atheroscleoris

• Atherosclerosis


  Hardening (sclerosis) of arteries (arterio-)

  
• Arteriosclerosis


  Medial hypertrophy - age and hypertension. Symmetrical and uniform.
• Atherosclerosis


  Related to hyperlipidaemia. Fatty fibrous plaques (atheromas) laid down on inner surface of vessels (intima). Focal changes.
• Thrombosis


  Consequence of atherosclerosis. Thrombus (clot) formed on inner surface of vessel. May shed off small particles - thromboemboli. Can occlude vessels.
• Atherosclerosis


  • A focal disease of large arteries (may also be found in atria). High pressure.
  • Does not occur naturally in animals.
  • Plaques occur at sites of haemodynamic stress - increased endothelial cell turnover. e.g. carotid bifurcation, coronaries, mesenteric, renal, aorta, ileac, popliteal.
• Endothelial damage


  Initiating event for atherosclerosis
• Non-Modifiable Risk Factors for Atherosclerosis

  • Family History of IHD or Hyperlipidaemia
  • Advanced Age
  • Male sex (and female post-menopause)
  • Ethnic Group
• Modifiable Risk Factors for Atherosclerosis

  • Hyperlipidaemia (dyslipidaemia LDL/HDL)
  • Cigarette smoking
  • Hypertension
  • Obesity (waist to hip ratio)
  • Diabetes mellitus
  • Physical Inactivity or Sedentary Lifestyle
  • Stress (psychosocial factors)
  • Diet poor in fruit and Fresh Vegetables
• Account for 80% of the elevated risk: INTERHEART 2004
• Theories of Atherosclerosis


  • Lipid Theory
  • Inflammatory Theory
• Lipid Theory


  High levels of blood cholesterol (LDC) injure endothelium and allow accumulation and local inflammation
• Inflammatory Theory


  Local inflammatory reaction possibly through local injury, through infection (chlamydial or helicobacter pylori) attracts macrophages
• Inflammation results from both pathways
• Initiating events in Atherogenesis

  • Earliest detectable evidence of pathophysiology is endothelial dysfunction.
  • Caused by: Hypercholesterolaemia – particularly oxidised LDL-c, Cigarette smoking, Hypertension, Diabetes (at least partly due to lipid changes), Infectious organisms, Elevated levels of epinephrine and norepinephrine
  • Associated with reduced PgI2 and NO biosynthesis
• Lipid Link to Atherosclerosis


  • Atheroma risk directly linked to total plasma ChE
  • There is a link to dietary ChE but 75% of plasma from liver
  • LDL and VLDL carry ChE to tissues and HDL away to liver
  • LDL/HDL is diagnostic factor for risk but coronary risk correlates best with TOTL ChE/HDL ratio
  • Triglycerides are not significant factor in risk
  • Low intake of saturated fats and ChE reduce risk but do not remove it
  • Lipid lowering agents reduce risk of end events and give some regression of atherosclerosis
• Endothelial "Phase"


  1. Lipids become oxidised (initially in the circulation later in the intima)

  2. Injury to endothelium causing the release of adhesion factors (VCAM-1). Attracts monocytes - activation and adherence.

  3. Endothelial cells bind LDL with endothelial transport of lipids (mainly LDL-C) into the intima

  4. Injured cells and monocytes generate free radicals and there is lipid peroxidation.

  5. Disruption of normal LDL receptors
• Spreading Damage


  1. Macrophages engulf oxidised lipids and become lipid saturated foam cells

  2. Macrophages move from blood stream into the endothelial layer–large part of the atheroma mass

  3. Cytokines from endothelial cells, macrophages and platelets cause smooth muscle proliferation and deposition of connective material.

  4. The fibrous material becomes a dense fibrous cap of connective material

  5. Underneath there is a much looser combination of lipid and necrotic cell debris and cholesterol crystals. Calcium builds - sclerosis
• Plaque Formation


  • The fibro-lipid (fibro-fatty) plaque: an accumulation of lipid-laden cells in the tunica intima, typically without narrowing the lumen, with a "fibrous cap" covering the atheromatous "core" of the plaque.
  • The fibrous plaque: is also localized within the wall of the artery resulting in thickening and expansion of the wall, containing collagen fibers, precipitates of calcium and, rarely, lipid-laden cells.

