What is cardiovascular disease?
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
What is a hemorrhagic stroke?
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
What is atherosclerosis?
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
What can happen if a atherosclerotic plaque (atheroma) ruptures?
Activated platelets undergo adhesion and aggression - can cause blood clots
→ blood clots can block vessels - stroke, myocardial infarction (heart attack)
What is cardiovascular risk?
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
How can cardiovascular risk be measured?
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
What factors automatically put you at high risk for developing CVD?
Age > 75years
Family history of premature CVD
Familial hypercholesterolaemia (FH)
Known type 2 diabetes
What factors can affect the chance of developing atherosclerosis?
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
What are lipoproteins?
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
What are apolipoproteins?
Signalling molecules
→ cell surface receptors that direct lipoproteins to specific tissue receptors and mediate enzymatic reactions
How are lipoproteins classified?
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
How are lipoproteins structured?
Central core containing cholesterol esters and triglycerides surrounded by phospholipids and various apolipoproteins
What are the 3 major pathways for lipid transport?
- Endogenous pathway (LDL)
- Reverse transport pathway (HDL)
- Exogenous pathway (chylomicrons)
What is the exogenous (intestinal) lipid transport pathway?
- Dietary fat triglycerides are transported into nacent chylomicrons (CM) in small intestines (Apo B-48)
- Circulation of CM from lymph into blood (some Apo C2+E transfer from HDL)
- 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)
- Remaining CM remnant circulates to the liver (Apo E with rR) and removed
(chylomicrons carry exogenous lipids around the body)
What is the endogenous lipid transport pathway?
- Endogenous cholesterol and triglyceride made in the liver packaged into nascent VLDL
- 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
- Forms IDL, 50% go to liver
- Degraded IDL forms LDL which may go back to the liver or deliver its contents to peripheral tissues
What is the reverse cholesterol transport pathway?
- HDL produced in liver and intestines
- Picked up various apolipoproteins, picks up cholesterol from capillaries
- Transports to adrenals, ovaries, testes - some cholesterol used to produced steroid hormones
- Various pathways remove HDL - end up in liver
How is atherosclerosis characterised?
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
What can cause atherosclerosis to become symptomatic?
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
What are the stages of the formation of atheromatous plaques (thrombosis)?
- Damage to vessel epithelial cells → exposure of collagen beneath epithelial cells, activates platelets and can lead to inflammatory process
- 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 - 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
Can crosstalk between nerves, immune cells and plaques drive atherosclerosis?
Yes
→ large change to nervous supply of plaque vessels
What are the complications of atherosclerosis?
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
What plaques are vulnerable to rupture?
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
How do you treat atherosclerosis?
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
What are statins?
Drugs that reduce the production of cholesterol
