lipids and cardiovascular disease.pdf

lipid and cardiovascular disease Case 1 george 56 yo male Cholesterol 7.7 mmol/l Triglyceride 3.6 mmol/l HDL cholesterol 11 mmol/l Non hdl cholesterol 6.6 mmol/l Ldl cholesterol 5 mmol/l GP suggested to be on statins Feeling well Has well controlled hypertension Non smoker and not a heavy drinker...

lipid and cardiovascular disease Case 1 george 56 yo male Cholesterol 7.7 mmol/l Triglyceride 3.6 mmol/l HDL cholesterol 11 mmol/l Non hdl cholesterol 6.6 mmol/l Ldl cholesterol 5 mmol/l GP suggested to be on statins Feeling well Has well controlled hypertension Non smoker and not a heavy drinker Lipids related to CVD Cholesterol Triglycerides Fatty acids Phospholipids Fat is a source of energy so the body prefers it as a source of energy The basic structure of cholesterol is a sterol nucleus which is synthesised from multiple molecules of acetyl co A The nucleus can be modified using side chains to form : cholesterol , colic acid which is the base of bile acids and steroid hormones Cholesterol is found in the cell membrane its a precursor of vitamine D Can also affect the signal transduction in the plasma membrane If the OH group in the cholesterol molecule is replaced it becomes ester as in entirely hydrophilic while cholesterol is amphiphilic which means its both polar and nonpolar As there's an OH group which is polar and the rest of the molecule is nonpolar Every nucleated cell in the body can make cholesterol as ts a highly regulated process Triglycerides Glycerol backbone linked to fatty acids The body only makes even numbers of the fatty acids They are completely hydrophobic Saturated : hydrogens in single bonds only , solid at room temp Unsaturated : hydrogens found in one or more double bonds , liquid at room temp Monounsaturated : olive oil Polysaturated : omega-3 omega-6 In natural fatty acids double bonds are always in cis configuration > hydrogens are on the same side of the double bond which causes a bend in the chain Human body cannot make trans fatty acids Trans fatty acids are created through hydrogenation In TFA hydrogens are on opposite sides of the chain Excess take of both SFA USFA leads to increased levels of LDL which is linked to CVD Essential fatty acids FAs that the body cannot synthesise but are important for normal physiological function 1-alpha linolenic acid - omega 3 converted into EPA and DHA 2-eicosapentaenoic acid EPA - omega 3 Found in fish and seafood Important for anti-inflammatory processes and cell membrane fluidity 3-docosahexaenoic acid DHA Also found in fish and seafood Essential for brain development, retina function , and neuronal membrane Arachidonic acid (an omega-6 fatty acid) Converted into PGs, thromboxanes and leukotrienes which are involved in inflammation immune response and blood clotting Balance between omega-3 and omega-6 Omega-3 (epa & dha) : anti-inflammatory Omega-6 (AA) : pro-inflammatory Excess omega 6 from processed food can cause chronic inflammation Triglycerides can be stored in adipocytes and they’re nonpolar Phospholipids Hydrophilic head Glycerol backbone and a phosphate group Hydrophobic tail Which is formed by two FAs Because these fats are highly hydrophobic they need to be shape-changed to travel in our body So they are packaged in a ball-like complexes in which the hydrophobic lipids reside inside the balls and the hydrophilic parts reside outside Whats inside the ball is Triglyceride Cholesterol ester Phospholipd tails fre e cholesterols Apolipoproteins which act as an identifier proteins that direct their through the body Core lipids surrounded by phospholipids monolayer with proteins attached to it Lipid metabolism The majority of dietary fat consists of triglycerides Fat also contains fat soluble vitamins like A,K,D,E -emulsification by bile acids: Bile acids are produced in the liver and stored in the gallbladder, and they are released in the small intestine (duodenum) Bile acids emulsify fats by breaking large fat droplets into small micelles to increase the surface area for fat digestion -hydrolysis of triglycerides In the pancreas there is pancreatic lipase which act in the intestinal lumen They hydrolyse TAG by removing two fatty acids leaving behind : Monoacylglycerol which is a glycerol backbone with one FA acid attached 2 free fatty acids -Micelles : The breakdown products which are fatty acids , cholesterol , fat soluble vitamins Combine with bile salts to form micelles which are essential for transporting hydrophobic lipids in a watery environment Micelles deliver their contents to the intestinal brush border membrane FA and MAG diffuse across the membrane into enterocytes Cholesterol majority from is also absorbed Fat-soluble vitamins enter the intestinal cells along with the lipids Once inside the enterocyte FA and MAG are re-sterfied to form new TAGS Cholesterol is esterified into cholesteryl esters TAGS , cholesteryl esters and fat soluble vitamins are packaged into chylomicrons which are the lipoprotein that deliver fats for tissue for energy , these enter the lymphatic system first then the bloodstream Breakdown by lipoprotein lipase : LPL enzyme breaks down TAGs to fatty acids Fatty acids are absorbed by tissues As TAGs are removed, chylomicrons shrink → become chylomicron remnants which travel to the liver for further processing 1-endogenous cholesterol transport (VLDL to LDL) pathway The liver produces cholesterol and packages it into VLDL VLDL are large and they mostly contain TAGs Tissues extract TAGs making very low density lipoprotein smaller which forms IDL Intermediate density lipoproteins IDL continues losing TAGs becoming low density lipoprotein LDL is mainly cholesterol and binds to LDL receptors on cells to deliver cholesterol LDL is bad cholesterol because it has high cholesterol content LDL is prone to oxidation making its structure abnormal Oxidised LDL cross links with blood vessel walls in which the immune system will recognize it is damaged and engulfs it This process forms foam cells leading atherosclerosis plaque -reverse cholesterol transport pathway (HDL pathway) HDL is good cholesterol It functions in collecting damaged LDL and cholesterol from the bloodstream It returns it to the liver where it can be excreted TAGs need to be broken down into fatty acids for energy This happens by an enzyme called hormone sensitive lipase Which is activated by glucagon when energy is needed It breaks down triglycerides into fatty acids inside the adipose tissue And then fatty acids gets released in the bloodstream for energy Key points : ✔ Chylomicrons deliver dietary fats to tissues. ✔ VLDL transports liver-made fats → converted into LDL, which delivers cholesterol.​ ✔ Excess LDL (especially oxidised LDL) contributes to atherosclerosis.​ ✔ HDL helps remove excess cholesterol, preventing cardiovascular disease.​ ✔ Triglycerides are broken down when energy is needed by hormone-sensitive lipase. Classification of lipoproteins Chylomicrons and chylomicron remnant VLDL IDL LDL HDL How is CVD linked to cholesterol levels ? ApoB - apolipoprotein B is the structural protein of lipoproteins Acts as a scaffold molecule for lipoproteins It provides the structural integrity to lipoproteins such as VLDL LDL AND IDL LDL composition and structure : Contains TAGs and cholesteryl ester in the inside And its composed of phospholipids from the outside and cholesterol Its a metabolic byproduct after removing the tags and fa’s from larger lipoproteins (VLDL > IDL > LDL) It is not an energy source for the tissues Its highly concentrated with cholesterol Cholesterol in LDL is used for Bile acid synthesis ( in the liver ) Steroid hormone production ( adrenal glands , ovaries , placenta , testicles ) Because of its small size LDL penetrate the arterial intima Oxidised LDL triggers immune system activation >foam cell formation Which leads to atherosclerotic plaque formation which increases CVD risk atherosclerosis in coronary artery Apo B - the structural protein of lipoproteins It acts as a scaffold molecule for lipoproteins It provides structural integrity to lipoproteins such as VLDL LDL & IDL The role of LDL in atherosclerosis LDL gets trapped in the subendothelial layer of the blood vessel it goes through oxidative modification making it more atherogenic immune response The immune system recognizes LDL as damaged Monocytes go to the site and they enter the blood vessel layer and differentiate into macrophages They engulf the oxidised LDL via scavenger receptors However excess cholesterol is toxic to macrophages leading to foam cell formation Foam cells die and attract more macrophages worsening