Atherosclerosis Flashcards
Where does atherosclerosis come from?
Greek- athero= paste
sclerosis= hardness
Coat thickens so much as to close up and stop blood movement
Why can atherosclerosis result in?
Heart attack, stroke and gangrene
Initially thought of and what is it now known as?
Initially- lipid storage disease
now- chronic inflammatory disease influenced by many factors= inflammatory cells and cytokines
Main problem with atherosclerosis
If the plaque ruptures- thrombosis formation and death
Pathogenesis
Lifestyle choices, medical conditions and haemodynamic of blood flow
begin at birth but develops over lifetime
often remains symptomless for majority of life until advanced
Risk factors
Modifiable- physical inactivity, stress, obesity, diabetes, dyslipidaemia, hypertension, smoking
Non- modifiable- genetics, gender, age, inflammation, family history
Distribution of atherosclerotic plaque
Found within the peripheral and coronary arteries
focal distribution along the artery length
-may be governed by haemodynamics= changes in tuburlance/flow
- alter gene expression
- areas prone to atherosclerosis
Atherosclerosis is composed of what
Complex lesion consisting of: lipids necrotic core connective tissue fibrous cap- made from SMC and ECM
What happens if the plaque occludes
restrict blood flow- angina
or it may rupture- thrombus formation/ death
Response to injury hypothesis of atherosclerosis
First suggested in 1856- Rudolph Virchow and updated by Russell ross in 1993/9
indicated by an injury in the endothelial cells which leads to endothelial dysfunction
What does healthy endothelium produce to protect against atheroma?
NO and other mediators which protect
alter NO biosynthesis- affects BP control, regional blood flow, predisposes to atherosclerosis
send signals to inflammatory cells which accumulate and migrate into the vessel, leading to inflammation
Stimulus adhesion
Chemoattractants
chemicals that attract leukocytes are released from the site of injure and a concentration gradient is produced
damaged EC also express adhesion molecules
the adhesion cascade
Capture rolling slow rolling firm adhesion transmigration - following down vessel wall and migrate through by chemoattractant
LDL passing though and out of the arterial wall- When?
when in excess, accumulate in the arterial wall- deliver cholesterol
What generate free radicals
Macrophages and EC
LDL is oxidised by and what happens?
free radicals (oxLDL)- engulfed by macrophages to form foam cells release more proinflammatory cytokines
Cytokines found in plaques
IL-1,6,8,IFN-g, TGF-b, MCP-1 and PDGF
Progression of atherosclerosis 1- fatty streaks, what happens?
- earliest lesion of atherosclerosis
- appear at very early age
- accumulation of lipid laden macrophages (foam cells) and T lymphocytes within the intimal layer of the vessel wall form fatty streaks
- damage endothelium- allow macrophages in
progression of atherosclerosis 2- intermediate lesions?
layers composed of:
- foam cells
- VSMC
- EC lipids and cholesterol
- T lymophocytes
- adhesion and aggregation of platelets to vessel wall
progression of atherosclerosis 3- protective mechanism
reverse cholesterol transplant
- pathway for plaque reduction involving HDL
- HDL contain apo-A1 interact with foam and collect cholesterol
- mature HL travels to liver and releases cholesterol
- HDL then recirculates back
progression of atherosclerosis 4- fibrous plaque or advanced lesion
- thought to need an added impetus= another risk factor or area of disturbed flow
- cytokine release cells cause SMC proliferation and deposition of connective tissue
- leads to dense fibrous cap
What is fibrous cap composed of?
ecm- collagen (strength) and elastin (flexibility)
Lipid core
Necrotic and apoptotic debris, smc, foam cells, macrophages, t lymphocytes
Cap and core=
Artheromatous plaque
What does the Artheromatous plaque do?
may be calcified
impedes blood flow
prone to rupture
bigger the plaque= more narrowing and pain
Cyles of vascular inflammation and LDL results in formation of necrotic cap
- LDL enters vessel wall
- macrophage engulf and LDL become foam cells
- LDL lysed, cholesterol released crystalizes
- crystals in the foam cells induce apoptosis
- extracellular lipid pool within the arterial wall
- further attraction of macrophages
Human coronary atherosclerotic plaque looks like
Yellow core
lipids separated from lumen by fibrous cap
opposite plaque is an arc of normal vessel wall
Progression of atherosclerotic plaque 5- plaque rupture
Plaque constantly growing and receding
fibrous cap- resorbed and redoposited in order to be maintained
increase VMSC and matrix proteins to stabalise
What does a large number of macrophages predispose the plaque to?
