Atherosclerosis: Lipids & Lipoproteins

• Disorders of blood flow in the systemic circulation

Atherosclerosis - Lipids

• Lipoproteins are packages of insoluble lipids transported in blood.
• Lipoproteins include cholesterol, triglycerides, phospholipids, and proteins.
• Triglycerides are used in energy metabolism.
• Cholesterol produces cell membranes, steroids, and bile acid.
• Abnormal lipoprotein metabolism is a predisposing factor to atherosclerosis.

Lipoproteins Types

• HDL (high-density lipoprotein) is "GOOD" cholesterol.
• HDL removes cholesterol from arterial walls to the liver.
• LDL (low-density lipoprotein) deposits cholesterol in arterial walls.
• LDL accumulates in sub-endothelial space.
• VLDL (very-low-density lipoprotein) delivers triglycerides to cells for energy.
• Chylomicrons are the largest, least dense lipoproteins.
• Chylomicrons transport dietary triglycerides and cholesterol from the intestinal epithelial cells to the liver, skeletal muscle, and adipose tissue.

Aetiology of atherosclerosis

• Risk factors that cannot be modified:
  • Familial hypercholesterolaemia
  • Age and gender (men ≥45 years, women ≥55 years)
  • Type 1 Diabetes Mellitus
• Modifiable risk factors:
  • HDL cholesterol <40 mg/dL
  • Elevated C-reactive protein (CRP) levels
  • High homocysteine levels

Pathogenesis of atherosclerosis

• Formation of fibrofatty lesions in the intimal lining.
• Pathologic process that causes coronary, cerebral, peripheral arteries, and aorta diseases.
• There are three types of lesions associated with atherosclerosis: fatty streaks, fibrous atheromatous plaque, and complicated lesions.
• Development can begin in childhood with fatty streaks.
• Lesions of atherosclerosis advance with aging.
• Multiple factors contribute to pathogenesis, including endothelial dysfunction and dyslipidemia.
• Endothelium dysfunction is an active biologic interface between blood and tissues and is a risk factor effect.
• Dysfunction is due to loss of NO and microtears and leukocytes are recruited, starting the inflammatory process.
• Entry of circulating fat and cholesterol causes oxidisation of LDLs.
• This attracts circulating monocytes, which become macrophages to restore vessel wall integrity.
• Inflammatory mediators are released, and smooth muscle cells grow and enter.
• Macrophages and migrating smooth muscle cells consume ox-LDLs (foam cells).
• Oxidised LDL is cytotoxic at high levels, resulting in death of macrophages and smooth muscle cells.
• This causes deposition of cell contents and cholesterol crystals, leading to necrotic core formation in the arterial wall.
• Fibrous cap involves fibrin infiltration (stiffening wall), calcium deposition (hardening of vessel wall), and fibrous plaque with connective tissue and lipids.

Atherosclerotic plaque

• Continues to grow and cause narrowing of the vessel, which leads to production of ischemia.
• "Stable” plaque has a small lipid pool, thick fibrous cap and a preserved lumen.
• "Vulnerable” plaque has a large lipid pool, thin fibrous cap, and many inflammatory cells.
• "Vulnerable" plaque can commonly rupture and cause a thrombus, resulting in narrowing.
• Plaque progression involves two processes: chronic (slow narrowing) and acute (rapid luminal obstruction).
• Plaque cap splits, necrotic material traps platelets, and thrombus formation reduces size of or blocks artery lumen and limits NO to vasodilation.