Atherosclerosis Flashcards
What vessels does atherosclerosis most commonly occur in?
Large arteries, not veins
Where especially can atherosclerosis occur in arteries?
At bifurcations where there is turbulent flow
What type of a disease is atherosclerosis?
A type of chronic inflammation which shows many features of wound repair
Where do atheromas form?
Within the intima layer of arteries
What is the first stage of atherosclerosis?
Accumulation of LDL and the inflammation of the arterial wall is the first stage of atherosclerosis.
How does atherogenesis first arise?
Qualitative changes in the inner arterial surface.
What are the changes to the endothelium which promote atherogenesis?
Endothelial cells of the inner layer normally oppose white blood cell attachment, but as they dysfunction, endothelial cells express adhesion molecules.
Permeability increases
What happens after WBC adhere to the intima?
WBC migration into the intima.
5. Inside the intima, monocytes mature and transform into macrophages that uptake the LDL particles to yield foam cells.
What changes facilitate LDL to migrate into the intima?
Both the composition of the extracellular matrix beneath the endothelium and the changes in endothelial permeability
How does cholesterol enter the intima?
Carried by LDL
What changes happen inside the newly invaded intima?
Monocytes mature and transform into macrophages that uptake the LDL particles to yield foam cells.
What are foam cells?
Macrophages which have uptaken LDL
What changes are there to SMC in the growing atheroma?
Smooth muscle cells are transferred from the middle layer of the arterial wall into the tunica intima. Proliferate
What happens eventually to make SMC and macrophages?
The smooth muscle cells and macrophages die in advanced lesions by apoptosis.
What makes up the necrotic core of the atheroma?
Dead SMCs and macrophages
How can an advanced plaque develop?
Development of intra-plaque microvessels from the adventitia
What causes the pathology associated with plaques?
Plaques generally cause stenosis and limit blood flow, which can lead to tissue ischemia.
Fibrous cap of a plaque can rupture,
What happens when the fibrous cap of a plaque ruptures?
Blood coagulation components come into contact with the thrombogenic plaque and produce thrombi.
What is the role of endothelial cells?
Provide a smooth, anti-thrombogenic surface for blood flow
What vasodilators does the endothelium secrete?
Nitric oxide (EDRF), Prostaglandin I2 (PGI2) aka prostacyclin
What vasoconstrictors does the endothelium secrete?
Endothelin, Angiotensin II
What antithrombotic factors does the endothelium secrete?
Tissue plasminogen activator (tPA), Prostaglandin I2 (PGI2)
What prothrombotic factors does the endothelium secrete?
Thombonxane A2, plasminogen activator inhibitor
What is the role of smooth muscle cells in the artery?
Provide muscular arteries with their elasticity
Mediate vasodilation and vasoconstriction
Play a key role in regulating blood pressure
What induces SMC apoptosis in vulnerable plaques?
Macrophage-induced SMC apoptosis seen in vulnerable plaques
What do SMC secrete in stable plaques?
Secrete elastin and collagens in stable plaques
What secretes important SMC growth factors?
Platelets (e.g PDGF)
What vasoactive mediators do SMC secrete?
5-HT, TxA2
Platelet lifespan
8-10 days in the circulation
What marker is associated with foam cells?
CD68
What receptors promote LDL uptake by macrophages?
Scavenger receptors
What do macrophages secrete in atherosclerosis?
Inflammatory mediators (IL-1, TNF-a)
Growth factors (M-CSF, PDGF, FGF)
Why do macrophages have a role in plaque rupture?
Secrete MMPs important in breaking down the fibrous cap
What wider immune cells promote atherosclerosis
CD4 cells
How do DCs activate CD4 cells in atherosclerosis?
Dendritic cells enter plaques and are exposed to LDL/oxLDL and activates Tcells via presentation of ApoB.
Th1 role in atherogenesis
Interferon-g and has pathogenic effects, including less collagen fiber formation, higher expression of major histocompatibility complex class II, enhanced protease and chemokine secretion, upregulation of adhesion molecules, induction of proinflammatory cytokines, and enhanced activation of macrophages and endothelial cells.
Th2 role in atherogenesis
Involvement of TH2 cells are contradictory, with some showing pro-atherosclerotic effects and others showing protective effects.
What plasma components have a role in atherosclerosis?
Lipoproteins (LDL, modified LDL, HDL)
Coagulation cascade components
C- Reactive Protein (CRP)
Complement components
Oxidants / anti-oxidants
What are lipoproteins?
Complex particles that have a central hydrophobic core of non-polar lipids, primarily cholesteryl esters and triglycerides. This hydrophobic core is surrounded by a hydrophilic membrane consisting of phospholipids, free cholesterol, and apolipoproteins.
What are lipoproteins in order of density?
Chylomicrons Very low density lipoprotein (VLDL) Intermediate density lipoprotein (IDL) Low density lipoprotein (LDL) High density lipoprotein (HDL)
What lipoproteins are pro-atherogenic?
VLDL, IDL and LDL are pro-atherogenic. HDL is anti-atherogenic (reverse cholesterol transport and anti oxidant properties)
What lipoprotein is antiatherogenic
HDL
Why is HDL antiatherogenic?
Mediates reverse cholesterol transport
Important source of anti-oxidants
Why are free radicals bad for atherosclerosis?
oxLDL is more readily taken up by macrophages (forming foam cells)
Relative Risk
Relative risk is the ratio of the likelihood of CHD developing in persons with and without a given risk factor
Absolute Risk
Absolute risk is the probability of developing CHD in a finite period, (e.g. within the next 10 years)
Non-modifiable risk factors
A personal history of CHD
A family history of CHD
Advanced age
Gender
Modifiable risk factors
High plasma LDL Cholesterol (>5.2mmol/L)
Hypertension (>140/90mm Hg)
Physical inactivity / Obesity (BMI > 30)
Smoking
Diabetes
What is the cause of familial hypercholesterolaemia?
Mutations diminish the number of functional LDL receptors in the liver.
As a result, LDL is not endocytosed and converted to cholesterol, and remains high in the plasma.
What is an angioplasty?
Minimally invasive endovascular procedure used to widen narrowed or obstructed arteries or veins, typically to treat arterial atherosclerosis.
A deflated balloon attached to a catheter (a balloon catheter) is passed over a guide-wire into the narrowed vessel and then inflated to a fixed size.
The balloon forces expansion of the blood vessel and the surrounding muscular wall, allowing an improved blood flow.
A stent may be inserted at the time of ballooning to ensure the vessel remains open, and the balloon is then deflated and withdrawn
What is CABG?
Surgical procedure to restore normal blood flow to an obstructed coronary artery.
CABG is often indicated when coronary arteries have a 50 to 99 percent obstruction.
Surgery anastomoses conduit vessel which is harvested from the patient and grafted between the aorta and just below the lesion.
How do statins work?
Reduce cholesterol levels by inhibiting the hepatic enzyme 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase
Increase hepatic LDLR expression
Lower plasma LDL-C, lower plasma TGs, raised plasma HDL
How do anti PCSK9 antibodies work?
Alirocumab monoclonal antibody can be used to bind to PCSK9 before it can bind to LDL receptors and lead to their sequestering.
What is an anti PCSK9 antibody example?
Alirocumab
What does a PCSK9 gain of function mutation mean?
Individual gets atherosclerosis young
What does a PCSK9 loss of function mutation mean?
Resistance to atherosclerosis