Rupture
increase matrix metalloproteinases and gelatinase- cap becomes weak and rupture provides a substrate for thrombus formation and vessel occlusion
Rupture can be induced by
Cholesterol crystallization
Large necrotic plaque can rupture with
Haemorrhage
plaque lap is tonr and leads to rupture
Small necrotic plaque rupture
Erosion - wearing away
plaque disruption
The torn cap projects into the lumen of the artery and thrombus is contained with the plaque core
Plaque rupture- why it happens?
thin fibrous cap collagen poor fibrous cap large lipid cap many macrophages fibrin rich thrombus
How does erosion happen?
prosteoglycan glycosaminoglycan rich little or no lipid core neutrophils and NETS many smooth muscle cells platelet rich thrombus
Mechanism of erosion
- resting endothelial cell
- activated endothelial cell
- sloughed endothelial cells
- resting platelet and grammalogue
- activated platelet and granulocyte
- rich platelet thrombosis
* disturbed flow
Lipoproteins
Lipids are transported around the body as these
General structure of lipoproteins
central core is hydrophobic lipid (triglyceride cholesterol) surrounded by hydrophilic (free cholesterol, phospholipids, apolipoproteins)
Lipids classification
According to density
- chylomicrons= ApoB-48, diameter 100-1000nm
- LDL- ApoB-100, diameter 20-30nm
- Very low density lipoproteins- ApoB-100 diameter 30-80nm
- HDL- APOA1/A2, diameter 7-20nm
Lipids transport by 3 pathways
- Exogenous- gut to liver, dietary
- endogenous- liver to cells
- reverse- cells to liver
Exogenous pathway
- Lipids are digested
- lipids assemble with apoplipoproteins B-48 into nascent chylomicrons
- chylomicrons move into liver and bloodstream, HDL donate apopliporteins C-11 and E- mature chylomion. AC-11 can only bind adipose and ApoE cannor bind hepatocytes
- LDL catalyses hydrolysis reaction releasing glycerol and fatty acid from chylomicrons- absorbed into tissue
- remnants are endocytosed and hydrolysed within lysosomes and this releases glycerol and fatty acid in the cell
Endogenous pathway
- triclylglycerol and cholesterol are assembled with apolipoprotein
- HDL donates apolipoprotein C-II and E
- Apolipoprotein C-II activates LDL, causing hydrolysis of VDL particles and the release of glycerol and fatty acids- these can be absorbed by adipose tissue and muscle
- the hydrolysed VLDL particles are now called IDL
IDL
Contain multiple AoE binding LDLR with high affinity
LDL binds
Tissue via ApoC endocytosed, hydrolysed with lysosome release cholesterol
or
LDLR on liver via ApoB 100 removed from circulation
What is the lipoprotein reverse cholesterol pathway?
removes cholesterol from peripheral tissues and returns to liver
Mechanism of Reverse cholesterol
ApoA1 of HDL bind to transport protein ABC-A1 or ABC-G1 in macrophages/ foam cells and absorb cholesterol
- HDL then transports cholesterol via liver
What are the 2 pathways HDL transports cholesterol back to the liver?
