Atherosclerosis Anca Bacrea Alexandru Schiopu Atherosclerosis l l

Atherosclerosis Anca Bacârea, Alexandru Schiopu

Atherosclerosis l l The term atherosclerosis, which comes from the Greek words atheros (meaning “gruel” or “paste”) and sclerosis (meaning “hardness”), denotes the formation of fibrofatty lesions in the intimal lining of the large and medium-size arteries such as the aorta and its branches, the coronary arteries, and the large vessels that supply the brain. Atherosclerosis contributes to more mortality and more serious morbidity than any other disorder in the western world.

Risk Factors l l The cause or causes of atherosclerosis have not been determined with certainty. Epidemiologic studies have identified predisposing risk factors: l Unchangeable risk factors l Age l Male gender § Men are at grater risk than are premenopausal women, because of the protective effects of natural estrogens. l Family history of premature coronary heart disease § Several genetically determined alterations in lipoprotein and cholesterol metabolism have been identified.

Risk Factors l Changeable risk factors – life style risk factors: l Hyperlipidemia l The presence of hyperlipidemia is the strongest risk factor for atherosclerosis in persons younger than 45 years of age. l Both primary and secondary hyperlipidemia increase the risk. l Cigarette smoking l Hypertension l High blood pressure produces mechanical stress on the vessel endothelium. l It is a major risk factor for atherosclerosis in all age groups and may be as important or more important than hypercholesterolemia after the age of 45 years. l Diabetes mellitus l Diabetes elevates blood lipid levels and otherwise increases the risk of atherosclerosis. l Insufficient physical activity l A stressful lifestyle l Obesity

Risk Factors l There a number of other less well-established risk factors for atherosclerosis, including: l High serum homocysteine levels l Homocysteine is derived from the metabolism of dietary methionine l Homocysteine inhibits elements of the anticoagulant cascade and is associated with endothelial damage. l Elevated serum C-reactive protein l It may increase the likelihood of thrombus formation; l Inflammation marker; l Infectious agents l The presence of some organisms (Chlamydia pneumoniae, herpesvirus hominis, cytomegalovirus) in atheromatous lesions has been demonstrated by immunocytochemistry, but no cause-and-effect relationship has been established. l The organisms may play a role in atherosclerotic development by initiating and enhancing the inflammatory response.

Pathology and pathogenesis l l The lesions associated with atherosclerosis are of three types: l The fatty streak l The fibrous atheromatous plaque l Complicated lesion The latter two are responsible for the clinically significant manifestations of the disease.

Pathology and pathogenesis l l l Fatty streaks are thin, flat yellow intimal discolorations that progressively enlarge by becoming thicker and slightly elevated as they grow in length. They consist of macrophages and smooth muscle cells that have become distended with lipid to form foam cells. These occurs regardless of geographic setting, gender, or race. They increase in number until about age 20 years, and then they remain static or regress. There is controversy about whether fatty streaks, in and of themselves, are precursors of atherosclerotic lesions.

Pathology and pathogenesis l l The fibrous atheromatous plaque is the basic lesion of clinical atherosclerosis. It is characterized by the accumulation of intracellular and extracellular lipids, proliferation of vascular smooth muscle cells, and formation of scar tissue. The lesions begin as a elevated thickening of the vessel intima with a core of extracellular lipid (mainly cholesterol, which usually is complexed to proteins) covered by a fibrous cap of connective tissue and smooth muscle. As the lesions increase in size, they encroach on the lumen of the artery and eventually may occlude the vessel or predispose to thrombus formation, causing a reduction of blood flow.

Pathology and pathogenesis l l l The more advanced complicated lesions are characterized by l Hemorrhage l Ulceration l Scar tissue deposits Thrombosis is the most important complication of atherosclerosis. It is caused by slowing and turbulence of blood flow in the region of the plaque and ulceration of the plaque.

