Macrophages and Atherosclerosis

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Macrophages and Atherosclerosis

• Natasa MilutinovicStephen PahutaJelena
  SparavaloBrandon Thomas

natasa.milutinovic_at_utoronto.ca stephen.pahuta_at_utor
onto.ca jelena.sparavalo_at_utoronto.ca brandon.thoma
s_at_utoronto.ca
March 4, 2009
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Background

• Atherosclerosis comes from the Greek words athero
  (meaning gruel or paste) and sclerosis (meaning
  hardening)
• It is a progressive disease characterized by the
  accumulation of macrophages, cholesterol, cell
  debris and fibrous connective tissue within
  arterial walls
• It is a major cause of cardiovascular disease,
  including stroke and heart attack, and it
  contributes to the death of 17 million people
  worldwide every year

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Healthy Arterial Wall

• Consists of 3 layers
• Thin smooth layer (tunica intima) helps
  blood flow
• Muscular elastic layer (tunica media)
  helps the pulse circulate blood
• Outer layer (tunica adventitia) protects
  artery

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• Lusis, A.J. Atherosclerosis Nature 407,233-240
  (2000).

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Cholesterol

• Cholesterol is a natural fat-like substance,
  required to build and maintain cell membranes and
  their fluidity
• 20-25 of total daily cholesterol is produced in
  the liver
• Also found in foods high in saturated fats
• Cholesterol is carried in blood complexed with
  lipoporteins
• High Density Lipoproteins (HDL) - takes
  cholesterol from the blood to the liver for
  processing.
• Low Density Lipoproteins (LDL) - major carriers
  of cholesterol in blood for use within cells

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Etiology

• Exact cause is unknown
• Risk factors
• -smoking
• -high blood pressure
• -diabetes
• -high cholesterol
• -family history of heart disease
• This can damage the smooth lining of the artery
  and contribute to atherosclerosis

20th Century Fox
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Initiation and Progression

• Diets high in fat and cholesterol lead to an
  accumulation of lipoproteins in the tunica
  intima.
• Within days or weeks, monocytes begin adhering to
  the endothelial surface. These monocytes then
  migrate across endothelium into the intima, where
  they proliferate and differentiate into
  macrophages.
• Macrophages engulf the lipoproteins, forming foam
  cells
• Macrophages do not have sufficient affinity for
  native LDL for the formation of foam cells
  however, LDL is oxidized in the intima, resulting
  in recruitment of monocytes to the site and this
  oxidative modification is sufficient to be
  recognized by specialized receptors on the
  macrophages, called scavenger receptors
• Over time, the foam cells die, releasing their
  contents into the lesion, at which point the
  lesion can be termed a fatty streak.

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• Smooth muscle cells, which have migrated from the
  tunica media, secrete fibrous elements
  encapsulating the content within plaques
• As the plaque gets bigger, the body tries to
  preserve the blood flow through the artery by
  keeping the opening of the artery the same and
  expanding toward the tunica adventitia until a
  critical point is met
• If the plaque continues to grow its expansion
  will eventually intrude on the inner opening of
  the vessel as the elastic layer cannot stretch
  any more, impeding blood flow
• Calcium may be deposited over time in the plaque
  making it hard and inflexible
• This reduces the ability of the artery to expand
  to increase blood flow when needed (ie during
  exercise)

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http//en.wikipedia.org/wiki/Atherosclerosis
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Complications

• The resulting increase in pressure at the
  narrowing can damage the fibrous capsule covering
  the plaque
• May rupture resulting in a blood clot that can
  completely block the artery
• The location of blockage determines the
  consequences
• Can be as severe as heart attack or stroke
• Life threatening

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Complications (contd)

