Lectures 16 and 17 Atherosclerosis Flashcards
When is inflammation good?
fighting against pathogens, parasites, tumours
wound healing
When is inflammation bad?
myocardial reperfusion injury atherosclerosis IHD rheumatoid arthritis asthma inflammatory bowel disease shock excessive wound healing restenosis
What is modern day clinical problem with inflammation?
availability of antibiotics and advance trauma surgical techniques make the magnitude of inflammatory response a bigger treat than infection or injury
Define Atherosclerosis
chronic inflammatory disease influenced by many factors involving a vast array of inflammatory cells and cytokines
describe the pathogenesis of atherosclerosis
influenced by lifestyle and medical choices
influenced by the haemodynamics of the blood
can begin before birth and take years or decades to develop
symptoms often indicate advanced state of disease
beings with initial insult to artery wall
What are the non-modifiable risk factors of atherosclerosis?
age gender - male genetics inflammation family history of CV disease
What are the modifiable risk factors of atherosclerosis?
dyslipidaemia diabetes hypertension obesity smoking/alcohol stress physical activity
Where are atherosclerotic plaques most likely to form?
peripheral and coronary arteries - at bifurcations
distribution impacted by haemodynamic factors
What is the mechanism that initiates atherosclerosis?
endothelial dysfunction
altered NO biosynthesis
accumulation of inflammatory cells
Give examples of atherosclerotic stimuli
How do they lead to atherosclerosis?
adhesion - chemoattractants - transmigration of leukocytes oxidised LDL (oxLDL) - engulfment by macrophages forming foam cells which release more pro-inflammatory cytokines
What cytokines are found in atherosclerotic plaques?
IL-1, IL-6, IL-8 IFN-gamma TGF-beta MCP-1 PDGF
What is the process of atherosclerosis progression?
stage 1 - endothelial dysfunction, accumulation of lipid-laden macrophages with migrate into the vessel all (chemotaxis) and form foam cells (LDL engulfed) forming fatty streaks in the intimal layer - appear from 10 years old
stage 2 - intermediate lesions - foam cells and T-lymphocytes. VSMC migration into intima. platelet adhesion and aggregation to vessel wall. lipid transport in balance - LDL delivery and HDL removing cholesterol
stage 3 - added impetus needed - fibrous cap (collagen and elastin) with lipid core containing necrotic and apoptotic debris, SMCs, foam cells and macrophages
stage 4 - thinning of the cap, MMPs, weakening cap prone to rupture. may impeded blood flow.
What is the function of the reverse cholesterol transport pathway?
How does the reverse cholesterol transport work?
removes cholesterol from peripheral tissues and returns it to the liver
HDL contains apo-A1 particles that interact with ABC-A1 or ABC-G1 transport proteins in foam cells (macrophages) to adsorb cholesterol
mature HDL travels to liver to release cholesterol which is processes for excretion - indirectly or directly
HDL continues to recirculate
What is the difference between a ruptured and eroded plaque?
ruptured - thin fibrous cap, collagen-poor fibrous cap, large lipid core, many macrophages and fibrin-rich thrombus
eroded - proteoglycan and glycosaminoglycan rich, little-or-no lipid core, neutrophils and NETs, many smooth muscle cells and platelet-rich thrombus
What is the structure of lipoproteins?
central core of hydrophobic lipid - triglycerides and cholesterol
surrounded by hydrophilic coat - phospholipids, free cholesterol and apolipoproteins
What are the different classifications of lipoproteins?
What are the diameters of each lipoprotein class?
chylomicros - 100-1000nm
very-low density lipoprotein (VLDL) - 30-100nm
low density lipoprotein (LDL) - 20-30nm
high density lipoprotein (HDL) - 7-20nm
What apolipoproteins do each class of lipoproteins contain?
chylomicros - apoB-48
VLDL - apoB-100
LDL - apoB100
HDL - apoA1 and apoA2
What are the three lipoprotein transport pathways?
exogenous (dietary)
endogenous
reverse cholesterol
Describe the exogenous lipoprotein pathway
lipids are digested
chylomicrons assembled with apoB-48 and move into the liver then subsequently into the bloodstream
HDL donates apoC-II and apoE to form mature chylomicrons which activate lipoprotein lipase (LPL)
LPL catalyses a hydrolysis reaction releasing glycerol and fatty acids which can be absorbed by the tissue
remnants endocytosed and hydrolysed by lysosomes
chylomicron remnants taken up into the liver - cholesterol is stored and secreted into bile which can be oxidised into bile acids or converted into VLDL
What is the function of ApoC?