Mechanisms l There is increasing evidence that atherosclerosis is at least partially the result of: l (1) endothelial injury with leukocyte (lymphocyte and monocyte) adhesion and platelet adherence l (2) smooth muscle cell emigration and proliferation l (3) lipid engulfment of activated macrophages l (4) subsequent development of an atherosclerotic plaque with lipid core

Mechanisms l l One hypothesis of plaque formation suggests that injury to the endothelial vessel layer is the initiating factor in the development of atherosclerosis. l Possible injurious agents are: l Products associated with smoking; l Immune mechanisms; l Mechanical stress, such as that associated with hypertension. Hyperlipidemia, particularly LDL with its high cholesterol content, is also believed to play an active role in the pathogenesis of the atherosclerotic lesion.

LDL - cholesterol l l l The LDL is removed from the circulation by either LDL receptors or by scavenger cells such as monocytes or macrophages. Approximately 70% of LDL is removed by way of the LDL receptor dependent pathway. Although LDL receptors are widely distributed, approximately 75% are located on hepatocytes; thus the liver plays an extremely important role in LDL metabolism. Tissues with LDL receptors can control their cholesterol intake by adding or removing LDL receptors. The scavenger cells, such as the monocytes and macrophages, have receptors that bind LDL that has been oxidized or chemically modified. The amount of LDL that is removed by the “scavenger pathway” is directly related to the plasma cholesterol level. When there is a decrease in LDL receptors or when LDL levels exceed receptor availability, the amount of LDL that is removed by scavenger cells is greatly increased. The uptake of LDL by macrophages in the arterial wall can result in the accumulation of insoluble cholesterol esters, the formation of foam cells, and the development of atherosclerosis.

Mechanisms l l l One of the earliest responses to elevated cholesterol levels is the attachment of monocytes to the endothelium. The monocytes emigrate through the cell-to-cell attachments of the endothelial layer into the subendothelial spaces, where they are transformed into macrophages. Activated macrophages release free radicals that oxidize LDL. Oxidized LDL is not recognized at the cell receptor level and so, it can not be internalized and it longer remains into the blood stream. Oxidized LDL is toxic to the endothelium, causing endothelial loss and exposure of the subendothelial tissue to blood components: l It has chemotactic effect on lymphocytes and monocytes; l It has chemotactic effect on smooth muscle cells from the arterial media and stimulates production of MG-CSF, cytokines, adhesion molecules in the endothelium; l It inhibits endothelium derived releasing factor (EDRF), favoring vasospasm; l It stimulates specific immune system (production of antibodies against oxidized LDL).

Mechanisms l l l Endothelial disruption leads to platelet adhesion and aggregation and fibrin deposition. Platelets and activated macrophages release various factors that are thought to promote growth factors that modulate the proliferation of smooth muscle cells and deposition of extracellular matrix in the lesions: elastin, collagen, proteoglycans. Activated macrophages also ingest oxidized LDL to become foam cells, which are present in all stages of atheroscleroticplaque formation. Lipids released from necrotic foam cells accumulate to form the lipid core of unstable plaques. Connective tissue synthesis determinates stiffness, calcium fixation and further ulceration of atheromatous plaque.

Glycosylation and atherosclerosis l l Glycosylation is a process that affects lipoproteins, circulating proteins and proteins component of the arterial wall. Effects: l Glycated LDL stimulates platelet aggregation and forms covalent bounds with the proteins of the arterial wall. l Glycated HDL blocks cholesterol efflux from the cells. l Collagen glycosylation increases arterial wall stiffness, activates macrophages and stimulates lipoprotein adherence. l Glycosylated proteins form circulating antigens which generates antibody and circulating immune complexes that will lead to other arterial lesions.

Modern theory of atherosclerosis l Multifactor theory: l Structural and functional injury of vascular endothelium; l Response to injury of immune cells and smooth muscle cells; l The role of lipoproteins in initiation and progression of lesions; l The role of growth factors and cytokines; l The role of repeated thrombosis in lesions progression.

