Atherosclerosis and heart disease Flashcards
What are the modifiable risk factors of heart disease?
- Smoking
- Lipids intake
- Blood pressure
- Diabetes
- Obesity
- Sedentary lifestyle.
What are the non-modifiable risk factors of heart disease?
Age, sex and genetic background
What three factors when combined increase heart disease risk exponentially?
1) Smoking
2) Hypertension
3) High cholesterol
What happens to low density lipoproteins once deposited in the subintimal space?
Binds to matrix proteoglycans and becomes oxidised by reactive oxygen species released by macrophages
What is the step of atherosclerosis?
Coronary artery at lesion-prone location (adaptive thickening of smooth muscle)
What is a type II lesion?
Macrophage transmigration into the subendothelial space, phagocytosis oxidised lipoproteins forming foam cells.
What is a type III lesion?
Preatheroma: Small pools of extracellular lipid
What is a type IV lesion?
Atheroma - core of extracellular lipid forms
What is a type V lesion?
Fibroatheroma, progressive fibrosis; thickening the fibrous cap; separating the lipid core from the lumen
What is a complicated lesion?
Fissure and haematoma and thrombus formation
How do complications arise due to plaque formation?
Due to extensive growth of the lipid cores, narrowing the lumen (stenosis or plaque ruptures)
When is the window of opportunity for primary prevention?
Intermediate and advanced lesions
Life-style changes
Risk factor management
What is the intervention of arterial stenosis?
Balloon angioplasty PCI
What is the function of vascular endothelial cells?
Barrier function (to lipoproteins)
Leukocyte recruitment
What is the function of monocytes/macrophages?
Foam cell formation
Cytokine and growth factor release
Major source of free radicals
Metalloproteinases
What is the function of vascular smooth muscle cells?
Migration and proliferation within the tunica media
Collagen synthesis
Remodelling and fibrous cap formation
What is the function of platelets?
Thrombus generation - presents in acute MI, and unstable angina
Cytokine and growth factor release
What is the function of T-lymphocyte?
Macrophage activation
Which type of treatment during clinical trials had fewer major adverse cardiovascular events (MACE)?
Anti-Il-1 treatment
Which CD macrophage lysosome protein is brown-dyed when associated wot an antibody?
CD68
How are macrophage subtypes regulated?
Combination of transcription factors binding to regulatory sequences of DNA
What is the main function of inflammatory macrophages?
Phagocytose pathogens
What are the three classes of resident macrophages?
Alveolar resident macrophages
Osteoclasts
Spleen (reticuloendothelial)
Where are LDLs synthesised?
Within the liver
What do LDLs transport?
Cholesterol
Where is cholesterol abnormally deposited?
Arterial intima
What are the docking molecules that assist with lipid binding?
Apoproteins
What are contained within LDL micelles?
Cholesterol esters
Which class of lipoproteins transport cholesterol from the peripheral tissues (arteries) to the liver?
High-density lipoproteins (HDLs)
-reverse cholesterol transport
What type of transporter are HDLs involved in?
Reverse cholesterol transport
How are LDLs oxidised?
Free radicals are released by activated macrophages
What is the fate of cholesterol within the sub-endothelial space?
Binds to proteoglycans and ultimately oxidised
What extracellular matrix protein binds to cholesterol in the sub-endothelial space?
Proteoglycan
How does proteoglycan-cholesterol binding influence oxidation?
Increases the susceptibility to modification
What is familial hyperlipidaemia?
An autosomal disorder that impairs lipoprotein metabolism by down-regulating LDL receptor expression
What is the effect of the down-regulation of LDL receptors?
Diminishes the clearance of LDLs from the plasma
Massively elevated cholesterol (20mmol/L)
Excessive production of VLDLs .
Which type of protein is retained within the sub-endothelial space in FH?
Apolipoprotein B-100
Retained due to interactions with the extracellular matrix. Therefore, this allows reactive oxygen species to modify the surface phospholipids and unesterified cholesterol.
How are circulating LDLs ingested in FH?
By unregulated scavenger receptors
What are the presentations of FH?
Xanthomas and atherosclerosis
What is a xanthoma?
Yellow plaques that occur predominantly besides the inner canthus of the eyelide
How is cholesterol regulated?
Negatively regulated by cellular cholesterol (LDL-receptors are sensitive to extracellular serum cholesterol), and are present on the cell surface membrane of hepatocytes
Which receptors are sensitive to extracellular serum cholesterol?
LDL receptors
What can be deduced by the fact that in LDL-R negative patients, macrophages continued to accumulate cholesterol?
The presence of scavenger receptors - that are unresponsive to negative feedback facilitated by the continued intake of oxidised LDL.
What are the functions of macrophage scavenger receptor A (CD204)?
Binds to oxidised LDL
Binds to gram positive bacteria (staphylococci and streptococci)
Binds to dead cells
Which type of macrophage scavenger receptor binds to malaria parasites?
MSRB (CD-36)
What are the functions of macrophage scavenger receptor B?
- Binds to oxidised LDL
- Binds to malaria parasites
- Binds to dead cells.
Which oxidative enzymes are released by macrophages, that can modify native LDL?
NADPH oxidase (superoxide O2)
Myeloperoxidase
Which types of molecules are upregulated by IL-1?
VCAM-I
Vascular cell adhesion molecule-1
What is the function of VCAM-I?
Mediates tight monocyte binding involves in recruitment
Which type of chemokine is released by activated macrophages that recruits monocyte?
Monocyte chemotactic protein-I MCP-I
Which type of receptors does MCP-I bind onto?
Monocyte G-protein coupled receptor CCR2
What are the effects of macrophage derived growth factors?
Recruit vascular smooth muscle and promote proliferation to deposit extracellular matrix.
Which types of growth factors are released by macrophages?
1) Platelet derived growth factor (PDGF)
2) Transforming growth factor beta (TGF-b)
What is the function of PDGF?
Support VSMC chemotaxis, survival and promote cell division.
What is the function of TGF-b?
Increases collagen synthesis and matrix deposition.
What is the effect on VSMCs by interactions of PDGF and TGF-b?
Contractile smooth conversion to synthetic atherosclerotic cells with reduced contractile filaments and an increase in matrix deposition genes
What are the two differences between normal medial contractile and synthetic atherosclerotic cells?
Decreased contractile filaments
And increase in matrix deposition genes
(In Synthetic)
Which type of proteinases are released by macrophages?
Metalloproteinases
What is the function of metalloproteinases released by macrophages?
Responsible for forming a proteolytic cascade to degrade collagen, requiring zinc in the active site
Which ion is involved in metalloproteinases?
Zinc
What are the impacts of metalloproteinases on the fibrous cap?
Potentiates thin fibrous cap degradation, increasing the susceptibility of plaque rupture
Rupture promotes coagulation - occlusive thrombus and cessation of blood flow
What is the consequence of a thin fibrous cap rupture by metalloproteinase activity?
Causes the release of necrotic foam debris into the arterial lumen, this initiates thrombosis that ultimately causes an infarction
Which OxLDL derived metabolite is toxic?
7-keto-cholesterol
Which transcription factor regulates inflammation and is activated by numerous inflammatory stimuli?
Nuclear kappa B
Which receptors are expressed by nuclear kappa B?
Scavenger receptors
Toll-like receptors
Cytokine receptors (IL-1)
Nuclear kapp B activates the gene expression of what in macrophages?
MMPs, Inducible nitric oxide synthase and interleukin - implicated in inflammation
What are the risk factors of athersclerosis?
Smoking Hypertension Diabetes Hyperlipidemia Localised disturbed flow
