1. atherosclerosis Jon Yap John A. Burns School of Medicine
Department of Cell and Molecular Biology

2. Atherosclerosis by the Numbers
Cardiovascular diseases are the leading global cause of death ~18 million deaths per year
Heart disease is the number one cause of death in the United States >375,000 people/year
Heart disease strikes someone in the US ~every 43 seconds
Heart disease is the leading cause of death among women, more than all forms of cancer combined
~735,000 heart attacks/year in the US killing ~120,000 people

3. Risk Factors Preventable Non-preventable Type II diabetes/blood sugar
High fat, high cholesterol diet
Tobacco smoking
Sedentary lifestyle
High blood-preassure
Obesity
Non-preventable
Advanced age
Heredity
Male

5. Atherosclerosis Circulating LDL infiltrate endothelial cell layer
LDL is modified (i.e. oxidation; ox-LDL)
Accumulation of ox-LDL elicits an immune response (recruitment of macrophages)
Activated macrophages release pro-inflammatory signaling molecules (cytokines)
Macrophages uptake ox-LDL via phagocytosis but are unable to digest the modified LDL
Lipid laden macrophages are characterized as foam cells
Foam cells accumulate forming the atherosclerotic plaque

6. Lipoproteins
Lipoproteins are a biochemical complex of proteins and bound lipids
Allow fats to move throughout the body
Low-density Lipoproteins
Capable of entering arterial intima (sub-endothelial space)
High-density Lipoproteins
Facilitate removal of cholesterol from the vasculature and to the liver (digestion and absorption of dietary fats)

7. LDL vs. HDL…
High serum levels of free cholesterol result in elevated LDL in the vasculature
LDL interacts with the ECM where it is retained
LDL is modified (oxLDL) and taken up by macrophages

8. LDL vs. HDL…
Reverse Cholesterol Transport: Free cholesterol is removed from the circulation by macrophages and is transferred back to the liver for digestion and biosynthesis of steroid hormones (i.e. androgens, estrogens, and glucocorticoids).

9. Macrophages and Atherosclerosis
Monocytes transmigrate through the endothelium in response to accumulating modified LDL and differentiate into macrophages
Mature macrophages are activated by modified LDL and secrete inflammatory mediators
Phagocytosis of modified LDL results in foam cell formation

10. Foam Cells
Foam cells are unable to metabolize and efflux the cholesterol that they have accumulated. As a result, they die which exacerbates the inflammatory conditions in and around the atherosclerotic lesion.

11. Atherosclerotic Plaque

12. Necrotic core

13. Thrombosis (Plaque Rupture)

14. Vascular Occlusion
Hemodynamic pathologies associated with atherosclerotic plaque: Aside from plaque rupture, stable plaques can completely occlude vessels. The resulting lack of blood flow can have profound implications
Coronary artery disease leading to myocardio infarction
Ischemic stroke due to lack of adequate bloodflow to the brain

15. Atherosclerotic Plaque
Plaque rupture without thrombus
Acute coronary thrombosis with disruption of fiberous cap  fatal myocardial infarction
Massive plaque rupture with resulting thrombus  fatal myocardial infarction

16. Summary
Atherosclerosis is an inflammatory disease, the progression of which can be attributed to a prolonged immune response that ultimately compromises the structural integrity of the entire vascular system.
Treaments
Statins (cholesterol lowering drugs)
Diet (decrease blood presure, cholesterol/fat intake)
Exercise (metabolic attenuation of caloric intake, loose weight)
Surgery (angioplasty, stent, bypass graft)

17. Questions?