Atherosclerosis or arteriosclerotic vascular disease (ASVD) is a clinical condition identified by thickening of the arterial walls due to the accumulation of cholesterol chiefly the low density lipoproteins. It is a syndrome affecting arterial blood vessels due to which they become hard. The hardening of arterial walls is due to the formation of multiple plaques. The atheromatous plaque is composed of three components chiefly, atheroma which is a nodular accumulation of soft material in the center of large plaques, followed by cholesterol crystals and calcified components. Atherosclerosis is a chronic disease that can remain asymptomatic for decades and the plaques may be stable or unstable. Stable atherosclerotic plaques tend to be asymptomatic and are loaded with extracellular matrix and smooth muscle cells while unstable plaques contain macrophages and foam cells along with extracellular matrix that are liable to rupture.
The soft plaque ruptures suddenly resulting in the formation of thrombus that obstructs blood flow causing death of tissues within 5 minutes. This event is known as infarction. If same process occurs in the arteries supplying brain then it is termed as a stroke. Atherosclerosis is a slow disease characterized by hardened and clogged arteries resulting 75% deaths all over the world due to cardiovascular strokes. 80-90% of Americans over the age of 30 die of heart attack caused by clogging of the arteries. Fat, cholesterol, calcium and other substances are responsible for the formation of plaques that make the arteries hard and obstruct blood flow resulting in heart attack. If the arteries that bring oxygen-rich blood to the heart are blocked then the person may suffer from chest pain, coronary artery disease or heart attack. Lowering the blood pressure, minimizing bad cholesterol levels and consumption of a healthy diet with enough proportion of fruits and vegetables, losing excessive body weight, quitting smoking and alcohol intake and regular exercise can minimize the risk of atherosclerosis.
Signs and symptoms
In majority of the cases people suffering from atherosclerosis don't have visible symptoms unless 40% of the arteries become blocked. The symptoms depend upon the fraction of arteries clogged with plaque. The most common symptoms of the coronary artery disease include chest, abdominal, back, jaw or shoulder pain, shortness of breath followed by weakness and perspiration. Cerebrovascular disease occurs due to narrowing of arteries of brain. The symptoms include weakness or paralysis on one side of body, problem in speaking, loss of vision in one eye, muscle weakness, dizziness, loss of balance and severe headache. Peripheral artery disease occurs when the arteries supplying the oxygen-rich blood to the arms and neck are clogged. The symptoms comprise pain, aching, numbness of limbs, cramps, hair loss, thickened nails, gangrene, and smooth, shiny skin surface.
Causes
The main cause of atherosclerosis is yet not known but it is believed that the inflammatory response initiated in the arterial walls due to excessive deposition of low density lipoproteins or bad cholesterol molecules causes this disease. When LDL molecules invade the cells they become oxidized by the action of free radicals forming toxic substances and atheroma appears. The LDL molecules are identified by the presence of heavy core carrying cholesterol to all parts of body. The immune system of the body becomes activated when the arterial wall is damaged by the LDL molecules and immediately releases macrophages and T-lymphocytes to absorb the oxidized-LDL molecules thus, forming foam cells.
The white blood cells of immune system are not able to process these LDL molecules for a long time so they start accumulating on the arterial walls making them hard. This hard covering of cholesterol results in narrowing of the arteries so the blood flow obstructs and blood pressure increases. Some researchers believe that atherosclerosis is the result of the infection caused in the smooth muscle cells of heart for example, chickens suffer from atherosclerosis when they are attacked by Marek's disease herpesvirus. Herpesvirus infection of the smooth muscles of heart causes cholesteryl ester (CE) accumulation. The accumulation of cholesteryl ester results in atherosclerosis. Infection with cytomegalovirus is also associated with the cardiovascular disease.
Risk factors
A number of anatomical, physiological and behavioral risk factors are known to be associated with atherosclerosis. The risk factors may be classified as congenital or acquired, modifiable or non-modifiable, classical or non-classical. Modifiable factors include diabetes or impaired glucose tolerance, high serum concentration of LDL or low concentration of high density lipoproteins. The LDL: HDL ratio becomes greater than 3:1. Tobacco smoking also increases the risk of stroke by 200%. Hypertension, vitamin B6 deficiency and elevated serum C-reactive protein concentration are other modifiable factors. The non-modifiable factors include, advanced age, male sex, familial history of coronary artery disease or atherosclerosis or genetic abnormalities like familial hypercholesterolemia. The uncertain factors include, obesity, hypercoagulability, post-menopausal estrogen deficiency, high intake of saturated fats, intake of trans fat, high carbohydrate intake, increased levels of triglycerides and homocysteine.
