Atherosclerosis

• Atherosclerosis is a chronic inflammatory disease affecting the arterial wall
• Characterized by the formation of plaques
• Plaques contain lipids, immune cells, smooth muscle, and connective tissue
• Plaque buildup narrows the arterial lumen
• Narrowing of the arteries impedes blood flow
• Potential outcomes include ischemia or infarction

Four Stages of Atherosclerosis Development

• Endothelial Dysfunction is the first stage
• Initiated by injury to the endothelial lining of arteries
• Causes of injury include hypertension, hyperlipidemia, smoking, diabetes, and oxidative stress
• Injured endothelium becomes inflamed
• Injured endothelium loses its ability to produce antithrombotic and vasodilatory substances like nitric oxide
• Adhesion molecules attract immune cells such as monocytes, which become macrophages
• Fatty Streak Formation is the second stage
• LDL cholesterol accumulates in the intima
• Oxidized LDL is phagocytosed by macrophages, transforming them into foam cells
• Fatty streaks, the earliest visible lesions, appear
• Fibrous Plaque Formation is the third stage
• Smooth muscle cells proliferate and migrate to the intima
• Smooth muscle cells secrete extracellular matrix, forming a fibrous cap over the lipid core
• This process narrows the lumen, potentially reducing blood flow
• Complicated (Ruptured) Plaque is the fourth stage
• Plaques can become unstable and rupture
• Exposed contents like collagen activate platelets, leading to thrombus formation
• Thrombus can partially or completely occlude the vessel, causing ischemia or infarction
• Alternatively, thrombus can embolize, blocking smaller vessels downstream

Risk Factors and Pathophysiologic Contributions

• Hypertension causes mechanical stress, damaging the endothelium and promoting dysfunction and inflammation
• Dyslipidemia, specifically elevated LDL, causes LDL to infiltrate the endothelium, become oxidized, and initiate form cell and plaque formation
• Smoking increases reactive oxygen species (ROS), which oxidizes LDL and impairs endothelial function
• Diabetes Mellitus promotes glycation of lipids and proteins, increases ROS and inflammation, and causes endothelial damage
• Obesity promotes systemic inflammation, dyslipidemia, and insulin resistance
• Sedentary Lifestyle reduces HDL, increases triglycerides, and insulin resistance
• Family History, Age, and Gender are non-modifiable risks
• These contribute to endothelial aging and inflammatory priming
• Metabolic Syndrome is a combination of factors, including waist circumference, blood pressure, glucose, HDL, and triglycerides, that increase risk

Causes and Consequences of Plaque Rupture

• Plaques with thin fibrous caps and large necrotic cores are unstable
• Proteolytic enzymes from macrophages degrade collagen, weakening the cap
• Mechanical stress from blood flow can trigger rupture

Consequences of Plaque Rupture

• Exposure of subendothelial contents leads to platelet activation
• Thrombus formation occurs through platelet aggregation and activation of the clotting cascade
• Vessel occlusion is another consequence
• Partial occlusion leads to unstable angina or transient ischemia
• Complete occlusion results in myocardial infarction, stroke, or sudden death