Cardiovascular risk (3)

Question 1

What is cardiovascular disease?

Answer 1

A class of disorders affecting the heart, blood vessels or both e.g.
→ coronary heart disease - thickening of the walls of the arteries that supply blood to the heart
→ cerebrovascular disease - i.e. stroke - complete blockage of a vessel in the brain
→ hypertensive heart disease - increase in bp
→ peripheral arterial disease - affects arteries in the limbs (impacts circulation)
→ rheumatic heart disease - infection (i.e. in gums) - heart valve damage
→ deep vein thrombosis and pulmonary embolism - blood clot due to poor circulation

Question 2

What is a hemorrhagic stroke?

Answer 2

Blood vessel in the brain ruptures
→ blood moves into the brain
→ blood supply to part of the brain is cut off - leading to brain damage

Question 3

What is atherosclerosis?

Answer 3

Thickening of the walls of blood vessels due a build up of lipid plaques
→ precursor of all CVD

causes:
→ reduced arterial lumen
→ loss of perfusion
→ loss of elasticity - increase chance of rupture
→ predisposition to thrombus (clot) formation

Question 4

What can happen if a atherosclerotic plaque (atheroma) ruptures?

Answer 4

Activated platelets undergo adhesion and aggression - can cause blood clots
→ blood clots can block vessels - stroke, myocardial infarction (heart attack)

Question 5

What is cardiovascular risk?

Answer 5

Epidemiological/statistical notion that can assist in assessing risk/benefit for treatments
→ often used for rationing limited health resources
→ measurement of the likelihood of a cardiovascular even happening
→ can be measured for populations (not accurate for the individual)
→ different algorithms are used e.g. Framingham - derived from large cohorts in clinical trails or prospective epidemiological studies

Question 6

How can cardiovascular risk be measured?

Answer 6

Risk of having a cardiovascular event in a 10 year period
Risk calculators include: Frammingham score, QRisk scores, NICE

lipid levels are a good indicator of risk - healthy/high risk people are only treated if…
→ total cholesterol levels = <5mmol/L (healthy) and <4mmol/L (high risk)
→ LDL levels = <3mmol/L (healthy) and <2mmol (high risk)
→ TG < 1.7mmol/L
→ HDL > 1mmol/L

Low risk = 10% or less CVD risk in 10 years
Intermediate risk = 10-20%
High risk = 20% or more

Question 7

What factors automatically put you at high risk for developing CVD?

Answer 7

Age > 75years
Family history of premature CVD
Familial hypercholesterolaemia (FH)
Known type 2 diabetes

Question 8

What factors can affect the chance of developing atherosclerosis?

Answer 8

Age, sex, genetics

Stress, personality, exercise, diet, obesity, infection

Hyperhomocysteinaemia (too much cysteine), hypercoagulable (blood clots easily), hyperlipidaemia (treatment - change lipid levels), insulin resistance, diabetes, hypertension, smoking

Question 9

What are lipoproteins?

Answer 9

Lipid protein complexes
→ necessary because lipids are insoluble in water - if you want to transport lipids in the bloodstream require specific proteins

5 major classes: chylomicrons, VLDL, IDL, LDL, HDL (also lipoprotein A)
→ positive correlation between LDL-C and CDV risk - don’t want LDL
→ inverse correlation with HDL-C and CVD risk - want more HDL

Question 10

What are apolipoproteins?

Answer 10

Signalling molecules
→ cell surface receptors that direct lipoproteins to specific tissue receptors and mediate enzymatic reactions

Question 11

How are lipoproteins classified?

Answer 11

According to density - what they predominantly transport
C = colesterol, TG = triglyceride, PL = phospholipids,

Chylomicron (CM) → dietary TG (95%)
Very low-density lipoprotein (VLDL) → TG (65%) from liver to tissues
Intermediate-density lipoprotein (IDL) → PL (35%) and Protein (25%) from partial hydrolysis of VLDL
Low-density lipoprotein :( (LDL) - Lipoprotein A is a version→ C (50%) and protein (25%) from hydrolysis of IDL, takes C to tissues
High-density lipoprotein :) (HDL) → protein (55%) some C and PL (25%) from tissues to liver and exchanged proteins

Question 12

How are lipoproteins structured?

