Atherosclerosis Flashcards
- Define atherosclerosis and outline its five major stages.
Model Answer: Atherosclerosis is a chronic inflammatory disease characterized by the abnormal accumulation of lipids, immune cells, and fibrous elements within the arterial wall, forming plaques.
The five stages are:
1. Endothelial dysfunction – loss of vasoprotective functions.
2. Lipid accumulation – retention of ApoB100 lipoproteins (e.g., LDL) in the sub-intimal space.
3. Leukocyte recruitment and foam cell formation – monocytes infiltrate, differentiate into macrophages, and engulf lipids.
4. Fibrous plaque formation – smooth muscle cells migrate and proliferate, creating a fibrous cap.
5. Plaque rupture – breakdown of the cap due to inflammation, leading to thrombosis.
- What are foam cells and how do they form in atherosclerosis?
Model Answer: Foam cells are lipid-laden macrophages found in atherosclerotic lesions. They form when monocytes migrate into the intima, differentiate into macrophages, and take up modified lipoproteins (e.g., oxidized LDL) via scavenger receptors (e.g., CD36, SR-A).
Foam cells become pro-inflammatory and are unable to efficiently efflux cholesterol, exacerbating lesion development.
- Describe the structure and functions of the major classes of lipoproteins.
Model Answer: Lipoproteins are spherical particles composed of:
* A core of cholesteryl esters and triglycerides.
* A surface of phospholipids, free cholesterol, and apolipoproteins.
Major classes include:
* Chylomicrons (CM) – high triglycerides, transport dietary fat.
* VLDL – triglyceride-rich, converted to IDL and LDL.
* IDL – intermediate, cholesterol-carrying.
* LDL – carries cholesterol to peripheral tissues.
* HDL – collects excess cholesterol and transports it back to the liver (reverse cholesterol transport).
- How do statins reduce plasma LDL cholesterol? Outline the mechanism of action.
Model Answer: Statins inhibit HMG-CoA reductase, the rate-limiting enzyme in cholesterol synthesis.
This leads to:
1. ↓ Intracellular cholesterol.
2. ↑ Expression of LDL receptors on hepatocytes.
3. ↑ Uptake of LDL from plasma.
4. ↓ Plasma LDL cholesterol levels by 20–50%.
- Explain how inflammation contributes to the progression of atherosclerosis. Include roles of cytokines, macrophages, and smooth muscle cells.
Model Answer:
* Endothelial dysfunction allows lipid and immune cell entry.
* Monocyte recruitment via adhesion molecules and chemokines (e.g., CCL2).
* Macrophages engulf oxidized LDL via scavenger receptors (CD36, SR-A) and form foam cells, which secrete pro-inflammatory cytokines (IL-1β, TNF, IL-6).
* Chronic inflammation impairs cholesterol efflux (via ABCA1/G1) and efferocytosis.
* Smooth muscle cells (VSMCs) migrate, proliferate, and may also become foam-like, contributing to the fibrous cap and necrotic core.
* Persistent inflammation leads to fibrous cap thinning and plaque rupture.
statins as treatments for atherosclerosis, including mechanisms and limitations.
Mechanism
Effects
Efficacy
Side Effects
Limitations
Statins
Inhibits HMG-CoA reductase → lowers LDL
↓ LDL, ↑ LDL receptor expression
20–50% reduction in LDL-C
Myopathy, ↑ liver enzymes
Not anti-inflammatory
Colchicine as treatments for atherosclerosis, including mechanisms and limitations.
Mechanism
Effects
Efficacy
Side Effects
Limitations
Colchicine
Inhibits microtubule polymerization; broad anti-inflammatory
↓ inflammation, cytokine release (IL-1β, IL-6)
↓ CV events (e.g., in COLCOT trial)
GI issues, neuropathy, contraindicated in renal disease
Non-specific, multiple drug interactions, not effective for all.
- A patient has stable coronary artery disease. Explain how foam cells contribute to plaque instability and suggest how anti-inflammatory therapies might help.
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Model Answer: Foam cells accumulate due to impaired cholesterol efflux and become pro-inflammatory, secreting cytokines (IL-1β, TNF) that degrade extracellular matrix and kill VSMCs.
This leads to fibrous cap thinning, promoting plaque rupture.
Anti-inflammatory therapies (e.g., canakinumab, colchicine) reduce cytokine levels, improving plaque stability, but must be used cautiously due to immunosuppression risks (e.g., sepsis with IL-1β inhibition).
- Describe the rationale for using TRAIL (TNF-related apoptosis-inducing ligand) as a potential therapeutic in atherosclerosis. Include its roles in endothelial function and macrophage behavior.
Model Answer:
* TRAIL levels are reduced in patients with coronary and peripheral artery disease.
* In ApoE-/-TRAIL-/- mice, atherosclerosis accelerates with larger necrotic cores and unstable plaques.
* TRAIL promotes endothelial function (angiogenesis, vascular repair) and regulates macrophage lipid efflux (via ABCA1/G1).
* Therapeutic agonistic TRAIL-R2 antibodies improved blood flow and vessel sprouting in PAD models.
* Thus, TRAIL has anti-inflammatory and endothelial-protective properties, making it a promising target.
