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L1: Pathogenesis and treatment of atherosclerosis
Definition and health impact of atherosclerosis
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Atherosclerosis is a disease of the ARTERIES - narrowing of lumen over time as a result of
plaque build up
Atherosclerosis in coronary arteries causes coronary heart disease (CHD)

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Mechanisms of atherogenesis: the role of leukocytes and lipids in atherosclerosis
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Happens over decades
Disfunction of endothelial cells causes an inflammatory process
Thrombotic event:
- Erosion of fibrous cap of plaque - its contents get spilled into blood stream
- allows contact of blood with thrombogenic lipid core
- Platelet aggregation and thrombus formation occludes coronary artery
- Can cause: sudden death, myocardial infarction or unstable angina
Endothelial dysfunction and lipid accumulation
- High conc
...

Functions
Structural components of cell membranes (cholesterol and
phospholipids)
- Precursor of steroid hormones and bile acids
- Major sources of energy (triglycerides and free fatty acids)
- They travel through our bodies as chylomicrons - packed with proteins and lipids
- Depending on balance of protein/lipids: LDL no protein, HDL high protein
Movement of fat:
- Exogenous: dietary fat enters chylomicrons and travels in capillaries where
lipoprotein lipases can break off individual fatty acids
- These can then move into the liver to the endogenous pathway
Statins
Discovered as a fermentation product, later synthesised synthetically
Mechanism of action
- Inhibit 3-hydroxy-3-methyl-glutaryl-CoA (HMG-CoA) reductase, a rate-limiting
enzyme in hepatic cholesterol biosynthesis, which leads to:
- up-regulation of LDL receptors in liver and increased removal of Apo
B–containing lipoproteins from the circulation
- reduction in the synthesis and secretion of lipoproteins from the liver
- Has anti inflammatory properties ( reason unknown)
- enhanced DNA repair and reduced senescence (aging) in vascular
smooth muscle cells ( reason unknown)
Reduce LDL by 25 to 50%
Reduce the incidence of vascular events and mortality by 25-40%
Key Clinical Trials with Statins
1
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MRC/BHF Heart Protection Study
- 20,000 patients with or at high risk of CHD
- Simvastatin (40 mg) or placebo for 5 years
- Highly significant reductions (~30%) in mortality, heart attacks and
strokes in treatment group
Side effects
Common side effects: n Headache, fatigue, GI intolerance, flu-like symptoms
Increase in liver enzymes (in 0
...
5% of cases) in dosedependent manner; serious liver
problems are rare
Myopathy (muscle pain/weakness accompanied by increased serum creatine kinase)
Occurs in 0
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4% of patients
- Rare cases of rhabdomyolysis (severe case of myopathy - can induce myoglobinuria
and renal failure)

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- Presence of muscle toxicity requires the discontinuation of the statin
Effect of statins on RhoGTPases
- Statins inhibit HMG-CoA which further down the line would have produced
geranylgeranyl - PP
- This prevents the geranyaltion of rho GTPases ( RhoA, Rac1, Cdc-42)
- One of the things that Rho GTPases do is drive inflammation
- Geranylation - addition of lipid to protein so that it can move through guanine
exchange factors in the lipid bilayer, which activate it
- Activation = inflammation later down the line
- Leukocytes
- RhoGTPases do a lot for a cell, so reducing them reduces their roles
- Reduced receptors of leukocytes, reduced motility and
directionality,reduced adhesion molecules

Treatment of atherosclerosis
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Statins lower LDL (immediate) = endothelial function restored = inflammation reduced =
ischemic episodes reduced = vulnerable plaques established = vascular events reduced (
over years)
Life style is changed first and drugs are only introduced after

CANTOS study – reducing inflammation without lipid lowering
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Focuses on iL1- beta antibodies - proinflammatory molecule that can lead to endothelial cell
activation
Inactive Pro iL1- beta antibodies are transformed to active iL1- beta antibodies by caspase 1
Signal 1 ; PAMPs and DAMPs enter cell through toll like receptor
Leads to activation of Nf- kB a proinflammatory transcription factor
These transcribe for the production of inactive NLRP3’s which can assemble into an
inflammasome
Signal 2: could be ATP, reactive oxygen or crystalline components
The inflammasome needs signal 1 & 2 to from which then activates caspase 1 which turns pro
iL1- beta antibodies into iL1- beta antibodies
Canakinumab Study
A randomized, double-blind trial of canakinumab, a therapeutic monoclonal antibody targeting
interleukin-1β
Antiinflammatory therapy targeting the interleukin-1β innate immunity pathway with
canakinumab at a dose of 150 mg every 3 months led to a significantly lower rate of recurrent
cardiovascular events than placebo, independent of lipid-level lowering
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- Cholesterylester transfer protein (CETP) transfers cholesterylesters from HDL
to VLDL/LDL
- Genetic CETP deficiency in humans associated with elevated HDL
- CETP inhibitors: torcetrapib (Pfizer), dalcetrapib (Roche), evacetrapib (Eli
Lilly) and anacetrapib (Merck) elevate HDL/lower LDL
Target lesion-associated inflammation
- Darapladip inhibits lipoprotein-associated phospholipase A2, reduces
circulating inflammatory markers and attenuates necrotic core expansion
within lesion in patients with CHD
Mobilisation of cholesterol from existing lesions

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Cyclodextrin, an FDA-approved substance used for the administration of
lipophilic drugs, shown to dissolve cholesterol crystals, induce reverse
cholesterol transport and regress atherosclerosis in mouse models
PCSK9 inhibitor
- PCSK 9 prevents LDL from being taken up and broken down in the
hepatocytes
- Inhibiting PCSK 9 increases receptor availability for LDL to bind and be
broken down



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