Mechanisms l As a result of all presented above atherosclerosis can be defined as vicious inflammatory process.

Clinical Manifestations l l l The clinical manifestations of atherosclerosis depend on the vessels involved and the extent of vessel obstruction. Atherosclerotic lesions produce their effects through: l narrowing of the vessel and production of ischemia; l sudden vessel obstruction caused by plaque hemorrhage or rupture; l thrombosis and formation of emboli resulting from damage to the vessel endothelium; In larger vessels such as the aorta, the important complications are those of thrombus formation and weakening of the vessel wall. In medium-size arteries such as the coronary and cerebral arteries, ischemia and infarction caused by vessel occlusion are more common. Although atherosclerosis can affect any organ or tissue, the arteries supplying the heart, brain, kidneys, lower extremities, and small intestine are most frequently involved.

Coronary heart disease l l l The term coronary heart disease (CHD) describes heart disease caused by impaired coronary blood flow. In most cases, it is caused by atherosclerosis. Diseases of the coronary arteries can cause: l Angina l Myocardial infarction or heart attack l Cardiac dysrhythmias l Conduction defects l Heart failure l Sudden death

Coronary circulation l l l There are two main coronary arteries, the left and the right, which arise from the coronary sinus just above the aortic valve. Although there are no connections between the large coronary arteries, there anastomotic channels that join the small arteries. The primary factor responsible for perfusion of the coronary arteries is the aortic blood pressure. Changes in aortic pressure produce parallel changes in coronary blood flow. The contracting heart muscle influences its own blood supply by compressing the intramyocardial and subendocardial blood vessels. As a result, blood flow through the subendocardial vessels occurs mainly during diastole. l Thus, there is increased risk of subendocardial ischemia when a rapid heart rate decreases the time spent in diastole, and when an elevation in diastolic intraventricular pressure is sufficient to compress the vessels in the subendocardial plexus.

Coronary circulation l l Blood flow usually is regulated by the need of the cardiac muscle for oxygen. Even under normal resting conditions, the heart extracts and uses 60% to 80% of oxygen in blood flowing through the coronary arteries, compared with the 25% to 30% extracted by skeletal muscle. Because there is little oxygen reserve in the blood, myocardial ischemia develops when the coronary arteries are unable to dilate and increase blood flow during periods of increased activity or stress. Heart muscle relies primarily on fatty acids and aerobic metabolism to meet its energy needs. Although the heart can engage in anaerobic metabolism, this process relies on the continuous delivery of glucose and results in the formation of large amounts of lactic acid.

Pathogenesis of coronary heart disease (CHD) l l Atherosclerosis is by far the most common cause of CHD, and atherosclerotic plaque disruption the most frequent cause of myocardial infarction and sudden death. More than 90% of persons with CHD have coronary atherosclerosis. Most, if not all, have one or more lesions causing at least 75% reduction in cross-sectional area, the point at which augmented blood flow provided by compensatory vasodilation no longer is able to assure even moderate increases in metabolic demand. There are two types of atherosclerotic lesions: l the fixed or stable plaque, which obstructs blood flow l l commonly implicated in chronic ischemic heart disease: stable angina, variant or vasospastic angina, and silent myocardial ischemia; the unstable or vulnerable plaque, which can rupture and cause platelet adhesion and thrombus formation l commonly implicated in unstable angina and myocardial infarction.

Pathogenesis of coronary heart disease (CHD) l l Plaque disruption may occur with or without thrombosis. Platelets play a major role in linking plaque disruption to acute CHD. As a part of the response to plaque disruption, platelets aggregate and release substances that further propagate platelet aggregation, vasoconstriction, and thrombus formation. Because of the role that platelets play in the pathogenesis of CHD, antiplatelet drugs (e. g. , low-dose aspirin) are frequently used for preventing heart attack.

