18 Flashcards
main underlying cause of cardiovacular disease
atherosclerosis
what is atherosclerosis
disease in which laques build up in the walls of the arteries
what dictates the progression of atheroschlerosis
enviroment, diet, and genetics
disease of aging
atheroschlerosis
it is multifactorial:
-lipid disorder
-inflammatory disorder
-hypotensive disorder
what happens in atheroschlerosis
excess deposition of lipids (TGs and cholesterol) into macrophages within arterial walls
sites of lipid deposition can calcify leading to harderining of the blockage
-the calcified cap can break away and lead to total blockage of smaller vessels
how do plaques form step by step
-monocyte attracted to oxidized lipoproteins that aggregate and stick to extracellular matrix
-monocyte differentiates into macrophage
-foam cell (macrophage) ingests lipoprotein
-free cholesterol accumulates in membranes and droplets
-cholesterol rich plaques form
multifactorial CVD features
very high LDL cholesterol correlates with atherosclerosis
-some with normal cholesterol have heart attacks and some with high do not
-low HDL cholesterol negatively associated with heart disease
pathogenic forms of LDL
sdLDL
oxLDL
sdLDL
formed due to excess hydrolysis of LDL triglycerides. occurs when LDL levels are high
cannot bind to LDL receptor, cannot be readily moved from circulation, susceptible to chemical modifications such as oxidation
oxLDL
LDL protein and lipid can be oxidized
dietary antioxidants (vit A, C, E) can prevent oxidation of LDL
LDL particle size and CVD
LDL particle size is important is atherosclerosis
small dense LLD are more atherogenic
oxidized LDL is more atherogenic
omega 3 FA reduce amount of sdLDL
canadian recomendation for blood lipid levels
routine screening in men over 40 and women over 50
and earlier if have risk facotrs such as smoking, high BP, family history of early CVD, abdominal obesity, chronic inflamatory conditions
High LDL
leads to excess lipid deposiiton and promotes atherosclerosis
low LDL
reduce lipid depositoin and reduce progression of atherosclerosis
high HDL
excess RCT and reduce progression of atherosclerosis
low HDL
less RCT thus excess deposited lipids from LDL are not removd
strategies to lower LDL and prevent atherosclerosis
formation of mevalonate from acetyl coA
statins which inhibit HMG CoA reductase to lower cholesterol snthesis
bile acid binding resins
drugs to lower LDL
a common target of choleserol lowering drugs
HMG CoA reductase which is the rate limiting step in cholesterol synth
resemble mevalonate
statins
this resemblance leads to competitive inhibitors of HMG CoA reductase
first statin found
lovastatin found in fungi
lowers serum cholesterol
statins benifits
improve circulation, stabilize plaques by removed cholesterol rom them and reduce vascular inflamation
bile acid/ salt binding resins, what do they do
lower LDL by removing cholesterol from the liver in the form of bil eacids and salts to prevent the cholesterol from being packaged into VLDL
increasing the rate of RCT
examples of bile acid/ salt binding resins
cholestyramine and colestipol
what drugs lower LDL
fibrates and LDL receptor degradation inhibitors
fibrates
lower LDL by reducing liver triglyceride synthesis anad increasing fat oxidation (reduce VLDL)
examples of fibrates
fenofibrate, gemfibrozil
LDL receptor degradation inhibitors
injectable treatment of antibodies that inhibit LDL recptor degradation via PCSK9
example of LDL receptor degradation inhibitors
alirocumab
avolocumab
medications that lower LDL effectivenes
not more than 60% of the general population
increase activity of CETP
increases LDL levels
CETP inhibitor
torcetrapib was desgined to raise levels of HDL
but lots unexpetedly died bc it raise blood pressure in some and inc mortality after 2 yrs in 15k ppl
dugs that raise HDL
to date, all drgus tested that riase HDL have provided no benifit or inc of detrimental outcomes
-raise BP/ hypertension
-inc death from cardiovascular disease
HDL functionality
how efficicently HDL can remove cholesterol from extra hepatic tissues
some pop have high HLD but not effetcive and some that teh oposite
lowering dietary cholesterol intake and CVD
minor impact on blood cholesterol for most
diet and CVD
inc HDL activity for scavenging cholesterol (omega 3 FA and cholesterol efflux)
-down regulatino of cholesterol synthesis (polyunsaturated FA)
-polyunsaturated FA inhbit CETP activity and raise HDL
-fibre inc bile acid and cholesterol excretion
