L1- Artherosclerosis

Question 1

What is atherosclerosis?

Answer 1

• Hardening and narrowing of the arteries due to plaque formation
• Leads to angina and thrombosis which can cause stroke and MI
• Progressive disease
• Can develop into coronary/cerebrovascular/peripheral vascular disease over time

Question 2

What is the mechanism of atherogenesis?

Answer 2

1. Lipid accumulation in tunica intima causes endothelial dysfunction. Reduced NO (antithrombotic) synthesis.
2. Leukocyte contribution causes sterile inflammation, release of DAMPs and tissue damage. Monocytes clear up oxidised LDL in intima and become foam cels (static, necrotic)
3. Smooth muscle cells form fibrous cap in intima by proliferation and matrix formation

Question 3

What is the difference between stable and vulnerable plaques?

Answer 3

• Vulnerable plaques are likely to rupture and cause thrombosis
• Vulnerable plaques have a larger lipid pool, thinner fibrous cap and many inflammatory cells

Question 4

What are the risk factors for atherosclerosis?

Answer 4

• Age
• Male gender
• Smoking
• Diet
• Diabetes, dyslipidaemia, hypertension, obesity

Question 5

What are circulating lipids?

Answer 5

• Free cholesterol
• Cholesteryl esters
• Phospholipids and triglycerides
Sources of energy, cell membranes and steroid hormones

Question 6

What drugs are used to treat atherosclerosis?

Answer 6

• STATINS- lipid lowering
• Inhibit HMG-COA reductase enzyme in hepatic cholesterol synthesis
• Leads to up-regulation of LDL receptors of liver
• Increased removal of Apo-B containing lipo-proteins from circulation
• Reduction in synthesis and secretion of lipids from liver

Question 7

What are the positive effects of statins?

Answer 7

• LDL lowered
• Endothelial function restored
• Inflammation reduced
• Ischaemic episodes reduced
• Vulnerable plaques stabilised

Question 8

How do statins lower inflammation?

Answer 8

• Inhibiting HMA-COA prevents production of RHO-GTPases
• Prevents actin cytoskeleton functioning so impacts migration of leukocytes into intima
• Less RHO-GTPases means less adhesion moelcules so less entry of monocytes into artery wall

Question 9

What are the adverse effects of statins?

Answer 9

Common-
• Headache
• Fatigue
• GI intolerance, Flu like symptoms

Rare-
• Increase in liver enzymes and serious liver problems
• Myopathy

Question 10

What are other drugs used in combination with statins?

Answer 10

• Anti-platelet medications: Aspirin reduces chance of thrombosis
• Beta-blockers- lower HR/BP/MI risk
• ACE inhibitors- lower BP
• Ca2+ channel blockers- lower BP
• Diuretics- lower BP

Question 11

What was the Cantos trial?

Answer 11

• Showed inflammation is major driver of CVD
• IL-1b is a proinflammatory cytokine produced by inflamasome protien which requires 2 signals
• Therapy targeting IL1b reduced CVD events, independent of lipid lowering