Atherosclerosis

Question 1

What is atherosclerosis?

Answer 1

Disease of the arteries, it involves the narrowing of arteries caused by the deposition of cholesterol (plaques).

Question 2

How does thrombosis occur?

Answer 2

Erosion of the fibrous cap causes contents of plaque to leak and come into contact with the bloodstream causing platelet aggregation, thus a thrombus forms.

Question 3

What can thrombosis cause?

Answer 3

Sudden death, unstable angina and myocardial infarction.

Question 4

What is myocardial infarction?

Answer 4

It is caused by a thrombotic event which cuts off blood flow downstream of the clot, nutrients and oxygen are unable to be delivered to cells which are non-regenerative, thus die.

Question 5

What is the cause endothelial dysfunction?

Answer 5

It is the first stage of atherogenesis, it is caused by reduced NO synthesis and high concentrations of atherogenic lipoproteins (LDL).

Question 6

What is the role of NO in the artery?

Answer 6

NO is responsible for smooth muscle relaxation, thus is a vasodilator.

Question 7

What is sterile inflammation?

Answer 7

Caused by Damaged-associated Molecular Patterns (DAMPs) which are danger molecules released from our damaged/dying cells. Does not involve pathogens or infection.

Question 8

What is the contribution of leukocytes in atherosclerosis?

Answer 8

Monocytes have receptors which detect DAMPs, tissue debris attract immune cells. Macrophages and lymphocytes are recruited but produce cytotoxic components when taking up debris thus cause more damage. This amplifies the inflammatory response and thus causes more damage to tissues.

Question 9

What is the process of anti-inflammation caused by PAMPs?

Answer 9

PAMPs cause an acute inflammatory response which causes neutrophils to ingest bacteria and recruit monocytes. Monocytes differentiate into macrophages which ingest bacteria. When neutrophils die, M1 macrophages engulf them (efferocytosis) which drives anti-inflammatory processes and repair (resolvins, TGFs etc.) These stimulate stromal cells to divide and restore tissue.

Question 10

What are foam cells?

Answer 10

Macrophages that have ingested cholesterol and recruit inflammatory cytokines, this drives endothelial cells to become activated which recruit more.

Question 11

Why does the number of foam cells continue increase?

Answer 11

They are unable to egress after ingesting cholesterol and unable to undergo efferocytosis.

Question 12

What is the fate of foam cells?

Answer 12

They undergo secondary necrosis due to defective efferocytosis; macrophages eat the apoptotic bodies.

Question 13

What causes the thinning of the fibrous cap?

Answer 13

Matrix metellaproteinase eats away at the fibrous cap which causes the cap to rupture and leak plaque contents.

Question 14

What is the difference between stable vs vulnerable plaques?

Answer 14

Stabilised: small lipid pool, thick fibrous cap, preserved lumen
Vulnerable: large lipid pool, thin fibrous cap, many inflammatory cells

Question 15

What are the features of a healed ruptured plaque?

Answer 15

Narrow lumen and fibrous intima.

Question 16

What are the major non-modifiable risk factors for atherosclerosis?

Answer 16

Age, male gender, family history of CHD, menopause

Question 17

What are the major modifiable risk factors for atherosclerosis?

Answer 17

Biomedical: dyslipidaemia (high LDL/low HDL), hypertension, diabetes, abdominal obesity
Behavioural: smoking, physical activity, diet

Question 18

What are the components of a chylomicron?

Answer 18

Cholesterol, phospholipids, cholesterol ester, triglycerides, proteins.

Question 19

What is the mechanism of action of statins?

Answer 19

Statins inhibit HMG-CoA reductase which is a rate-limiting enzyme in hepatic cholesterol biosynthesis which leads to:
- up-regulation of LDL receptors in liver
- increased removal of Apo B-containing lipoproteins from the circulation
- reduction in synthesis and secretion of lipoproteins from liver
- anti-inflammatory action
- enhanced DNA repair and reduced senescence in vascular smooth muscle cells

Question 20

What are the adverse effects of statins?

Answer 20

Headache, fatigue, GI intolerance, flu-like symptoms; increase in liver enzymes; myopathy.

Question 21

What other drugs are used in combination with statins?

Answer 21

Anti-platelet medications (aspirin) to reduce thrombosis; beta-blocker medications which reduce heart rate and blood pressure; ACE inhibitors which lower blood pressure; calcium channel blockers which lower blood pressure; diuretics which also lower blood pressure.

Question 22

How do statins effect leukocytes entering tissues?

Answer 22

They can reduce the expression of all adhesion molecules so fewer leukocytes enter tissue.

Question 23

What is the role of RHO GTPase in leukocytes and endothelial cells?

Answer 23

Found to have a positive impact on increasing NO production which blocks some pro-inflammatory effects.

Question 24

How can PCSK9 inhibitors be used to treat atherosclerosis?

Answer 24

PCSK9 proteins prevent LDL being taken up and broken down in the liver as they prevent binding. PCSK9 inhibitor prevents LDL receptors from being degraded thus allowing more LDL receptors to be available for LDL to be broken down.