16. Atherosclerosis and coronary heart disease Flashcards
(40 cards)
6 Modifiable risk factors that contribute to coronary heart disease
Smoking Lipids intake Blood pressure Diabetes Obesity Sedentary lifestyle
3 Non-modifiable risk factors that contribute to coronary heart disease
Age
Sex
Genetic background
How has epidemiology of contributory factors to coronary heart disease changed?
Reduced hyperlipidaemia (statin treatment) Reduced hypertension (antihypertensive treatment) Increased obesity = Increased diabetes
If risk factors are general, why is atherosclerosis focal?
Carotid artery bifurcates into internal and external
When blood hits outer wall a vortex is created by the disturbance in geometry
Plaque forms where there is more disordered blood flow
Describe the development of atherosclerosis
- Lesion prone location, develops increase in interstitial matrix in intima
2.Becomes more inflammatory with macrophage foam cells - Some macrophages start to die and release the fat = Fat in artery wall
- Pools of fat coalesce, form core of extracellular lipid and dead macrophage= necrotic core
- Inflammation triggers fibrotic thickening/ scarring
- If fibrous thickening does not happen enough, fibrous cap can crack apart mechanically, triggers a thrombus to form
Thrombi can block coronary artery and cause MI
What are the main inflammatory cells in atherosclerosis?
Macrophages
Which form of lipoprotein is ‘bad’? What does it do?
Low density Lipoproteins (LDL)
Carries cholesterol from liver to rest of the body including arteries.
What are Oxidised/ modified LDL(s)?
Due to action of free radicals on LDL.
Families of highly inflammatory and toxic forms of LDL found in vessel walls.
What are the 2 classes of macrophages and how are their roles different?
Resident: involved in maintaining homeostasis
Inflammatory: kill microorganisms
What causes the oxidation of LDLs?
Free radicals
Describe what happens to LDLs after endothelial activation
Endothelial activation increases membrane permeability
LDLs enter and are oxidised by free radicals and become stuck in the subendothelial layer
OxLDLs are phagocytosed by macrophages to form foam cells
Foam cells accumulate and stimulate chronic inflammation
What is Familial Hyperlipidaemia? State 2 clinical features.
Autosomal recessive disease
Massively elevated blood cholesterol level (20 mmol/L)
Failure to clear LDL from blood
Xanthoma (accumulations of foam cells in the skin)
Early atherosclerosis
What is the LDLR regulated by?
It is negatively regulated by intracellular cholesterol
What is the second LDL receptor? (not LDLR)
Scavenger receptor
Not under feedback control by intracellular cholesterol
Pathogen receptors that ‘accidentally’ binds to OxLDLs
Other than OxLDL what does Macrophage scavenger receptor A bind to? What is it AKA?
AKA: CD204
Gram-positive bacteria
Dead cells
Other than OxLDL what does Macrophage scavenger receptor B bind to? What is it AKA?
AKA: CD36
Malaria parasites
Dead cells
What determines the function of the second LDL receptor?
Level of OxLDL present
Low levels: abnormal materials are taken up by macrophages and cleared safely by reverse cholesterol transport.
High levels: it triggers an inflammatory reaction
How do macrophages within plaques generate free radicals that further oxidise lipoproteins? Which 2 enzymes are involved?
Have oxidative enzymes that can modify native LDL, causes a cycle
(Macrophages think OxLDL a bug, oxidise it further= further inflammation)
NADPH Oxidase
Myeloperoxidase
How do macrophages within plaques become foam cells?
Phagocytose OxLDLs
OxLDLs accumulate
Become enlarged foam cells
What do plaque macrophages express? Why?
Express inflammatory factors
To recruit monocytes
What cytokines are released by macrophages?
IL-1: upregulates VCAM-1
VCAM-1 mediates tight monocyte binding
What chemokines are released by macrophages?
Monocyte chemotactic protein-1 (MCP-1)
MCP-1 binds to a monocyte G-protein coupled receptor CCR2
Attracts monocytes
What 2 growth factors are produced by macrophages and how do they affect vascular smooth muscle cells (VSMCs)? (“wound healing” role)
Platelet derived growth factor (PDGF): stimulates VSMC chemotaxis, survival and division
Transforming growth factor-beta: stimulates collagen synthesis and matrix deposition, makes fibrous cap thicker
Describe how the normal function of a VSMC is different to the atherosclerotic VSMC
Normal: more contractile filaments and less collagen deposition
Atherosclerotic: fewer contractile filaments and more collagen deposition