There is a very close relation between the dietary fat and atherosclerosis. The American Heart Association and the American Diabetes Association and the National Cholesterol Education Program recommend low intake of fat in the diet as it is atherogenic. Professor Walter Willett suggests that intake of unsaturated and polyunsaturated fats can reduce the risk of heart attack. The exact role of dietary oxidized fats in humans is not yet understood. Laboratory animals when fed on dietary fats developed atherosclerosis. Laboratory rats when fed on the DHA-containing oils showed significant accumulation of phospholipid peroxide in blood, liver and kidneys. In a study rabbits were allowed to feed on heated soybean oil and they developed symptoms of atherosclerosis.
Pathophysiology
Atherogenesis is the process of formation of atheromatous plaques identified by the deposition of fatty substances in the subendothelial spaces of arterial walls. The development of athermatous plaques is a slow process and it may take several years to flourish well as it is acted upon by a number of factors like cellular processes and other vascular events. One recent theory suggests that the leukocytes especially the monocytes begin to attack the endothelial lining of the arteries for unknown reasons resulting in the formation of athermatous plaques.
Cellular processes
The beginning of athermatous plaque is identified by adherence of the monocytes on the endothelial lining of arteries followed by their migration to the sub-endothelial spaces resulting in activation of macrophages. The presence of oxidized lipoprotein molecules in the arterial walls or elevated levels of glucose act as key factors for formation of athermatous plaques but real causes are not known. Fatty streaks may or may not be present. When the low density lipoproteins present in the blood plasma get oxidized in the endothelial wall of the arteries then the risk of cardiovascular disease increases. A complex series of biochemical reactions participate in the oxidation of low density lipoproteins for example, enzymes like Lp-LpA2 and presence of free radicals in the endothelium. Inflammatory response is the primary symptom that arises when the wall of the blood vessels is attacked. Monocytes enter the arterial wall through the blood stream and start adhering to it and the redox signaling factors like VCAM-1 accelerate the process. Here the monocytes differentiate into macrophages that ingest the oxidized LDL molecules. These oxidized LDL molecules finally get converted into foam cells and the arterial wall now gets loaded with high lipid concentration. These foam cells finally die and propagate the inflammatory process.
Calcification and lipids
The vascular smooth muscle cells surrounding the athermatous plaques show the presence of intracellular microcalcifications. As the cells die, extracellular calcium accumulation occurs between the muscle wall and outer portion of atheromatous plaques. The low density lipoprotein particles are responsible for delivering cholesterol to the wall of the blood vessels. For the stimulation of macrophages cholesterol must be released from the low density lipoprotein molecules so that the inflammatory response may be produced. The process is hampered if high density lipoproteins remove the cholesterol from the tissues and send them back to the liver. Foam cells and platelets encourage proliferation of smooth muscle cells which in turn ingest lipids and finally get transformed into foam cells. A protective fibrous cap is usually formed between the fatty deposits and artery lining. These caps produce enzymes that cause enlargement of the arteries.
Visible features
Two types of athermatous plaques are identified. First is the fibro-lipid plaque characterized by the presence of lipid-laden cells underneath the intima of arteries. The endothelium has a fibrous cap surrounding the atheromatous core of the plaque. The core consists of lipid-laden cells with high concentration of cholesterol, cholesterol ester content, fibrin, proteoglycans, collagen, elastin and cellular debris. In advanced plaques the core is marked by the presence of extracellular cholesterol deposits that form cholesterol crystals. The periphery of the plaques is characterized by the presence of younger foam cells and capillaries. The plaques cause tremendous damage when they rupture. The second type of atheromatous plaques is the fibrous plaques also present under the intima and are responsible for the expansion and thickening of the arterial wall. The fibrous plaques are rich in collagen fibers, precipitates of calcium and very rarely lipid-laden cells.
Due to the presence of atheromatous plaques the muscular portion of the arterial wall forms small aneurysms. The muscular portion of the arterial wall however remains strong although it is remodeled to compensate for the atheromatous plaques. The atheromas present within the walls of the vessels are soft, fragile with very little elasticity. The arteries constantly expand and contract with each heart beat. The calcium deposits present on the outer portion of the atheroma and muscular wall result in loss of elasticity and cause stiffening of the arteries. In advances stages the calcium deposits are easily visible in the computerized tomography (CT) or electron beam tomography (EBT).
Rupture and stenosis
Although the disease is very slow and takes years to flourish completely it may become dangerous if the atheroma ulcerates causing immediate blood clotting at the site of atheroma ulcer. This causes enlargement of clot that obstructs blood flow. A complete blockage of the arteries results in the development of ischemia of myocardial muscles thus, increasing the risk of heart attack. If heart attack is not fatal then the fibrous organization of the clot in the lumen may lead to stenosis or closure of the arterial lumen in the successive years. Stenosis is a slow but progressive process but ulceration is a sudden event.
