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

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

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

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

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)

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

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).

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

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.

Atherosclerotic Plaque

Necrotic core

Thrombosis (Plaque Rupture)

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

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

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)

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