Athersclerosis

Question 1

Define atherosclerosis

Answer 1

A progressive disease of the arteries. Accumulation of lipids and fibrous tissue in tunica intima

Question 2

What can atherosclerosis cause?

Answer 2

CHD and stroke - underlying cause of 50% deaths in west

Question 3

What is myocardial ischemia?

Answer 3

An imbalance of demand and supply of oxygenated blood to arteries. Mainly occurs when there is an increase in demand of O2…exercise (angina of effort)

Question 4

What happens when the fibrous cap ruptures?

Answer 4

Thrombogenic lipid core comes into contact with blood - platelet aggregation and thrombus formation which can occlude coronary arteries resulting in sudden death or a MI

Question 5

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

Answer 5

Non-modifiable: male gender, menopause, history of CHD, age

Modifiable; diet, exercise, smoking, obesity, high LDL/HDL, hypertension etc

Question 6

Describe the mechanism of atherogensis.

Answer 6

Endothelial damage and lipid accumulation result in decreased NO production. LDL are oxidised. Endothelial cells expression adhesion molecules (VCAM) to which inflammatory cells attach. 
Inflammatory cells are attracted by chemotactic stimuli and migrate to intiman. Monocytes differentiate to macrophages.
Macrophages proliferate (in response to mitogenic stimuli) and ingest oxidised LDL to form foam cells.
Accumulated foam cells die to leave a lipid core. Fibrous cap forms to prevent contact with blood.

Problem is when cap ruptures.

Question 7

What does the treatment of atherosclerosis focus on?

Answer 7

Reduction of risk

Question 8

Describe the different lipoproteins, when they are found in the body and what APO they contain

Answer 8

Chylomicrons - postpyrandial, TG rich
VLDLs; fasting state, APOE
LDLs; high protein;lipid ration, APOB
HDL; highest protein lipid ratio; APO A (1and2)

Question 9

Statins - eg, how they work and side effects

Answer 9

Simvistatin
Inhibit HMG-CoA reductase (involved in cholestrol synthesis)
Result in:
- upregulated LDL receptors in liver and increased removal of LDL from circulation
- reduction synthesis and secretion of lipoproteins from liver
- lower serum LD by 50%
anti inflammatory actions
enhanced DNA repair and decreased SM senescence

Cause headaches, fatigue, GI intolerance and flu like symptoms.
increase liver enzymes
myopathy (muscle weakness/pain and increase creatine kinase).

Question 10

Bile acid resins

Answer 10

Cholestyramine
inhibit enterohepatic shunt…increase bile acid synthesis from cholestrol
increase hepatic LDL receptor expression and uptake…results in lowered serum LDL.

Side effects; GI intolerance
Drug interaction - bind other negatively charged drugs (excretion without absorption)
impede absorption of other drugs and fat soluble vitamins.

Question 11

Fibric acid derivatives

Answer 11

Gemofibrozil
Activate PPAR-alpha which regulated expression of protein involved in HDL synthesis and HDL mediated cholestrol reverse transport
Therefore increase HDL

Causes GI upset, gallstones and myopathy if used with statins.

Question 12

Nicotinic acid/niacin

Answer 12

Activates GPCR in adipocytes which inhibits lipolysis and to decrease FFA levels. This decreased hepatic VLDL production and decreases serum LDL.

But…itching, flushing, headaches, hepatotoxicity, hyperglycemia and decreased insulin sensitivity

Question 13

Exetimibe

Answer 13

blocks cholestrol absorption by indirectly inhibiting NPC1L1

But some GI intolerance and back/joint pain.

Question 14

How could you increase HDL?

Answer 14

Inhibit cholesterylester transfer protein
Torcetrapib
BUT increase mortality

Question 15

How could you target the lesion associated with inflammation?

Answer 15

Daraladip which inhibits lipoprotein assocaited PLA2…decrease inflammatory markers

Question 16

How could you stimulate reverse cholesterol transport?

Answer 16

Liver X receptor antagonists - decrease HDL secretion - inhibit atherosclerosis
But elevate inducible degrader of LDLR and therefore increases LDL

Question 17

How could you improve plaque stability?

Answer 17

Succinbucol which inhibit VCAM1
Use matrix metalloprotease inhibitors
Use ACE inhibitors (ramipril).