ATHEROSCLEROSIS

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ATHEROSCLEROSIS
MEDS 520, 2007
WWAMI Medical Program, MSU
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General Comments

• Arteriosclerosis
• Thickening and loss of elasticity of arterial
  walls
• Hardening of the arteries
• Greatest morbidity and mortality of all human
  diseases via
• Narrowing
• Weakening

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Three patterns of arteriosclerosis

• Atherosclerosis
• The dominant pattern of arteriosclerosis
• Primarily affects the elastic (aorta, carotid,
  iliac) and large to medium sized muscular
  arteries (coronary, popliteal)
• Monckeberg medial calcific sclerosis
• Arteriolosclerosis small arteries and arterioles
  (hypertension and DM)

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Non-Modifiable Risk Factors

• Age
• A dominant influence
• Atherosclerosis begins in the young, but does not
  precipitate organ injury until later in life
• Gender
• Men more prone than women, but by age 60-70 about
  equal frequency
• Family History
• Familial cluster of risk factors
• Genetic differences

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Modifiable Risk Factors(potentially controllable)

• Hyperlipidemia
• Hypertension
• Cigarette smoking
• Diabetes Mellitus
• Elevated Homocysteine
• Factors that affect hemostasis and thrombosis
• Infections Herpes virus Chlamydia pneumoniae
• Obesity, sedentary lifestyle, stress

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AHA Classification of atherosclerosis
Fig. 11.7
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Pathogenesis of atherosclerosis
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Normal Artery
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Atherosclerosis

• A disease of the intima
• A disease of the intima
• A disease of the intima
• Atheromas, atheromatous/fibrofatty plaques,
  fibrous plaques
• Narrowing/occlusion weakness of wall

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Major components of plaque

• Cells (SMC, macrophages and other WBC)
• ECM (collagen, elastin, and PGs)
• Lipid Cholesterol (Intra/extracellular)
• (Often calcification)

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Two major processes in plaque formation

• Intimal thickening (SMC proliferation and ECM
  synthesis)
• Lipid accumulation

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Response to injury hypothesis

• Injury to the endothelium
• (dysfunctional endothelium)
• Chronic imflammatory response
• Migration of SMC from media to intima
• Proliferation of SMC in intima
• Excess production of ECM
• Enhanced lipid accumulation

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Response to injury hypothesis (I)

• 1. Chronic EC injury (subtle?)
• EC dysfunction
• Increased permeability
• Leukocyte adhesion (via VCAM-1)
• Thrombotic potential

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Response to injury hypothesis (II)

• Accumulation of LDL (cholesterol)
• Oxidation of lesional LDL
• Adhesion migration of blood monocytes
  transformation into macrophages and foam cells
• Adhesion of platelets
• Release of factors from platelets, macrophages
  and ECs

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Response to injury hypothesis (III)

• Migration of SMC from media to intima
• Proliferation of SMC
• ECM production by SMC
• Enhanced lipid accumulation
• Intracellular (SMC and macrophages)
• Extracellular

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Response to Injury
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Endothelial Dysfunction
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Initiation of Fatty Streak
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Fatty Streak
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Fibro-fatty Atheroma
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Summary of Atherosclerotic Process

• Multifactorial process (risk factors)
• Initiated by endothelial dysfunction
• Up regulation of endothelial and leukocyte
  adhesion molecules
• Macrophage diapedesis
• LDL transcytosis
• LDL oxidation
• Foam cells
• Recruitment and proliferation of smooth muscle
  cells (synthesis of connective tissue proteins)
• Formation and organization of arterial thrombi

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Consequences of plaque formation

• Generalized
• Narrowing/Occlusion
• Rupture
• Emboli
• Leading to specific problems
• Myocardial and cerebral infarcts
• Aortic aneurysms
• Peripheral vascular disease

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Is Atherosclerosis Reversible

• Primate experiments
• High fat diet discontinued atherosclerotic
  lesions regress
• Humans
• Decrease fat and caloric intake (wars, famine,
  wasting disease), atheromas decrease.
• Angiography after cholesterol lowering, plaque
  size decreases
• What has to happen for plaques to regress?
• LDL lowered
• Mac ingest lipids
• Reverse cholesterol transport, depends on HDL

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Fatty Streak-Aorta
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Fatty Streak-Coronary Artery
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Consequences of Atherosclerosis
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Altered Vessel Function

• Vessel change
• Plaque narrows lumen
• Wall weakened
• Thrombosis
• Breaking loose of plaque
• Loss of elasticity

• Consequence
• Ischemia, turbulence
• Aneurysms, vessel rupture
• Narrowing, ischemia, embolization
• Athero-embolization
• Increase systolic blood pressure

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Late Changes

• Calcification
• An example of dystrophic calcification
• Cracking, ulceration, rupture
• Usually occurs at edge of plaque
• Thrombus formation
• Caused by endothelial injury,ulceration,
  turbulence
• Organization of thrombus
• More thrombus
• Encroachment
• Weakens vessel wall
• Bleeding
• Ulceration, cracking and angiogenesis

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ATHEROSCLEROSIS Pathology, Pathogenesis,
Complications, Natural History
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Complicated Lesions
Fibrous Plaques
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Complicated Lesions
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Neovas. Calcification Inflam. cells
Fibrous cap Cholesterol clefts
Elastin membrane destroyed
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Hemorrhage into Plaque
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Ulceration/Hemorrhage/Cholesterol Crystals
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Complicated Lesion/Calcification
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Foam Cells/Cholesterol Crystals
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Cholesterol Crystals/Foam Cells
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Thrombosis/Complicated Lesion
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Complicated Lesion/Ulceration/Thrombosis
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Common Consequences of Atherosclerosis in
Specific Vessels
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Aorta

• Aneurysm
• Pulsatile abdominal mass
• Abdominal pain
• Bleeding
• Atheroembolization
• Narrowing of lumen
• Usually not a problem

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Aortic Aneurysm
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Aortic Aneurysm
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Coronary Arteries

• Consequences of coronary artery atherosclerosis
  discussed next lecture

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Coronary Artery Atherosclerosis
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Coronary Artery Atherosclerosis
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Carotids and Cerebral Circulation

• Atherosclerosis with thrombosis can lead to brain
  infarction
• Red or white
• Coagulative or liquefactive
• Can lead to transient ischemic attacks (TIA), if
  narrowing is aggravated by mural thrombus or
  vasospasm

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Celiac and Mesenteric Arteries

• Narrowing primarily at aorta bifurcation
• Ischemia uncommon because of collateral
  circulation
• Ischemia can occur if more than 1 artery severely
  affected - ischemic entercolitis

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Renal Artery

• Progressive ischemic atrophy of kidney leads to
  gradual kidney failure (nephrosclerosis)
• Renal hypertension due to decreased perfusion

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Iliac and Femoral Arteries

• Aneurysms
• Vessel occlusion by plaque and thrombus
• Ischemia of leg muscles, especially during
  exercise (intermittent claudication)
• Ulcers of skin of legs and feet
• Gangrene of feet

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Atherosclerotic Disease

• Prevalence
• 6 million Americans with CAD
• 3 million Americans have had strokes
• Mortality
• 1.5 million deaths/yr in US due to myocardial
  infarction
• 0.5 million deaths/yr in US due to strokes

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Normal Artery
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Pathogenesis of Atherosclerosis

• Cause?
• Current hypothesis Response to Injury
• Initiated by endothelial dysfunction
• Disease of the intima
• Intimal thickening
• Intra- and extra-cellular lipid accumulation
• Chronic Inflammation
• Basic Lesion is termed atheroma, fibro-fatty
  plaque, or atheromatous plaque