Atherosclerosis
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- Created by: Estera
- Created on: 14-05-15 23:28
What is Atherosclerosis
A progressive disease of the arteries - accumulation of lipids and fibrous tissue in the tunica intima of blood vessel wall
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How many people die from atherosclerosis
80,000 a year. 17% of all male deaths and 12% of all womens)
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What is an early manifestation of atherosclerosis
Endothelial dysfunction and reduced NO synthesis
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what do high concentrations of atherogenic lipoproteins cause?
lipid accumulation and endothelial dysfunction
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Is endothelial dysfunction a cause or a consequence of lipid accumulation?
Unknown
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point one of inflammatory process
LDL becomes oxidised in the arterial intimate
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point two of inflammatory process
endothelial cells produce adhesion molecules (VCAM1) to which inflammatory cells can bind (monocytes,T lymphocytes)
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point three of inflammatory process
inflammatory cells migrate (attracted by chemotatic stimuli) into the arterial intima where monocytes differentiate into macrophages
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point four of inflammatory process
macrophages proliferate in the presence of mitogenic stimuli {promotes mitosis} (macrophage colony stimulating factor (M-CSF) and ingest oxidised LDL via scavenger receptors to form foam cells
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What are the two mechanisms for the formation of mature atheroma?
1)Accumulated foam cells undergo death leaving LIPID CORE 2) Proliferation and matrix formation by intimal synthetic smooth muscle cells form FIBROUS CAP
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What are the marks of a vulnerable plaque?
Thin fibrous cap, large lipid pool, many inflammatory cells, few smooth muscle cells
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What are the marks of a stable plaque?
Thick fibrous cap, small lipid pool, few inflammatory cells, dense ECM
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What measures may stabilise atheroma?
decrease in LDL, increase in HDL, decrease in oxidative stress, lower BP, decreased insulin resistance, decrease in Angiotensin II
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what does intracoronary thrombosis occur from?
Erosion or rupture of the fibrous cap (proteolytic enzyme release by inflammatory cells) or thrombogenicity of the lipid core.
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How does atherosclerosis give rise to myocardial ischaemia?
Critical stenosis limits coronary flow reserve and symptoms occur when demand for blood is increased due to insufficient blood flow
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What is this called?
stable angina
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What does erosion/ rupture of the fibrous cap do?
allows contact of blood with thromobogenic lipid core. This triggers platelet aggregation and thrombus formation which can occlude coronary artery
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Give some examples of lipids
Free cholesterol, cholesteryl (cholesterol attached by ester linkage to long fatty acid chain), triglycerides and phospholipids
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What are their functions?
Structural component of cell membrane, precursor of steroid hormones and bile acids major source of energy.
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What are lipoproteins?
Spherical particles that transport lipid in circulation, contain apoproteins
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What are the 4 classes of lipids
HDL (highest protein:lipid ratio, contain Apo A-I/A-II), LDL (higher protein:lipid ratio, contain Apo B), Chylomicrons (post-prandial, triglyceride-rich),VLDLs (fasting state, triglyceride-rich, contain Apo E)
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Name 3 structural features of an LDL
apoprotein B (Apo B) (facilitates binding to LDL receptors), CORE: cholesteryl ester (triglyceride), COAT: phospholipid and cholesterol
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What does LDL do?
Delivers cholesterol TO cells
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What does HDL do?
mediates reverse cholesterol transport to the liver, for excretion via bile acid
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What are statins?
Lipid lowering therapy
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What is the mechanism of action of statins?
inhibition of HMG-CoA reductase, a rate limiting enzyme in hepatic cholesterol biosynthesis
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What does inhibition of HMG-CoA lead to?
Upregulation of HDL receptors in the liver, increased removal of apoB containing lipoproteins, reduction of lipoproteins synthesised and removal from liver. Could also have anti-inflammatory function and increased DNA repair
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By how much do statins lower LDL?
25-50% (Reducing the incidence of vascular events and mortality by 25-40%)
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So what do statins achieve?
Immediately they lower LDL slowly increasing endothelial function, reducing inflammation and over years ischeamic episodes reduced, plaque stabilised and vascular events reduced
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What are some adverse effects of statins?
common -headache fatigue GI , Rare-increase in liver enzymes in dose dependent manner .In small number myopathy and in very rare cases cases of rhabdomyolysis (severe case of myopathy - can induce myoglobinuria and renal failure)
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Describe actions of bile acid resins
Inhibit enterohepatic recirculation of bile acids, thus increase bile acid synthesis from cholesterol, Increase hepatic LDL receptor expression and thus LDL uptake over all reduce serum LDL
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What are 3 examples of bile acid resins?
Cholestyramine, Colestipol, Colesevelam
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What are some adverse effects of bile acid resins?
GI intolerance: constipation, bloating, abdominal pain, flatulence
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What are drug drug interactions of bile acid resins?
Bind other negatively charged drugs and impede the absorption of drugs and/or fat-soluble vitamins
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How do fibric acid derivatives treat atherosclerosis?
acivate PPAR alpha which regulates expression of key proteins in HDL synthesis (Apo A1 and Apo A2) = HDL mediated reverse cholesterol transport and increased lipidprotein lipolysis (increase HDL and decrease triglycerides)
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What are some adverse effects of fibric acid derivatives?
GI upset, gal stones and myopathy
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How can Nicotic acid treat atherosclerosis? Give an example of drug.
Niacin- activates a GPCR in adipocytes to inhibit lipolysis and decrease plasma free fatty acid levels. This increases HDL and decreases hepatic production of VLDL (LDL precursor) thus reducing serum LDL
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What is an adverse effect of niacin (nicotine acid)
flushing, itching, headache, hepatotoxicity
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What is the mechanism of Ezetimibe
Lower absorption of cholesterol by inhibiting NPC1L1, a novel protein critical for intestinal absorption of cholesterol. Also lowers LDL
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What are some adverse effects of Ezetimibe?
well tolerated, but some GI upset, back/ joint pain and sinusitis
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What are some future possible treatments to increase HDL?
Cholesterylester transfer protein (CETP) transfers cholesterylesters from HDL to VLDL/LDL, genetic CTEP deficiency associated with increased HDL - CTEP antagonists
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What are some future therapies to 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 (without affecting LDL) but failed to produce a reduction in mortality
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How could you inhibit LDL receptor degradation?
Proprotein convertase subtilisin/kexin type-9 (PCSK9) is an enzyme that binds to LDL receptors in liver cells and targets them for lysosomal degradation. n Gain-of-function mutations in PCSK9 are one of the causes of genetic hypercholesterolaemia.
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Other cards in this set
Card 2
Front
How many people die from atherosclerosis
Back
80,000 a year. 17% of all male deaths and 12% of all womens)
Card 3
Front
What is an early manifestation of atherosclerosis
Back
Card 4
Front
what do high concentrations of atherogenic lipoproteins cause?
Back
Card 5
Front
Is endothelial dysfunction a cause or a consequence of lipid accumulation?
Back
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