Athersclerosis Flashcards
Whats the main difference bewteen HDL and LDL
HDL has Apoprotein A1 and LDL has Apoprotein B
Describe fat digestions
Fat in GI tract form water soluble micelles, which are absorbed into the duodenal enterocytes. All TG is absorbed but only 50% of cholesterol. The neterocytes form CM which drin via lymphatics and the throacic duct. In the plamsa, lipoprtein lipase hydolyses the CM, relase FFA and the CM remnant, which is tajen up by the liver
Describe the path of VLDL
Made in the liver, purpuse is to transport TG from the liver to the rest of the body. Whilst in the plasma, lipoprotein lipase exhancges TG fro cholesterl esters (from HDL). so the large VLDL–>small VLDL–> IDL–>LDL. the small VLDL is the most atherogenic and can be taken up by macrophages to form foam cells.
Whta does HDL do?
Trasports cholsetrol (intact) from the peripheral tissues to the liver to be excreted. It can also give cholesterol to LDL derivaties via Cholesterol Ester Transfer Protein.
Desrcibe the formation of a complicated atherosclrotic plaque. What are the key stages?
1) Increased endothelail permeability 2) Upregulation of adehsion molecules 3) Leukocyte adhesion and migration into the tunica intima. 4) Formation of foam cells 5) Adherenece and aggreation of platelets 6) Actiavtion of T cells 7) Migration of smooth muscle cells. 8) Formation of necrotic core covered by a firbous cap.
The key stages are in the middle, when the influx of leukocytes and the foam cells formation stimulate a chain of reactions involving T cells, platelets and most importnantly smooth msucle cells.
What is a type 2,4 ,5 and 6 lsion?
Type 2: macrophage foam cells. Type 4: atheroma, core of extracellualr lipid. Type 5: firboatheroma, fibrous thickeing. Type 6: complicated lesion, with a fissure, haematoma and thrombus probable.
What can get trapped in the endothelial wall and cause atherosclerosis?
VLDL, Remants, IDL, LDL and HDL!!! Everything except CMs themselves. LDL does not cause the associated inflammation.
3 characteristics of vulberable plaques
Thin fiborus cap, large nectroi core and less evidence of SM proliferatio. Size is not predicitive.
Which risk factors modify LDL risk?
HDL level, smoking hypertension and diabetes.
Describe the control fo HDL
Tends to be LOW when TG is high. Also lowered by smoking, obesity and PI.
What are first line drugs for hypercholesterolinaemia?
Statins.
Problems with bile-acid sequestrants?
Adherence due to strange tatse and texture. SI include bloating, nausea and constipation.
What is nicotinic acid and why is it not used much?
A B-complex viatmin. Severe SI inclduing GI distress, hyperglycaemia, hyperuricaemia and liver toxicity.
What do fibrates lower mainly? How do they work?
TG- less effective on LDL. they are PPAR-a agonistswhich incraeses FA utake and B-xodiation. Other positive effects on foam cell formation, thrombosis, inflammation and vasocontriction.
How do statins work?
They inhbits HMG-CoA reductase which is the rate limting step in the cholesterol synthesis patwhay in hepatocytes. Body makes 2/3rds of required cholesterol. In repsonse, LDL recptors increase so there is a removal of LDL cholesterol and precursos from the blood. This alos results in a an increase in HDL. (Can be detriental in development- cholestrol pathwya needed for modifcation of proteins like rho and ras) .
How do you increase the selectivity of a statin?
Incraese water-solubility.
What is currently the most potentn statin on the market?
Pravastatin
What is the rule of 6?
Double the dose, onlya 6% reduction. Not worth teh SI.
Give examples of how statins also prtect against CV disease.
They inhibit Rac1, which inhibits ROS which inhibits SM hypetohy and endothelial dysfunction. They also inhibit RhoA which inhibits endothelial dysfunction and SM proliferation.
What does ezetimibe do?
Inhibits cholesterol absoprtion from the SI (ezetimbie is converted to a glucornide once absorbed)
What do CETPi cause? Why is torcetrapib (only) not used?
Incrased HDL (CETP trasnfer choelsterol from HLD to LDL) . Torcetrapib= 60% incraese in mortality. Perhaps due to incraesed aldsertone sysnthises, elading to increased BP.
What are PCSK9i?
Proprotein Convertase Subtilisin/Kexin Type 9 inhibtors (PCSK9 is an endogenous LDL receptor inhibitor)