- indirect pathway- cholesterol esters transfer to VLDL and LDL particles via cholesterol ester transport protein (CETP), LDL bines to LDLR on liver
- Direct pathway- APOA1 of HDL bind SRB1 receptor on liver. Cholesterol transfer to liver . HDL recirculates
* Cholesterol in liver processed and secreted in bile or transported to intestine via ABC-G5/G8 for excretion
Dyslipidaemia
Imbalance of lipid transport- atherosclerosis
an abnormal amount of lipids in the blood
Hyperlipidaemia
Elevation of lipids in the blood
Primary cause of hyperlipidaemia
due to combination of diet and genetic, usually polygenic (involve multiple genes). can be monogenic (one gene)
Secondary causes of hyperlipidaemia
consequence of other conditions
diabetes, alcoholism, renal failure, liver disease and drugs
secondary forms are treated where possible by correcting underlying cause
How is primary dyslipidaemia classified
According to lipoprotein uptake
Six phenotype
the higher the LDL and lower then HDL the higher the risk of
Type IIa
Familial hypercholesterolaemia
- LDL receptor deficiency
- increased LDL lipoprotein
- high risk of atherosclerosis
- 1:500 (heterozygous)
Treatment for IIa
bile acid resins
statins
niacin
Familial hypercholesterolaemia
genetic disorder causing very high LDL levels in the blood and early cardiovascular disease
mutations are rare but exist
FH mutations in
- LDLR gene (encodes the LDL receptor protein, which removed LDL from the circulation)
- Apdiopoprotein B (ApoB) which is part of LDL that binds with the receptor
Heterozygous and homozygous FH
Hetero- LDLR gene defect may have been premature CVD at the age of 30-40, 1:500
homozygous- LDLR gene defect may cause severe CVD in childhood, rarer 1 in a million
How are heterozygous and homozygous treated?
Hetero- statins, bile acid or lipid lowering agents that lower cholesterol levels
homo- does not respond to medical therapy and may require other treatments, including LDL apheresis or liver transplant
Treating dyslipidaemia or atherosclerosis
- statins
- fibrates
- inhibitors of cholesterol absorption
- PCSK9 inhibitor
What are statins?
- HMG-CoA reductase= rate limiting enzyme in cholesterol synthesis
- regulate cholesterol levels by targeting HMG-CoA
- specific reversible competitive inhibitor
Short acting statins
- given orally at night to reduce cholesterol early morning
- deferentially absorbed and extracted by liver
- subject to extensive presystemic metabolism via cytochrome P450 and glucuronidation pathway
Mechanism of statins
cholesterol synthesis in liver causes LDL receptor synthesis
LDLR causes LDL clearance from plasma to liver
statins reduce plasma LDL and increase HDL
Pleiotropic effects
products of the melovonate pathway are involved in lipidation ie react with protein to add a hydrophobic group
- fatty group anchors to localise the protein in organelles
- important membrane bound enzyme are modified by that way by inhibiting melavonate pathway- statins also affect lipidation
What can the pleiotropic effect cause?
- improved endothelial function
- reduced vascular inflammation
- reduced platelet aggregability
- increased revascularisation in ishaemic tissue
- increase circulating endothelial progenitor cells
- stabilisation of atherosclerotic plaque
- antithrombic plaque
- enhanced fibrinolysis
- inhibition of germ cell migration
- immune suppression
- protection against sepsis
What is the primary prevention of atherosclerosis?
arterial disease in “at risk” patients elevated serum cholesterol conc +/- for atherosclerosis
What is secondary prevention of atherosclerosis
MI or stroke inpatients with symptomatic disease (have had angina, MI or stroke)
What does atorvastatin do?
lowers serum cholesterol in patients with homozygous familial hypercholesterolaemia
What is heterozygous FH
serve drug resistant dyslipidaemia statin treatment is combined with other drugs
What can statins not be used?
During pregnancy
HMG-CoA reductase guides migrating primordial germ cells
What are the adverse effects of statins?
Muscle pain GI disturbance rash raised conc of liver enzymes in plasma insomnia skeletal muscle damage- rare dose related, more common in patients with low lean body mass or uncorrected hypothyroidism
Controversy around statins
A lower treatment threshold is proposed by NICE so that millions more people are at a lower risk of heart attack or stroke
Low risk patients- 99.3 % of patients see no benefit
Effectiveness in high risk patients
side effects are neligable compared to the benefits in cutting the risk of having a heart disease
statins increase the risk of developing diabetes by 1% in women
Why might not all data about statins side effects/ effectiveness be available?