• Transient Ischemic Attack (TIA)-also referred to
  as a mini stroke-caused by blockage of blood
  supply to a particular area of the
  brain-results in temporary neuralgic dysfunction
• Angina Pectoris-severe chest pain due to a lack
  of oxygen supply to the heart muscle-due to
  blockage of coronary artery
• Aneurism-causes the artery wall to weaken,
  causing it to bulge under the pressure from the
  blood-can rupture and the resulting bleed called
  a hemorrhage can be fatal
• Intermittent Claudication
• -cramping pain in the legs caused by poor
  circulation in the arteries
• -can result in amputation of the limb

http//www.torrancememorial.org/images/angina.gif
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Clinical Diagnosis

• Atherosclerosis typically begins in early
  adolescence, and is usually found in most major
  arteries, yet is asymptomatic and not detected by
  most diagnostic methods during life.
• It is usually diagnosed after other complications
  have arisen and another condition has been
  diagnosed, such as coronary artery disease.
• Tests Coronary angiography, CT scan, Chest
  X-Ray, blood tests

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Treatment

• Anticoagulants
• minimize secondary clotting and embolus formation
• Vasodilators
• symptomatic relief, lower blood pressure
• Cholesterol lowering agents (statins)
• Decrease amount of LDL in blood
• Surgical treatment is available for those
  unresponsive to pharmacological intervention -
  short term
• Balloon angioplasty - open up narrowed vessels
  and promote an improved blood supply
• Coronary artery bypass surgery restores blood
  supply to the heart
• Few medications have actually been found to clear
  up plaque. Most medications are used to treat the
  complications of atherosclerosis
• New treatments that target the disease at the
  level of the vessel wall or that increase HDL
  levels are needed

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Prevention

• Most effective means of reducing atherosclerotic
  build up and its deadly consequences. 
• Lifestyle adjustments
• Quitting smoking
• Diet low in saturated fat and high in fibre
• Exercising regularly
• Maintaining a healthy weight. 
• Aspirin (ASA) taken in small daily doses has been
  proven to reduce the risk of heart attack and
  stroke by inhibiting the formation of blood
  clots.

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Summary

• Atherosclerosis is a progressive disease
  characterized by the accumulation of macrophages,
  cholesterol, cell debris and fibrous connective
  tissue within arterial walls
• Exact cause is unknown but exacerbated by genetic
  and environmental factors
• Risk factors include smoking, high blood
  pressure, diabetes, high cholesterol, and family
  history of heart disease
• Initial lesions are formed by accumulation of
  lipoproteins within the artery wall
• Macrophages contribute to progression of
  atherosclerosis (only cells in the body that have
  scavenger receptors)
• Monocytes in blood?migrate to artery wall in
  response to lipoprotein accumulation and
  oxidation within the intima, proliferate and
  differentiate to macrophages?recognize oxidized
  lipoproteins via scavenger receptors, phagocytose
  lipoproteins, swell and form foam cells?die and
  release contents into plaque, build up called
  fatty streak
• Complications include blood clots leading to
  stroke or heart attack, aneurisms, TIA, angina
  pectoris, and intermittent claudication
• Treatment is palliative and preventive, not
  curative

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References

• Lusis, A.J. Atherosclerosis Nature 407,233-240
  (2000).
• Nissen SE, Nicholls SJ, Sipahi I, et al (2006).
  Effect of very high-intensity statin therapy on
  regression of coronary atherosclerosis the
  ASTEROID trial JAMA 295 (13) 155665.
• Scholkens, B.A. et al. ACE Inhibition and
  Atherogenesis. Can J Physiol Pharmacol 80(4)
  354-9 (2002).
• http//en.wikipedia.org/wiki/Atherosclerosis
• http//www.nhlbi.nih.gov/health/dci/Diseases/Ather
  osclerosis/Atherosclerosis_Diagnosis.html
• http//www.nhlbi.nih.gov/health/dci/Diseases/Ather
  osclerosis/Atherosclerosis_WhatIs.html
• http//www.torrancememorial.org/images/angina.gif
• http//healthpsych.psy.vanderbilt.edu/Medication.g
  if