Atherosclerosis and Angina

Question 1

Define Atherosclerosis

Answer 1

Atherosclerosis is a chronic progressive disease characterised by the buildup of plaque within the walls of arteries. This plaque primarily consists of lipids but contains other substances. Over time, this accumulation causes the arteries to narrow and harden, impeding blood flow. Atherosclerosis can affect arteries throughout the body, leading to various cardiovascular complications such as heart disease, stroke, and peripheral artery disease.

Question 2

Explain the pathophysiology of Atherosclerosis

Answer 2

1. Dysfunctional Endothelium on the vascular wall allows LDLs to enter the tunica intima
2. These LDLs become oxidised and are unable to leave the tunica intima
3. The presence of these oxidised-LDLs causes the endothelium to express adherence molecules which cause circulating monocytes to bind
4. Monocytes enter the cell via diapedesis and become macrophages which then engulf the oxidised-LDLs to become Foam Cells
5. Foam Cells cause the migration of Smooth Muscle Cells from the tunica media to the tunica intima. These SMCs then proliferate and there is increased collagen synthesis leading to the hardening of the plaque
6. The foam cells can die, releasing their contents which can attract neutrophils and cause inflammation in the area, which is now a plaque.

Question 3

What are the risk factors for Atherosclerosis?

Answer 3

• Hypercholesterolaemia = More LDLs to infiltrate
• Hypertension = Increased BP results in more force on endothelium and so greater chance of damage
• Diabetes = Increased glucose can damage endothelium
• Smoking = Damages endothelium
• Obesity
• Sedentary lifestyle
• High-fat diet

Question 4

What are some complications of Atherosclerosis?

Answer 4

The plaque forms a physical blockage in the lumen of the artery. This may cause reduced blood flow and hence oxygen to the area that the artery supplies, particularly at times of increased demand, resulting clinically in angina the plaque may rupture, potentially causing a complete occlusion of the artery.

This may result in a myocardial infarction if the atherosclerosis is in the coronary arteries, Carotid artery disease if in the carotid arteries (can cause transient ischaemic attacks) and Peripheral Artery Disease

Question 5

Describe the Exogenous Cholesterol Pathway

Answer 5

1. Fat and Cholesterol coming from the diet (exogenous = outside generated) are assembled into chylomicrons.
2. Chylomicrons travel to adipose tissue
3. Adipose tissue expressing lipoprotein lipase causes fatty acids to be deposited from the chylomicrons
4. After depositing these fatty acids, the chylomicrons are smaller and known as chylomicron remnants
5. Empty HDL are generated from steps 3 & 4
6. Chylomicron Remnants travel to the liver and are broken down by apolipoprotein E into fatty acids and cholesterol

Question 6

Describe the Endogenous Pathway

Answer 6

1. Free fatty acids and cholesterol in the liver are packaged into VLDL
2. VLDL travels to adipose tissue and deposits fatty acids at adipose tissue expressing lipoprotein lipase
3. After depositing fatty acids, the VLDL is now IDL
4. Empty HDL is produced as a byproduct (which can then collect LDL from the periphery).
5. IDLs are absorbed from the blood by the liver.
6. IDLs are then broken down by hepatic lipase into LDLs (triglycerides are removed in this process).
7. LDLs have relatively high cholesterol content whilst having minimal fatty acids and glycerol content.
8. LDL circulates and is absorbed by various tissues via binding to LDL receptors.
9. Excess LDL is absorbed by the liver via LDL receptors. .

Question 7

What are statins and how do they work?

Answer 7

Statins are the most widely used drug to lower cholesterol and hence are used in patients with cardiovascular disease.

They do this by inhibiting HMG-CoA reductase, the rate-limiting enzyme in hepatic cholesterol synthesis. This decreases hepatocyte (liver cell) intracellular cholesterol levels

Decreased cholesterol concentration in hepatocytes leads to upregulation of hepatic LDL receptors.

More LDL is taken up by the liver, decreasing the level of circulating LDL and reducing foam cell formation

Question 8

Define Angina

Answer 8

Angina is chest pain caused by an imbalance between oxygen supply (decreased coronary blood flow) and oxygen demand (increased myocardial oxygen consumption), which leads to a decrease in the oxygen supply/demand ratio and myocardial hypoxia.

Question 9

What is the chest pain from Angina like?

Answer 9

Often described as squeezing, pressure, heaviness or tightness which may radiate to the arms, neck or jaw

Question 10

What are the types of Angina?

Answer 10

Stable Angina, Unstable Angina and Variable Angina

Question 11

What is Stable Angina?

Answer 11

Stable Angina is caused by Atherosclerotic narrowing of epicardial coronary arteries.

When a vessel is narrowed beyond ‘critical stenosis’ value (typically >70%), myocardial tissue beyond the stenosis will not receive adequate blood flow.

Ischaemia occurs during physical exertion due to increased myocardial O2 demand in the face of reduced supply.
Stable Angina is ‘Demand’ or ‘exertional’ ischaemia (Demand increases and the supply is insufficient)

Question 12

What is Unstable Angina?

Answer 12

Unstable Angina is caused by transient formation and dissolution of a clot within a coronary artery.

Clots form in response to plaque rupture or endothelial dysfunction (inability to inhibit clot formation via NO and prostacyclin release).
The thrombus reduces blood flow and leads to ischaemia (can cause MI if the clot does not dissolve quickly enough)

Unstable Angina is ‘Supply’ ischaemia (supply is insufficient for a normal demand). It occurs at rest and is often more prolonged.

Question 13

What is Variable Angina?

Answer 13

Variant angina is caused by coronary vasospasm which temporarily reduces coronary blood flow

Question 14

What is the overarching message for treatment of angina?

Answer 14

Reduce myocardial oxygen