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Atherosclerosis is a disease of arterial blood vessels or veins that have been surgically moved to function as an artery. Athēra is porridge in Greek, as the plaque changes have a foamy appearance under high power light microscopy. Sclerosis denotes hardening.
Atherosclerosis is commonly referred to as a "hardening" or "furring" of blood vessels, but this is an oversimplification. Vascular lesions known as atheromas (or atheromata or atheromatous plaques) develop in the vessel wall, and in late stages may reduce or restrict blood flow in the lumen (stenosis), as well as rupturing and leading to downstream tissue damage.
Symptoms
Atherosclerosis typically begins in later childhood, is usually found in most major arteries, 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, and 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 may cause Peripheral artery occlusive disease (PAOD).
According to United States data, 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 symptom onset).
Most artery flow disrupting events occur at locations with less than 50% lumen narrowing (~20% stenosis is average). Cardiac stress testing, 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
Atherogenesis is the developmental process of atheromatous plaques. It is characterized by a remodeling of arteries involving an accumulation of macrophage cells forming atheroma or atheromatous plaques, which contain an excess of fatty cellular membranes within the arterial wall. The plaques are always located between the intima lining and muscular portion of the artery wall, typically 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.
The initial damage to the blood vessel wall results in a "call for help", an inflammation response. Monocytes (a type of white blood cell) enter the artery wall from the bloodstreams. The monocytes differentiate into macrophages, which ingest oxidized cholesterol, slowly turning into large "foam cells" – so described because of their changed appearance resulting from numerous internal cytoplamic vesicles and resulting high lipid content. Microscopically, 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, 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.
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 which 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 and egg shaped, 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[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.
- 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 rare lipid-laden cells.
In effect, small aneurysms of the muscular portion of the artery wall form aneurysms just large enough to hold the atheroma which 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, as they progress, lead to a loss of elasticity, 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.
Stenosis and rupture
Although the disease process tends to be slowly progressive over decades, it usually remains asymptomatic until the atheroma obstructs the bloodstream in the artery. This is either by stenosis or by rupture of the atheroma, or often by a combination of both. Stenosis is slowly progressive, with plaque rupture is a sudden event that occurs specifically in atheromas with thinner/weaker fibrous caps that have become "unstable".
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 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) develop.
Diagnosis of plaque-related disease
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 only on detecting 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.
70% lumen stenosis used to be considered by cardiologists 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".
Though any artery in the body can be involved, usually only severe narrowing or obstruction of some arteries, those which 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%.
Risk factors
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):
- aging and being male (women have more problems after menopause, but hormone replacement therapy worsens rather than improves the event rates)
- tobacco smoking
- having close relatives who had heart disease or a stroke at a relatively young age
- having diabetes or just upper normal blood glucose and insulin levels, even though not considered to be in the diabetes range (any glycosolated hemoglobin, HbA1c, above 5.0 according to a European trial reported in 2001)
- having high blood pressure
- dyslipidemia (elevated cholesterol or triglyceride levels):
- being physically less active, especially aerobic exercise
- chronic sub-clinical scurvy (vitamin C deficiency, now rare in most parts of the world)
- being obese (especially central obesity, which is abdominal or male-type obesity)
- chronic inflammation appears to predispose to atherosclerosis, which may be indicated by elevated C-reactive protein levels
- elevated fibrinogen blood concentrations
- elevated levels of homocysteine
- having trouble managing stress, especially anger, and having symptoms of depression
Treatment
If atherosclerosis leads to symptoms, the symptoms (such as angina pectoris) can be treated. Medicines are usually the first step in treating cardiovascular diseases, and with improvements, have increasingly become the most effective method over the long term. However, medicines are critised 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 anticoagulants (anti-clotting agents) which target platelets, taking Omega 3 oils from salt-water fish meats, exercising and losing weight are the usual focus of treatments which have proved to be helpful in clinical trials.
Dramatic lowering of lipoprotein levels, including to very abnormally low levels for adults (especially of the smaller lipoprotein particles), and elevating the large particle (HDL) can slow, stop, or even partially reverse the buildup of plaque, as demonstrated in clinical trials. LDL lowering can reduce the macrophage and lipid content and size of unstable plaques, making them more stable and less prone to rupture. Lowering lipoprotein little a, a genetic variant of the LDLipoproteins, can be achieved with large daily doses of vitamin B3, niacin. Niacin also tends to shift LDLipoprotein particle distribution to larger particle size and improve HDLipoprotein 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 (ezetimibe and others, and to a much lesser extent fibrates have been the most successful in changing dyslipidemia patterns and improving clinical outcomes. Dietary changes to achieve this 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.
Aerobic exercise, weight loss, and dietary changes can also help in major ways, but are often more problematic for many to achieve and continue long term.
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.
Unfortunately, high dose supplements of vitamin E and/or C, with the goal of improving antioxidant protection, have failed to produce any beneficial trends in human, double blind, clinical research trials. On the other hand, the statins, and some other medications have been shown to have significant antioxidant effects, perhaps part of their basis for theraputic success.
The french paradox research shows that drinking red wine,Cabernet Sauvignon or purple grape juice high in flavanoid antioxidants can reduce platelets from sticking and reduce coronary heart disease.
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, both before and especially after people are symptomatic. However, treating asymptomatic people remains controversial in the medical community.
Patients at risk for atherosclerosis-related diseases are increasingly being treated prophylactically with low-dose aspirin and a statin. The high incidence of cardiovascular disease led Wald and Law (2003) to propose a Polypill, a once-daily pill containing these two types of drugs in addition to an ACE inhibitor, diuretic and beta blocker and folic acid. They maintain that high uptake by the general population by such a Polypill would reduce cardiovascular mortality by 80%.
Recent research
Progress on methods to improve HDLipoprotein particle concentrations and function, which in some animal studies largely reverses and remove atheromas, are being developed and researched. The most dramatic demonstrations of potential HDL efficacy to reverse atherosclerosis has been with the rare Apo-A1 Milano human genetic variant of the HDL protein.
Genentic expression and control mechanism research, including (a) the PPAR peroxisome proliferator activated receptors known to be important in blood sugar and variants of lipoprotein production and function and (b) of the multiple variants with the proteins which form the lipoprotein transport particles, is progressing.
Some controversial research has suggested a link between atherosclerosis and the presence of nanobacteria in the arteries, though trials of current antibiotic treaments have not been successful in improving outcomes. If this suspicion should be verified in further research, then additional bases for inflammation and options for treatment of the disease may be found.
References
- Steven Nissen: Atherosclerosis Development, Clinical Cardiology Vol 27 (Suppl IV), 17-20, July 2004
- Wald NJ, Law MR. A strategy to reduce cardiovascular disease by more than 80%. BMJ 2003;326:1419. PMID 12829553.
- Peter Libby: Atherosclerosis: The New View, Scientific American Vol 286, No. 5, May 2002
- Steven Glasgov: Compensatory Enlargement of Human Atherosclerotic Coronary Arteries, N Engl J Med, 316:131-1375, 1987
- Merck Manual: Atherosclerosis, http://www.merck.com/pubs/mmanual/section16/chapter201/201b.htm
- Atlas of Pathology
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