Diagnosis
Stenosis can be detected by angiography and stress testing. These methods generally focus on the detection of narrowing of arteries but not on the atherosclerosis disease. Human clinical studies have indicated that severe symptoms occur in the areas of heavy plaques. Plaques finally rupture leading to occlusion of the arterial lumen within few minutes causing permanent debility and even death. Ruptured plaques are sometimes known as complicated plaques. The extracellular matrix of the lesion breaks and exposes the thrombogenic material resulting in the formation of thrombus. The thrombus so formed grows in size, travels downstream and occludes a narrow artery. Once the artery is blocked blood and oxygen are not able to pass through it causing death of the cells followed by necrosis and poisoning. Serious complicated plaques can damage the organ tissues resulting in severe problems.
Greater than 75% lumen stenosis of the bigger arteries is considered as the hallmark of cardiovascular disease by the medical experts as the symptoms of angina or chest pain are detected by the stress testing. Atheroma plaques are responsible for most of the problems associated with heart. In order to cause a cardiovascular disease any artery of the body can be clogged but severe narrowing of arteries that supply blood to the critically important organs is considered as the key factor of the disease. Obstruction of blood flow in the arteries supplying heart muscles result in heart attack. Obstruction of blood flow in the arteries supplying brain causes stroke. These events are life changing and can result in permanent impairment of organs involved as the lost heart and brain cells do not grow back to significant extent.
Over the last few decades techniques other than angiography and stress testing have been developed that can detect atherosclerotic disease more easily and with greater accuracy. These methods include both anatomic detection methods and physiologic measurement methods. The anatomic methods include coronary calcium scoring by using computerized tomography, carotid intimal media thickness (IMT) measurement by ultrasound and intravascular ultrasound (IVUS). However, the physiologic methods include lipoprotein subclass analysis, HbA1c, hsCRP and homocysteine detection. The metabolic syndrome combines both anatomic and physiologic methods. Both anatomic and physiologic methods have many advantages for example, anatomic methods can detect some aspects of the actual atherosclerotic disease before the symptoms may appear. Physiologic methods are however, less expensive and can slow down disease progression. Apart from advantages these methods are also coupled with disadvantages like anatomic method is very expensive like the IVUS while the physiologic methods do not track the current state of the disease.
Treatment
Healthy lifestyle choices are helpful in the prevention and treatment of atherosclerosis. A medial expert may prescribe drugs to lower blood cholesterol levels as well as control blood pressure. Nutrition and dietary supplements can be associated along with the medications. Some herbs have given positive results in lowering blood cholesterol levels as well as in reducing the risk of heart disease. Commonly prescribed cholesterol lowering drugs include statins that are easy to take and have little or no interaction with other drugs. Their side effects include myositis, joint pain, stomach problems and liver damage. Individuals suffering from liver disease as well as pregnant females must not take statins. Niacin is also used to lower blood cholesterol. It is effective in increasing the HDL levels but the side effects include redness of skin, headache, stomach problems, dizziness and liver damage. Niacins should not be taken without the prescription of the doctor. Bile acid sequestrants are also used against the elevated levels of blood cholesterol. The common side effects associated with them include bloating, constipation, and heartburn. Individuals with high levels of triglycerides must not take these drugs.
The common blood pressure lowering drugs include beta blockers that slow down the heart beat and reduce the proportion of stress reducing hormones in the body. Angiotensin converting enzyme (ACE) inhibitors block the formation of angiotensin in the body and thus, prevent narrowing of the blood vessels. As the blood vessels relax the blood pressure is lowered. Calcium channel blockers block calcium from entering the arteries thus resulting in the relaxation of blood vessels and lowering of blood pressure. Side effects include constipation, nausea and headache. Angiotensin II receptor blockers (ARBs) are used for blocking the effects of angiotensin formed in the body resulting in the lowering of blood pressure. Diuretics help an individual to get rid of excess water and sodium from the body. This results in declination of blood volume and lowering of blood pressure. Sometimes drugs of these classes can be combined depending upon the condition of the individual. Blood thinning drugs like aspirin, heparin, warfarin are used to prevent the formation of blood clots.
Both surgical and nonsurgical procedures may be used depending upon the narrowing and blockage of the arteries. Nonsurgical procedures include angioplasty which is used for the widening of the narrowed arteries followed by atherectomy which includes removal of plaques from the arteries. Surgical procedures include bypass surgery and endartectomy used for the removal of plaques from the carotid and peripheral arteries. Healthy diet can help in reducing the elevated levels of blood cholesterol, lower blood pressure and control obesity that are the risk factors for the cardiovascular disease. A number of herbs have also given promising results in lowering the cholesterol levels for example, hawthorn, garlic, olive leaf extract, guggul, red yeast rice and psyllium. Acupuncture may also help in reducing the risk of heart attack. It can be of help to the individuals who want to quit smoking. Homeopathy can also help in reducing the risk of heart disease.
Preventive care
A person can remain free from the risk of heart disease by quitting smoking, regular exercise for about 30 minutes in a day. Eating healthy foods like fruits, vegetables and whole grains that are low in saturated fat but high in fiber content. A normal body weight is maintained. Reduction of stress and lowering of blood pressure also help in staying away from the risk of cardiovascular diseases.
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