Pathogenesis of coronary heart disease (CHD)

Myocardial infarction l l Acute myocardial infarction (AMI), also known as a heart attack, is characterized by the ischemic death of myocardial tissue associated with atherosclerotic disease of the coronary arteries. Diagnosis: l 1. Pain l The pain typically is severe and crushing, often described as being constricting, suffocating. It usually is substernal, radiating to the left arm, neck, or jaw, although it may be experienced in other areas of the chest. l Gastrointestinal complaints are common. There may be a sensation of epigastric distress; nausea and vomiting may occur. l 2. ECG l Elevation of the ST segment usually indicates acute myocardial injury. l When the ST segment is elevated without associated Q waves, it is called a non–Q-wave infarction. A non–Q-wave infarction usually represents a small infarct that may evolve into a larger infarct. l 3. Enzymes

Enzymes l Myoglobin is an oxygen-carrying protein, similar to hemoglobin, that is normally present in cardiac and skeletal muscle. It is a small molecule that is released quickly from infarcted myocardial tissue and becomes elevated within 1 hour after myocardial cell death, with peak levels reached within 4 to 8 hours. It rapidly eliminates through urine (low molecular weight). Because myoglobin is present in both cardiac and skeletal muscle, it is not cardiac specific. l Creatine kinase (CK), formerly called creatinine phosphokinase, is an intracellular enzyme found in muscle cells. Muscles, including cardiac muscle, use ATP as their energy source. Creatine, which serves as a storage form of energy in muscle, uses CK to convert ADP to ATP. CK exceeds normal range within 4 to 8 hours of myocardial injury and declines to normal within 2 to 3 days. There are three isoenzymes of CK, with the MB isoenzyme (CK-MB) being highly specific for injury to myocardial tissue.

Enzymes l The troponin complex consists of three subunits (i. e. , troponin C, troponin I, and troponin T) that regulate calcium-mediated contractile process in striated muscle. These subunits are released during myocardial infarction. Cardiac muscle forms of both troponin T and troponin I are used in diagnosis of myocardial infarction. Troponin I (and troponin T; not shown) rises more slowly than myoglobin and may be useful for diagnosis of infarction, even up to 3 to 4 days after the event. It is thought that cardiac troponin assays are more capable of detecting episodes of myocardial infarction in which cell damage is below that detected by CK-MB level.

Myocardial infarction

Effects of AMI l l l The principal biochemical consequence of AMI is the conversion from aerobic to anaerobic metabolism with inadequate production of energy to sustain normal myocardial function. The ischemic area ceases to function within a matter of minutes, and irreversible myocardial cell damage occurs after 20 to 40 minutes of severe ischemia. The term reperfusion refers to re-establishment of blood flow through use of thrombolytic therapy or revascularization procedures. l Early reperfusion (within 15 to 20 minutes) after onset of ischemia can prevent necrosis. l Reperfusion after a longer interval can salvage some of the myocardial cells that would have died because of longer periods of ischemia.

Peripheral arterial disease (PAD) l l l PAD refers to the obstruction of large arteries not within the coronary, aortic arch vasculature, or brain. It can result from atherosclerosis, inflammatory processes leading to stenosis, an embolism, or thrombus formation. It causes either acute or chronic ischemia (lack of blood supply). Often PAD is a term used to refer to atherosclerotic blockages found in the lower extremity. Risk factors contributing to PAD are the same as those for atherosclerosis. Risk of PAD also increases in individuals who are over the age of 50, male, obese, or with a family history of vascular disease, heart attack, or stroke.

Peripheral arterial disease (PAD) l l About 20% of patients with mild PAD may be asymptomatic; Symptoms include: l Claudication - pain, weakness, numbness, or cramping in muscles due to decreased blood flow; l Sores, wounds, or ulcers that heal slowly or not at all ; l Noticeable change in color (blueness or paleness) or temperature (coolness) when compared to the other limb ; l Diminished hair and nail growth on affected limb and digits.