Answer 12

Central core containing cholesterol esters and triglycerides surrounded by phospholipids and various apolipoproteins

Question 13

What are the 3 major pathways for lipid transport?

Answer 13

1. Endogenous pathway (LDL)
2. Reverse transport pathway (HDL)
3. Exogenous pathway (chylomicrons)

Question 14

What is the exogenous (intestinal) lipid transport pathway?

Answer 14

1. Dietary fat triglycerides are transported into nacent chylomicrons (CM) in small intestines (Apo B-48)
2. Circulation of CM from lymph into blood (some Apo C2+E transfer from HDL)
3. At various adipose tissues and muscle triglyceride is hydrolysed by LPL (lipoprotein lipase) into FFA (free fatty acids) and glycerol - used by tissues (via Apo C)
4. Remaining CM remnant circulates to the liver (Apo E with rR) and removed

(chylomicrons carry exogenous lipids around the body)

Question 15

What is the endogenous lipid transport pathway?

Answer 15

1. Endogenous cholesterol and triglyceride made in the liver packaged into nascent VLDL
2. Circulated into blood, some HDL apolipoproteins transfer, carried to peripheral tissues - LPL cleaves releasing free fatty acid - used by organs or deposited in adipose tissue
3. Forms IDL, 50% go to liver
4. Degraded IDL forms LDL which may go back to the liver or deliver its contents to peripheral tissues

Question 16

What is the reverse cholesterol transport pathway?

Answer 16

1. HDL produced in liver and intestines
2. Picked up various apolipoproteins, picks up cholesterol from capillaries
3. Transports to adrenals, ovaries, testes - some cholesterol used to produced steroid hormones
4. Various pathways remove HDL - end up in liver

Question 17

How is atherosclerosis characterised?

Answer 17

Lipid deposition in the tunica intimata
Smooth muscle and ECM proliferation
Production of a protruding fibrous plaque
→ generally affects medium to large arteries
→ doesn’t tend to occur in veins or capillaries due to low pressure

Question 18

What can cause atherosclerosis to become symptomatic?

Answer 18

Vessel lumen is sufficiently narrowed → ischaemia
Sudden occlusion by plaque rupture and thrombosis → MI heart attack
Walls are weakened → aneurysm - artery splits, blood pools out
Blood clot breaks lose → embolism - are blood clot, blocks lungs

Question 19

What are the stages of the formation of atheromatous plaques (thrombosis)?

Answer 19

1. Damage to vessel epithelial cells → exposure of collagen beneath epithelial cells, activates platelets and can lead to inflammatory process
2. Causes changes:
   → tunica intima protrudes into lumen
   → under intima: smooth muscle cells proliferates, build up of macrophages (foam cells - m that engulfed LDLs), WBC build up, adherance of platelets, build up of extracellular matrix - fatty streak
3. End up with plaque - core of lipid, foam cells, increase in ECM bonded together with matrix proteins
   → ECM forms fibrous cap
   → binding of thrombus occludes blood vessels

Question 20

Can crosstalk between nerves, immune cells and plaques drive atherosclerosis?

Answer 20

Yes
→ large change to nervous supply of plaque vessels

Question 21

What are the complications of atherosclerosis?

Answer 21

Calcification of plaques → increase rigidity of vessel wall - don’t contract and dilate as they should do
Cap rupture → leading to thrombus formation
Haemorrhage → further narrowing of vessel
Embolisation of fragments at distal sites
Weakening of vessel → aneurysm
Microvessel growth → can cause surrounding vessels to grow

Question 22

What plaques are vulnerable to rupture?

Answer 22

In the coronary arteries behaviour of plaque is determined not primarily by its size but by its composition
→ plaques with large lipid cores, thin fibrous caps and inflammatory cell infiltrates are more likely to rupture - exposing thrombogenic material of the plaque core and precipitating acute coronary events

Question 23

How do you treat atherosclerosis?

Answer 23

Lifestyle changes → obesity, smoking, physical activity
Targeting hypertension → ACE inhibitors
High cholesterol → statins (reduce cholesterol)
Thrombus formation → antiplatelets (low-does aspirin, clopidogrel)
Surgery → coronary Cartier’s (MI), carotid arteries (stroke) - bypass, clears arteries

Question 24

What are statins?

Answer 24

Drugs that reduce the production of cholesterol