only bind to receptors found on adipose tissue
What is the function of ApoE?
only bind to receptors on hepatocytes
What is the endogenous lipoprotein pathway?
in liver - triglycerides and glycerol assembled with apoB-100 to form VLDL
HDL donates apoC-II and apo-E
apoC-II activates LPL causing hydrolysis of VLDL releasing glycerol and fatty acids which can be absorbed by adipose tissue and muscle
hydrolysed VLDL now called IDLs can be taken up into the liver, hydrolyses by hepatic lipase into LDL, or remain in circulation
IDLs return to the liver and are hydrolysed by hepatic lipase releasing glycerol and triglycerides leaving behind LDL
What is the indirect HDL cholesterol transport pathway?
cholesterol esters transfer to VLDL and LDL particles via cholesterol ester transport protein (CETP)
LDL binds to LDLR on the liver
What is the direct HDL cholesterol transport pathway?
Apo-A1 of HDL binds SRB1 receptor on liver
cholesterol transferred to liver
HDL recirculates
Define Dyslipidaemia
abnormal amount of lipid in the blood
What is primary dyslipidaemia?
cause - combination of diet and genetics
usually polygenic but can be monogenic
What is secondary dyslipidaemia?
consequence of other conditions - diabetes, alcoholism, chronic renal failure, liver disease and administration of drugs
Give examples of drugs that cause secondary hyperlipidaemia
isotretinoin - treatment of severe acne
tamoxifen
ciclosporine
protease inhibitors - HIV treatment
What are the dyslipidaemias Frederickson classifications?
Ia - familial hyperchylomicronemia Ib - familial apoprotein CII deficiency Ic IIa - familial hypercholesterolaemia IIb - familial combined hyperlipidaemia III - familial dysbetalipoproteinaemia IV - familial hypertriglyceridaemia V
Which dyslipidaemias raise the risk of atherosclerosis?
moderate risk - III and IV
high risk - IIa and IIb
What is the increased lipoprotein in different dyslipidaemias?
How are they treated?
Ia, Ib and Ic - chylomicrons - diet control
IIa - LDL - bile acid, resins, statins and niacin
IIb - LDL and VLDL - statins, niacin and fibrate
III - IDL - fibrate and statins
IV - VLDL - fibres, niacin and statins
V - VLDL and chylomicrons - niacin and fibres
What mutations cause FH?
LDLR gene mutation - encodes LDL receptor protein that removes LDL from circulation
apo-B mutation - part of LDL that binds with the receptor
How does a LDLR gene defect affect CVD?
heterozygous - premature CVD age 30-40
homozygous - severe CVD in childhood
What are the treatments for homozygous FH?
often don’t respond to medical therapy
alternative treatments - LDL aphaeresis (similar to dialysis) or liver transplant
What are the main dyslipidaemia/atherosclerosis treatments?
statins - HMG-CoA reductase inhibitors
fibrates
inhibitors of cholesterol absorption
PCSK9 inhibitor
Give examples of statins
HMG-CoA reductase inhibitors
simvastatin, lovastatin, pravastatin - specific and reversible
atorvastatin, rosuvastain - long-lasting inhibitors
What are the pharmacokinetics of statins?
short-acting given overnight to reduce peak cholesterol synthesis in the morning
efficiently absorbed and extracted by the liver
pre-systemic metabolism by cytochrome P450 and glucuronidation pathways
How do statins work?
decreases cholesterol synthesis and increased LDL receptor synthesis in liver
increased LDLR causes increased LDL clearance from plasma into liver
also reduce plasma triglycerides and increase HDL
How do statins affect lipidation?
statins inhibit the mevalonate pathway and as a result reduce lipidation
What effect does reducing lipidation have?
improved endothelial function
reduced vascular inflammation
reduced platelet aggregabaillity
increased neovascularisation of ischaemic tissue
increased circulating endothelial progenitor cells
stabilisation of atherosclerotic plaque
antithrombotic actions
enhanced fibrinolysis
inhibition of germ cell migration during development
immune suppression
protection against sepsis
Why is statin use not recommended during pregnancy?
