Week 1/2 - C - Histology (Vessels/heart layers) L.D.L/H.D.L/T.A.G, Atheroma formation/complications, Anti-Cholesterol drugs Flashcards
What are the three layers of the blood vessels? What is the predominant component of each layer?
Layer 1 - tunica intima (inner layer) - single layer of squamous epithelial cells known as endothelial cells Layer 2 - tunica media (middle layer) - made up predominantly of smooth muscle cells Layer 3 - tunica adventitia (outer layer) - predominantly supportive connective tissue
What separates the layers of the blood vessels from one another?
SEPARATED BY ELASTIC MEMBRANES Tunica intima and media separated by the internal elastic membrane Tunica media and adventitia separated by the external elastic membrane
What are the different layers of the heart? Between which two layers is the pericardial cavity?
* Endocardium, * Myocardium, * Epicardium * Serous pericardium (between visceral and parietal serous pericardium lies the pericardial cavity) * Fibrous pericardium
Which layer lines the inner surface of the heart including the valves? What is the structure of this layer? Which layer is the muscle layers? Describe a cardiac muscle cell?
The endocardium lines inner surface of the heart - composed of endothelium (single layer of squamous epithelium), basal lamina and connective tissue Myocardium is the thick muscle layer of the heart Cardiac muscle cells are single nucleus, branched, striated and involuntary
Epicardium is the outer layer of the heart What is the single layer of flattened simple squamous epithelium known as that is the ther outer part of the epicardium?
This is the mesothelium – mesothelial cells line the bodies serous cavities and produce lubricating fluid - the mesothelium in the epicardium is also known as the visceral serous pericardium
Which is the ‘good’ and which is the ‘bad’ cholesterol?
HDL (high density lipoproteins) are the good cholesterol LDL (low density lipoproteins) are the bad cholesterol
What is the main difference in the function of low and high density lipoproteins? What is the only orga with the capactiy to elimate cholesterol from the body? Which does smoking increase?
Cholesterol is delivered into the vessel wall by cholesterol-containing low-density lipoprotein (LDL) particles. HDL has a key role in transporting excess cholesterol from the cells to the liver for excretion Smoking increases LDL Smoking decreases HDL
How does the liver eliminate cholesterol from the body?
HDL transports excess cholesterol in the plasma to the liver The liver eliminates cholesterol either as cholesterol secreted into the bile or uses it to synthesize bile salts
What is the primary step in atherosclerosis? What are the risk factors for this?
The primary step in atherosclerosis is initiated by the dysfunction and injury of the endothelial lining of blood vessels Risk factors for injury to the endothelium include smoking high blood pressure, diabetes, toxins
After the primary enodthelial injury, what cells/particles invade the endothelium and what do they become?
After primary endothelial injury, there is the accumulation of LDLs and the migration of monocytes & platelets to the injury site The LDL invade the endothelium and beomce oxidised to atherogenic oxidised LDL (OXLDL) The monocytes cross the endothelium and become macrophages
How do the oxidised LDLs and macrophages form a fatty streak?
The macrophages ingest the OXLDL converting them to cholesterol-laden foam cells that form a fatty streak
After the formation of the fatty streak what happens in atherosclerosis disease progression? Where do smooth muscle cells migrate from?
Inflammatory substances are released from various cell types (usually due to the foam cells and platelets) causing the proliferation and migration of smooth muscles cells from the tunica media to the tunica intima
ATHEROSCLEROSIS PATHOGENSIS * Endothelial injury * LDL (becomes oxidised), monocyte (becomes macrophages) and platelet accumulation * OXLDL ingested by macrophages - foam cell/fatty streak * Platelets/foam cells release inflammatory substances that cause smooth muscle proliferate and migration * Fibrous cap formed What is the atheromatous plaque finally a combination of?
The atheromatous plaque * conists of a lipid core - the product of dead foam cells (when OXLDL are ingested by macrophages) * and an outer fibrous cap - formed by smooth muscle cells and connective tissue (collagen / elastin)
What is the progression of the atheromatous plaque?
The progression of the atheromatous plaque is * Fatty streak (macrohages ingested OXLDLD) * Fibrofatty plaque (fibrous cap (smooth muscle cells /collagen and elastin) over the fatty streak) * Complicated plaque - uusally means rupture
Progression of the disease is associated with further loss of luminal patency and arterial wall weakness What happens when the plaque ruptures?
When the plaque ruptures, this results in immediate blot clotting at the site of the atheroma - this results in blood clot formation (a thrombus) which can occlude the vessel
What is the major constituent of body fat?
The main constituent of body fats in human and animals are triglycerides (triacylglycerol) - they are made of glycerol and 3 fatty acids
What are the different types of triglyceride? Which is thought to be healthier?
Trigylcerides can be broadly separated into saturates/unsaturated fats Unsaturated fats are ‘healthier’ and promote an increase in HDL levels (promotes excretion of cholesterol) Saturated fats promote an increase in LDL levels which clogs arteries (plaque formation)
What are the recommended levels of cholesterol (HDL and non-HDL) and triglycerides in the blood?
