Atherosclerosis

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Atherosclerosis

• Anca Bacârea, Alexandru Schiopu

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Atherosclerosis

• 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.

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Risk Factors

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

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Risk Factors

• Changeable risk factors life style risk
  factors
• Hyperlipidemia
• The presence of hyperlipidemia is the strongest
  risk factor for atherosclerosis in persons
  younger than 45 years of age.
• Both primary and secondary hyperlipidemia
  increase the risk.
• Cigarette smoking
• Hypertension
• High blood pressure produces mechanical stress on
  the vessel endothelium.
• 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.
• Diabetes mellitus
• Diabetes elevates blood lipid levels and
  otherwise increases the risk of atherosclerosis.
• Insufficient physical activity
• A stressful lifestyle
• Obesity

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Risk Factors

• There are a number of other less well-established
  risk factors for atherosclerosis, including
• High serum homocysteine levels
• Homocysteine is derived from the metabolism of
  dietary methionine
• Homocysteine inhibits elements of the
  anticoagulant cascade and is associated with
  endothelial damage.
• Elevated serum C-reactive protein
• It may increase the likelihood of thrombus
  formation
• Inflammation marker
• Infectious agents
• 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.
• The organisms may play a role in atherosclerotic
  development by initiating and enhancing the
  inflammatory response.

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Pathology and pathogenesis

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

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Pathology and pathogenesis

• 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.

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Pathology and pathogenesis

• 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.

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Pathology and pathogenesis

• The more advanced complicated lesions are
  characterized by
• Hemorrhage
• Ulceration
• 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.

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Mechanisms

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

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Mechanisms

• One hypothesis of plaque formation suggests that
  injury to the endothelial vessel layer is the
  initiating factor in the development of
  atherosclerosis.
• Possible injurious agents are
• Products associated with smoking
• Immune mechanisms
• 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.

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LDL - cholesterol

• 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.

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Mechanisms

• 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
• It has chemotactic effect on lymphocytes and
  monocytes
• It has chemotactic effect on smooth muscle cells
  from the arterial media and stimulates production
  of MG-CSF, cytokines, adhesion molecules in the
  endothelium
• It inhibits endothelium derived releasing factor
  (EDRF), favoring vasospasm
• It stimulates specific immune system (production
  of antibodies against oxidized LDL).

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Mechanisms

• 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.

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Glycosylation and atherosclerosis

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

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Modern theory of atherosclerosis

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

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Mechanisms

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

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Clinical Manifestations

• The clinical manifestations of atherosclerosis
  depend on the vessels involved and the extent of
  vessel obstruction.
• Atherosclerotic lesions produce their effects
  through
• narrowing of the vessel and production of
  ischemia
• sudden vessel obstruction caused by plaque
  hemorrhage or rupture
• 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.

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Coronary heart disease

• 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
• Angina
• Myocardial infarction or heart attack
• Cardiac dysrhythmias
• Conduction defects
• Heart failure
• Sudden death

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Coronary circulation

• 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 are 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.
• 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.

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Coronary circulation

• 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.

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Pathogenesis of coronary heart disease (CHD)

• 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
• the fixed or stable plaque, which obstructs blood
  flow
• 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
• commonly implicated in unstable angina and
  myocardial infarction.

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Pathogenesis of coronary heart disease (CHD)

• 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.

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Pathogenesis of coronary heart disease (CHD)
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Myocardial infarction

• 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
• 1. Pain
• 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.
• Gastrointestinal complaints are common. There may
  be a sensation of epigastric distress nausea and
  vomiting may occur.
• 2. ECG
• Elevation of the ST segment usually indicates
  acute myocardial injury.
• When the ST segment is elevated without
  associated Q waves, it is called a nonQ-wave
  infarction. A nonQ-wave infarction usually
  represents a small infarct that may evolve into a
  larger infarct.
• 3. Enzymes

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Enzymes

• 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.
• 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.

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Enzymes

• 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.

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Myocardial infarction
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Effects of AMI

• 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.
• Early reperfusion (within 15 to 20 minutes) after
  onset of ischemia can prevent necrosis.
• Reperfusion after a longer interval can salvage
  some of the myocardial cells that would have died
  because of longer periods of ischemia.

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Peripheral arterial disease (PAD)

• 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.

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Peripheral arterial disease (PAD)

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