Questions: Atherosclerosis Development and Progression

Question 1

A patient has a coronary angiogram showing 40% luminal stenosis in one artery and 70% stenosis in another. Which plaque is most likely to cause a heart attack, and why?

• A. The 70% stenosis, because greater blockage means greater risk of complete occlusion
• B. The 40% stenosis, if it has a large lipid core and thin fibrous cap, because plaque rupture risk depends on composition not just size
• C. Both equally — stenosis percentage is the primary predictor of myocardial infarction
• D. Neither; only total blockage (100% stenosis) causes heart attacks

Answer: (B)

This is the counterintuitive key insight of atherosclerosis pathophysiology: a plaque with a large lipid core and thin fibrous cap is highly vulnerable to rupture regardless of stenosis degree. When it ruptures, the thrombogenic lipid core triggers rapid clot formation that can completely occlude the lumen. The 70% stenosis with a thick, stable fibrous cap may actually be safer in the short term. Angiography measures lumen narrowing, not plaque stability — this is why imaging alone can be misleading.

Question 2

Why do foam cells form in the arterial wall, and why can't macrophages stop accumulating cholesterol the way normal cells do?

• A. Macrophages lack the LDL receptor entirely, so they take up cholesterol indiscriminately
• B. Macrophages use scavenger receptors (not LDL receptors) to engulf oxidized LDL, and these receptors are not downregulated by intracellular cholesterol accumulation
• C. Oxidized LDL binds irreversibly to macrophage membranes, preventing normal receptor regulation
• D. Foam cell formation is a deliberate immune strategy — macrophages sacrifice themselves to remove dangerous oxidized cholesterol

Answer: (B)

Normal cells use LDL receptors, which are downregulated when intracellular cholesterol rises — a feedback mechanism preventing overload. Macrophages engulf ox-LDL via scavenger receptors that lack this feedback regulation. As a result, macrophages keep engulfing ox-LDL until they become lipid-engorged foam cells. When these cells die, they release their lipid contents into the plaque, amplifying the inflammatory cycle.

Question 3

Atherosclerosis is fundamentally a disease of excess cholesterol deposited passively in arterial walls.

• T. True
• F. False

Answer: False

This is the core misconception. Atherosclerosis is a chronic inflammatory disease. Cholesterol accumulation is necessary but not sufficient — endothelial injury and the subsequent inflammatory response are required. The sequence involves endothelial dysfunction, LDL oxidation, monocyte recruitment, foam cell formation, smooth muscle proliferation, and fibrous cap development. Without the inflammatory component, passive cholesterol deposition alone would not create the complex, vulnerable plaques that rupture.

Question 4

Plaque rupture causes a heart attack because the sudden release of lipid core material directly blocks the lumen mechanically.

• T. True
• F. False

Answer: False

Plaque rupture causes acute coronary events through thrombosis, not mechanical obstruction. When the fibrous cap ruptures, the highly thrombogenic lipid core (rich in tissue factor) is exposed to flowing blood, immediately activating the coagulation cascade and triggering platelet aggregation. The resulting thrombus — which can form within minutes — is what occludes the lumen and causes the infarction. The plaque material itself is secondary.

Question 5

Explain why statins reduce cardiovascular risk through two complementary mechanisms, and why the second mechanism (not direct inhibition) may actually drive most of the clinical benefit.

Model answer: Statins directly inhibit HMG-CoA reductase, reducing endogenous cholesterol synthesis in liver cells. As intracellular cholesterol falls, SREBP is released and upregulates LDL receptor expression on hepatocyte surfaces. These additional receptors pull more LDL out of the bloodstream, dramatically lowering circulating LDL. The upregulation of LDL receptors — the cell's compensatory response to the block — may account for much of the clinical LDL-lowering effect, beyond simple synthesis inhibition.

Understanding the feedback loop explains why statins are more effective than simply blocking one synthesis step would predict. The liver responds to lower intracellular cholesterol by aggressively clearing LDL from blood, amplifying the drug's effect. This also explains why combining statins with PCSK9 inhibitors (which prevent LDL receptor degradation) has additive effects.