Total cholesterol - 5mmol/l or below * HDL cholesterol - 1 or above * non-HDL cholesterol 4 or below * LDL cholesterol usually approx 2mmol/l less than total Triglycerides - 2.3mmol/l or below
Different drugs are prescribed to lower the lipid levels in the blood (lipids include cholesterol and triglycerides) These can be split between drugs that lower the lipid concentration and drugs that inhibit the absorption of cholesterol from the diet (DRUGS AIM –> LOWER LDL OR TAG) Statins and fibrates are two different drugs that lower lipid concentration in the blood * Which is first line for hypercholesterolaemia? * What is the mechanism of action of this drug?
Statins ar 1st line for hypercholesterolaemia - they lower LDL, TAG and increase HDL levels MOA - competitively inhibit the enzyme HMG-Coenzyme A reductase (3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase) This is the rate limiting step in cholesterol synthesis
How does competitive inhibition of HMG Coenzyme A reductase lead to a reduction in LDL levels?
Due to a reduction in hepatocyte cholesterol synthesis, there is a compensatory increase in LDL receptor expression and therefore enhanced clearance of LDL
* What drug is given 1st line in hypertriglyceridaemias? What do these drugs cause?
Fibrates are the drug of choice in patients with hypertriglyceridaemias They lower the TAG levels and LDL levels whilst slightly increasing HDL levels
Give two examples of statins and fibrates? Give side effects of both drugs?
Statins - atorvastatin, simvastatin Fibrates - bezafibrate and gemfibrozil Side effects - * for both drugs symptoms include myositis and rhabdomyolysis rarely * Do not co-prescribe these drugs
Discussed the lipid lowering drugs, statins and fibrates Now we discuss drugs which inhibit cholesterol absorption from the gut lumen into the enterocytes Which drug is often give as second line treatment for patietns with primary hypercholesterolaemia?
This would be ezetemibe
How does ezetemibe work?
Inhibits Niemann-Pick C1 like-1 (NPC1L1) transport protein in enterocytes of the duodenum, reducing the absorption of cholesterol. Causes a decrease in LDL with little change in HDL.
What is familial hypercholesterolaemia?
Familial hypercholesterolemia (FH) is a genetic disorder characterized by high cholesterol levels, specifically very high levels of low-density lipoprotein (LDL, “bad cholesterol”), in the blood and early cardiovascular disease. Usually caused due to defects with LDL receptors
For familial or non-familial primary hyperlipidaemia the treatment usually is as follows * Statins (HMG-Coenzyme reducatase A) 1st line (reduces cholseterol synthesis) * Ezetemibe (NPC1L1 inhibitor) 2nd line (reduces cholesterol absorption) * Fibrates or monoclonal antibody treatment are 3rd line options What monoclonal antibody treatment is an option? (usually prescribed in secondary care)
Proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors
Give examples of proprotein covertase subtilisin / kexin type 9 (PCSK9) inhibitors How are they administered?
PCSK 9 ihibitors eg alirocumab or evolocumab Administered as injections
Statins have already shown that when there is an increases in LDL receptor expression (due to defect in cholesterol, this causes an increase in the clearance of LDL How do the PCSK9 inhibitors work to increase LDL receptor expression? (LDL receptor = LDLR)
Normally, PCSK9 binds to the LDLR and promotes the degradation of this within the liver, therefore less receptors are available for LDL to bind to for degradation. LDL concentration increases PCSK9 inhibitors prevent the binding of PCSK9 to LDLR , meaning more available to bind to LDL and degrade this
* We have discussed histological layers of blood vessles/heart, how LDL/HDL and TAG all contribute towards increased cholesterol * We have discussed atheroma formation and the treatments to lower cholesterol / TAG levels NOW BACK TO ATHEROMA What are the complications associated with atheroma formation?
* Stenosis of the artery * Thrombosis * Aneursym (remember disease progression associated with narrowing of lumen and arterial wall weakness) * Dissection * Embolism
Arterial stenosis is due to narrowing of the arterial lumen resulting in reduced elasticity, reduced blood flow and potentially tissue ischaemia What are the clinical effects of cardiac ischaemia?
Reduced exercise tolerance Acute coronary syndrome * Stable angina * Unstable angina * Myocardial infarction Cardiac failure
Arteriol stenosis may affect any artery What happens when it affects * Coronary arteries * Carotid arteries * Renal arteries * Peripheral arteries
Coronary arteries - Acute coronary syndrome, Cardiac failure Carotid arteries - TIA, Stroke, Vascular dementia Renal arteries- hypertension and renal failure Peripheral arteries - Claudication and foot/leg ischemia
Thrombosis of course can cause ischaemia due to obstructing the blood supply to the organ Define an aneurysm? What is the most common site for an arterial aneurysm?
An aneurysm is an abnormal and persistent dilatation of an artery due to a weakness in its wall Commonest site of arterial aneurysm is the abdominal aorta
What are the complications of an aneurysm?
Aneurysm rupture Thrombosis Embolism Pressure erosion of adjacent structure Infection - due to stasis blood
What is an arterial dissection? How is a false lumen formed?
An arterial dissection is when there is a tear in the lumen of the artery causing a separation of the tunica intima from the tunica media - this leads to blood leaking out and flowing within this space - aka a false lumen
How may an atheroma cause an emboli?
Both the actual plaque itself or the thombus that has occured may break off and embolise
