fatty streaks may appear and disappear.
low-density lipoprotein (LDL) in blood plasma poses a risk for cardiovascular disease when it invades the endothelium and becomes oxidized.
The initial damage to the blood vessel wall results in an inflammation response. Monocytes (a type of white blood cell) enter the artery wall from the bloodstream, with platelets adhering to the area. The monocytes differentiate into macrophages, which ingest oxidized LDL, slowly turning into large "foam cells" %u2013 so-described because of their changed appearance. Under the microscope, the lesion now appears as a fatty streak. Foam cells eventually die, and further propagate the inflammatory process.
Calcification and lipids
Intracellular microcalcifications form within vascular smooth muscle cells of the surrounding muscular layer. 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 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.
Visible features
Although arteries are not typically studied microscopically, two plaque types can be distinguished:
The fibro-lipid (fibro-fatty) plaque is characterized by an accumulation of lipid-laden cells underneath the intima of the arteries, typically without narrowing the lumen due to compensatory expansion of the bounding muscular layer of the artery wall. Beneath the endothelium there is a "fibrous cap" covering the atheromatous "core" of the plaque. The core consists of lipid-laden cells (macrophages and smooth muscle cells) with elevated tissue cholesterol and cholesterol ester content, fibrin, 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.
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 aneurysms 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 atheromatous plaques.
However, atheromas within the vessel wall are soft and fragile with little elasticity. Arteries constantly expand and contract with each heartbeat, i.e., the pulse. In addition, the calcification deposits between the outer portion of the atheroma and the muscular wall lead to a loss of elasticity and stiffening of the artery as a whole.
Rupture and stenosis
Although the disease slowly progresses 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 orgnization of the clot within the lumen, covering the rupture and 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.
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.
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 platelets and the system of coagulation. The result is the formation of a 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 heart muscle, angina or heart attack develops.
Diagnosis of plaque-related disease
Angigraphy and sometimes Stress Testing have been used extensively to diagnose areas of severe stenosis and cardio vascular diseases in general. However, these methods detect only severe narrowing, not the underlying atherosclerosis disease. Most severe events occur in locations with heavy plaque, yet little or no lumen narrowing is present before the event suddenly occurs. Plaque rupture can lead to artery lumen occlusion within seconds to minutes, and potential permanent debility and sometimes sudden death.
77% lumen stenosis used to be considered as the hallmark of clinically significant disease because it is only at this severity of narrowing of the larger heart arteries that recurring episodes of angina and detectable abnormalities by stress testing 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."
Evidence has increased that people with diabetes, despite not having clinically detectable atherosclotic disease, have more severe debility than even non-diabetics who have already suffered atherosclerotic events. Thus diabetes has been upgraded to be viewed as an advanced atherosclerotic disease equivalent.
Physiologic factors that increase risk
Advanced age
Male sex
Having Diabetes or Impaired glucose tolerance (IGT)
Dyslipidemia (elevated serum cholesterol or triglyceride levels)
High serum concentration of LDL, lipoprotein, and / or very low density lipoprotein (VLDL) particles
Low serum concentration of functioning high density lipoprotein
Tobacco smoking
Having high blood pressure
Being obese
A sedentary life-style
Having close relatives who have had some complication of atherosclerosis
Elevated serum levels of homocysteine
Elevated serum levels of uric acid
Elevated serum fibrinogen concentrations
Chronic systemic inflammation
Stress or symptoms of clinical depression
Hypothyroidism
Treatment
If atherosclerosis leads to symptoms, the symptoms (such as angina pectoris) can be treated. Non-pharmaceutical means are usually the first method of treatment, such as cessation of smoking and/or 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.
In general, the group of medications referred to as statins have been the most successful, with the lowest rates of undesirable side-effects, approach to reducing atherosclerotic disease events. The newest statin, rosuvastatin, has been the first to demonstrate regression of atherosclerotic plaque within the coronary arteries.
However, for most people, changing their physiologic behaviors requires a combination of several compounds, taken on a daily basis and indefinitely. More human treatment trials have been done which demonstrate improved outcome for those people using more complex and effective treatment regimens.
Aerobic exercise, weight loss, and dietary changes can also help, but are generally much less effective and often more problematic for many to achieve and continue long term.
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 statins, niacin, intestinal cholesterol absorption inhibiting supplements have been the most successful in changing dyslipidemia patterns and improving clinical outcomes in secondary prevention.
In primary prevention, cholesterol lowering agents have also reduced the mortality rates, however longer periods are sometimes required to demonstrate the effect because of the usual delay until enough people show the effects of advancing disease without effective treatment. Dietary changes to achieve this have been more controversial, generally far less effective and less widely adhered to with success.
Some 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.
The statins, and some other medications have been shown to have significant antioxidant effects, perhaps part of their basis for major theraputic success.
Over the last about 18 years, the treatment data results have become so encouraging that some physician leaders are anticipating the day, probably within another 10 to 15 years, that clinical disability from atherosclerotic disease will become a disease only of the past, at least for those who enjoy the benefit of using the treatment advances.
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. Additionally, 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.
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