  
• Early atheroma (gross)


  • Damage to endothelia, (exacerbated by hypertension)
  • Insudation of cholesterol, formation of foam cells
  • Cholesterol esters deposited in intima, leading to 'fatty streaks or dots'
  • Observed in children, wide distribution - reversible
• Advanced (fibrous) plaque (20yrs)

  • Pro-inflammatory cytokines cause VSM migration from the media to the intima. Synthesis of collagen and elastin producing a fibrous (protective) cap
  • Variable amounts of lipid may be present
  • As the plaque enlarges, the base may start to become necrotic

  
• Progression of atheroma: 'advanced' to 'complicated' (20 - 30yrs)


  • The fibrous cap may slowly enlarge OR may rupture
  • Rupture of plaque cap leads to thrombosis. Rupture is likely if the base is necrotic, if there are large deposits of cholesterol, or high numbers of inflammatory cells are present.
  • After fibrin clot has formed, this may be incorporated into a new (larger) plaque and a new connective tissue cap is formed.
• Further progression of plaque

  • Gradual growth or further episodes of mural thrombosis causes stepwise progression of plaque which can have a layered appearance.
  • 70% of plaques show evidence of cap rupture with no evidence of clinical events.
  • High flow rates may predispose to plaque rupture but also may prevent the formation of large thrombi.

  
• Clinical horizon. (40-60yrs)


  • When the lumen of major arteries becomes narrowed by greater than 75%
  • Symptoms: Angina (Coronary arteries); Intermittent claudication (ileac arteries or abdominal aorta. Dizzy spells, visual disturbances (Carotid arteries).

  
• Clinical horizon continued


  • Symptoms may occur with less than 75% reduction of lumen diameter: Plaque disruption (or platelet thrombi) cause embolism at sites distal to the lesion.
  • Symptoms: AMI; arrhythmias; CVA*; peripheral ischaemia.
  • Symptoms generally less severe than with large vessel occlusion.
• Clinical horizon continued


  • Plaque rupture and thrombosis may completely occlude lumen.
  • Symptoms: AMI; CVA; sudden ischaemic pain.
  • This can occur even with no prior angiographically demonstrable reduction in lumen diameter. Plaque composition is more important than plaque size in determining stability.

  
• Aneurysm


  • A localized widening (dilatation) of an artery, vein, or the heart.
  • At the area of an aneurysm, there is typically a bulge and the wall is weakened and may rupture.
  • A fusiform aneurysm is shaped like a spindle.
  • Saccular is a sac like aneurysm.
  • A dissecting aneurysm - where the wall of an artery rips (dissects) longitudinally. Due to bleeding into the weakened wall.

  
• Clinical horizon continued


  • Weakening of arterial wall (usu. aorta) by necrosis (exacerbated by hypertension) may cause formation of aneurysms: (saccular; fusiform; dissecting).
  • Symptoms - none, mild discomfort or pain if pressing on nerve.
• Acute myocardial infarction (AMI)


  Sudden ischaemic pain
• Cerebrovascular accident (CVA)


  Sudden ischaemic pain
• Plaque composition is more important than plaque size in determining stability

  
• Aneurysm


  A localized widening (dilatation) of an artery, vein, or the heart

  
• Aneurysm


  • At the area of an aneurysm, there is typically a bulge and the wall is weakened and may rupture
  • A fusiform aneurysm is shaped like a spindle
  • Saccular is a sac like aneurysm
  • A dissecting aneurysm is where the wall of an artery rips (dissects) longitudinally due to bleeding into the weakened wall splitting the wall
• Peripheral arterial disease (Occlusive)


  Due to atherosclerosis (most common)
• Peripheral arterial disease (Occlusive)

  • Usually preferentially affects the lower limbs, but may also affect the upper limbs, particularly in heavy cigarette smokers (Buerger's disease)
  • Symptoms are intermittent claudication; cold; pain; gangrene
  • Pronounced colour changes: gangrene or sudden pain often indicate arterial occlusion due to thrombosis or embolism
• Buerger's Disease


  Disease of small and medium arteries, most commonly in smokers
• Raynaud's Disease


  Intermittent attacks of pallor or cyanosis usually on exposure to cold, bilateral or symmetrical (hands and feet), no organic disease - vasospasm
• Raynaud's syndrome


  Similar symptoms to Raynaud's Disease but may be secondary to organic disease of the arteries
• Acrocyanosis


  Persistent pallor and cyanosis (normal temp), bilateral or symmetrical (hands and feet), often accompanied by sweating
• Erythromelalgia


  Rare condition with pain, redness and heat - relieved by cooling and elevating the affected limb, (or aspirin)
• Chilblains


  Discolouration of the skin on exposure to cold, with swelling, pain, itching and sensation of heat