HMG-CoA reductase is important for migrating primordial germ cells
What are the adverse effects of statins?
muscle pain (myalgia) GI disturbance increased [liver enzyme] in plasma insomnia rash angio-oedema (rare) skeletal muscle damage - rare and more common in patients with low lean body mass or uncorrected hypothyroidism - myositis and rhabdomyolysis (severe)
What is the problem with statins?
99.3% of statin-treated patients see no benefit - does it make the side effects worth it for low-risk patients?
can slightly increase risk of developing diabetes - more common in women
What may future researchers like to study about the effect of statins?
the interaction of lifestyle and medication
statin users tend to consume more calories, gain weight and exercise less
Give examples of fibrates (fabric acid derivatives)
bezafibrate ciprofibrate gemfibrozil fenofibrate clofibrate
What is the pharmacology of fibrates?
activate of PPAR(-alpha) - induces transcription of genes that facilitate lipid metabolism (LDL, apoA-I, apoA-II)
fibrates are metabolised by cytochrome P450 (CYP3A4)
What are PPARs?
peroxisome proliferator-activated receptors
which are IC receptor modulating carbohydrate and fat metabolism, and adipose tissue differentiation
What is the effect of fibrates overall?
markedly decrease circulating VLDL and so decrease triglyceride levels
10% reduction in LDL
10% reduction in HDL
When are fibrates prescribed?
only when statins or ezetimibe are not tolerated
combined with other treatments in severe cases
What are the adverse effects and disadvantages of fibrates?
mild stomach upset
myopathy
clofibrate - only give to patients with removed gall bladder
combination with statin increases risk of muscle damage leading to kidney failure
fibrates shouldn’t be given to patients with advanced kidney disease
fibrates shouldn’t be given to alcoholics
Give examples of inhibitors of cholesterol absorption
ezetimibe (zetia)
resins
plant sterols/stanols
What is the action of ezetimibe?
blocks intestinal absorption of cholesterol by blocking transport protein NPC1L1 in the brush border of enterocytes
What is the effect of ezetimibe?
does not effect fat-soluble vitamins, triglycerides or bile acids
high potency
reduces LDL cholesterol by 17-19%
What is INEGY?
What is the effect of this treatment?
combination drug therapy
single tablet containing simvastatin (statin) and ezetimibe
decrease LDL levels by 25%
What are the advantages of INEGY?
What are the disadvantages of INEGY?
adv.
low potential to interact with other medications
convenience single table once a day
disadv.
expensive
Who are prescribed INEGY?
high dose statin patients with side effects
severe dyslipidaemia cases
shouldn’t be given to women who are breastfeeding
What are the side effects of INEGY?
mild diarrhoae abdominal pain headache rash angio-oedema
Give examples of resins
colestyramine, colestipol, colesevelam
How do resins work?
What are the results?
taken orally
remain in intestinal tract and bind bile acids preventing their absorption into the blood stream
liver compensates by increasing metabolism of endogenous cholesterol into bile acids
increased expression of LDL receptor
increased clearance LDL from blood
decrease concentration of LDL in plasma
What are the side effects of resins?
bloating constipation diarrhoea nausea interfere with absorption of fat-soluble vitamins, digoxin, warfarin, thyroid hormones, beta blockers and calcium channel blockers rarely used due to intolerance
Give an example of a PCSK9 inhibitor
evolocumab (repatha)
human monoclonal antibody (IgG2) for PCSK9
What is PCSK9?
pro protein converts subtilising/kexin type 9
negative regulator of LDLR leading to continued/increased LDL circulation
What is the mechanism of action of evolocumab?
binds to PSCK9
prevents PCSK9 binding to LDLR
prevents PSCK9-mediated LDLR degradation
allows increased binding LDL to LDLR lowering circulating LDL levels
When is evolocumab prescribed?
adjunction to diet and maximally tolerated statin therapy patients with HeFH patients or clinical CVD
adjunction to diet and LDL-lowering therapies for HoFH patients
What are the adverse effects of evolocumba (repatha)?
nasopharyngitis
upper respiratory tract infection
influenza
back pain
injection site reactions - erythema, pain, bruising
hypersensitivity reactions - rash, eczema, erythema, urticaria - indicates to discontinue treatment