Industry funded studies
not all data made available by researchers
industry/ non industry often show different results
Interaction of statins with other medication or lifestyle
statin users consume more, exercise less, increase weight
Names of fibrates
benzofibrate cipofibrate gemfabrazil fenofibrate clofibrate
Names of statins
Simvastatin Atorvastatin fluxastatin pravastatin rosuvastatin pituvastatin
What do fibrates do?
active PPAR especially PPARa
What is PPAR
peroxisome proliferator activated receptor
intracellular receptors that modulate carbohydrate and fat metabolism and adipose tissue differentiation
What does activating PPAR do?
induces the transcription of a number of genes that facilitate lipid metabolism
Fibrates metabolised by
Cytochrome P450 3A4
cyp3A4
enzyme, mainly found in the liver and intestine. oxidised small foreign organic molecules such as toxin or drugs so that they can be removed from the body
Effects of fibrates
decrease circulation VLDL
decrease triglyceride levels
* modest (10%) decrease in LDL and increase in HDL
Clinical use of fibrates
Rarely used
only when statins and ezetamide are not tolerated
can be combined with other lipid lowering drugs in patients with severe treatment resistant dyslipidaemia
Adverse effects of fibrates
- Mild stomach upset and myopathy (muscle pain)
- clofibrate increase risk for gallstones
- combination of statin and fibrate increases risk of muscle damage
- should not be taken by patients with advanced kidney disease
- fibrates should not be taken by alcoholics
What is Ezetimibe
Inhibitor of cholesterol absorption
one of a group of azetmide cholesterol absorption inhibitors
Action of ezetimibe?
Block intestinal absorption of cholesterol by blocking a transport protein (NPCIL1) in the brush border of enterocytes
Does not affect absorption of fat soluble vitamins, triglycerides or bile acids
Facts about ezetimibe?
- Does not affect absorption of fat soluble vitamins, triglycerides or bile acids
- has high potency= 10mg/reduced LDL cholesterol by 17-19%
- combination of statin = 25% reduction
Pharmacology of ezetimibe
administered by mouth
absorbed into intestinal epithelial cells and localises to the brush border
extensively metabolised to active metabolite (80%)
enterohepatic recycling results in slow elimination- half life approx. 22hrs
Advantages and disadvantages of ezetimibe
Advantages
- low potential to interact with other medications
- convenience of taking single tablet 10mg a day
Disadvantages
- expensive
Who is ezetimibe given to
Patients with side effects from high dose statins
supplementary to statins
Side effects of ezetimibe
Mild diarrhoea abdominal pain headache rash angioedema
What are resins
inhibitor of cholesterol absorption
1st cholesterol lowering drug to be used clinically
Names of resins
colestryamine, colestipol, colesvelan
How are they taken and pharmacology
Oral
- remain in intestinal tract and bind bile acid= preventing their absorption into their blood stream
- liver compensates by increasing metabolism of endogenous cholesterol into bile acids= increases expression of LDL receptors and clearance of LDL from blood= decrease LDL plasma conc
Side effects resin
bloating
diarrhoea
nasusea
constipation
What do resins interfere with the absorption of ?
Fat soluable vitamins digoxin diuretics warfarin thyroid hormones bb and ca blockers
How are resins taken
Oral
taken 1 hour after or 4-5 hours before food
rarely used
Plant sterols/stanols
Isolated from wood pulp
stanol ester- hydrolysed into stanols and fatty acids
how do sterols/stanols work
incorporated into mixed micelles replacing cholesterol
or
activate transporter proteins with enterocytes= increase movement from enterocytes back into the intestinal lumen and excreted
What is the result of using sterols
reduce cholesterol (40-45%) absorption into blood stream reduced serum total and ldl conc lower
Optimal efficacy
plant stanols taken with meal
retain efficacy long term
With and without plant stenol
without- 50% absorbed
with- 20% absorbed
PSCK9 inhibitor
evolucumob
raopatha- human monoclonal antibody (IgG2) to proprotein convertase subtilism/ kexin type 9
* negative regulator of LDLR
Mechanism for PSCK9 action
binds LDLR
complex internalises receptor undergoes lysosomal degradation
LDL continues to circulate
Evolocumab mechanism of action
binds PSCK9 preventing from binding to LDLR- prevents PSCK9 mediated LDLR degradation
What happens when LDL binds LDLR
internalises LDL releases
LDLR recycles back to the liver surface
increase the number of LDLR available to clear LDL from the blood, lowering LDL
Pharmacology of Rapatha
injection
140mg/2 weeks
adjunct to diet and statin for adult with HeFH or clinical CVD
Adverse effects of rapatha
back pain
reactions
nasopharyngitis