plaque development The accumulation of foam calls forms the fatty streak (early lesion of atherosclerosis) Macrophage driven inflammation increases oxidative stress and the release of cytokines/chemokines In response this recruits more macrophages leading to a worse LDL oxidation and foam cell formation Smooth muscle cell migrate to the lesion site they produce extracellular matrix to form a fibrous cap which acts as a barrier between the plaque and blood preventing the plaque rupture HDl prevents LDL oxidation by helping with removing excess cholesterol from foam cell ApoA-I and ApoE in HDL reduce inflammation and oxidative stress HDL mediated cholesterol efflux helps to slow down lesion formation and plaque progression Unmodified LDL is not taken up by macrophages LDL must be oxidised first to become atherogenic oxLDL triggers inflammation leading to athersclerotic lesions ✔ LDL infiltration & oxidation → triggers immune response. ✔ Macrophages engulf oxidised LDL, forming foam cells. ✔ Chronic inflammation and foam cell death worsen plaque growth. ✔ Smooth muscle cells try to stabilise the plaque, but inflammation weakens it. ✔ Plaque rupture → thrombus formation → heart attack/stroke. ✔ HDL prevents LDL oxidation and removes excess cholesterol. Hypercholesterolemia Cholesterol can be absorbed from the intestine majority of it is produced by the liver and can be also by the systemic tissue All cells in the human body has the capacity to synthesize chole de novo they do not rely on extracellular delivery of lipoprotein to them though they can use this exogenous source LDL receptor function More LDL taken by cells = less LDL in the bloodstream Less circulating LDL= less cholesterol going back to the liver Thereby the liver acts by reducing VLDL production thinking that cells have enough cholesterol If the LDL receptors are absent or defective calls cannot take up LDL​ Which means that more LDL will be circulating Which means that the liver mistakenly will assume that the cells do not have enough cholesterol levels so it would be producing more VLDL which later converts to LDL Increasing atherosclerosis risks High blood LDL → More LDL oxidation → Increased foam cell formation This is the basis of familial hypercholesterolaemia (FH), a genetic condition where LDL receptors are defective or missing. Key concepts ​✔ LDL receptors help regulate cholesterol balance.​ ✔ More LDL uptake by cells = Lower LDL levels in blood.​ ✔ Less LDL uptake (due to receptor deficiency) = More LDL in blood.​ ✔ The liver misinterprets this and keeps making more VLDL → worsening hypercholesterolaemia. Molecular basis of FH It's a genetic disorder where LDL-C accumulates in the blood increasing the risk of atherosclerosis and cardiovascular disease It happens due to defects in the LDL receptor pathway preventing proper clearance of LDL from circulation 1)​ LDLR mutation (defective LDL receptors) LDLR are supposed to bind to LDL particles and allow their uptake into cells removing them from circulation Mutations in LDLR : Defective or absent / LDL-C cannot bind properly to the receptor This leads to the accumulation of LDL-C in the bloodstream Which leads to an increased risk of plaque formation and cardiovascular disease 2)​ Defective ApoB protein A key protein on LDL particles that bind to LDL receptors for cellular uptake Dysfunctional ApoB : the binding of LDL-C to LDL receptors is impaired Even if LDL receptors are function LDL-C cannot be efficiently removed from circulation So LDL-C accumulates in the blood increasing atherosclerosis PCSK9 gain of function mutation PCSK9 is an enzyme that regulates LDL receptor recycling Under normal conditions LDL receptors are reused after binding LDL-C PCSK9 gain of function mutation Increased PCSK9 action leads to degradation of LDL receptors preventing their cycling Their results in fewer LDL receptors available to remove LDL-C form circulation LDL accumulates in the blood increasing CVD risk ✔ LDLR mutation → LDL cannot bind and be removed → More LDL-C in circulation.​ ✔ ApoB dysfunction → Impaired LDL binding to receptors → More LDL-C in circulation.​ ✔ PCSK9 overactivity → LDL receptors are degraded too quickly → More LDL-C in circulation. This explains why FH leads to severely high cholesterol levels and early-onset cardiovascular disease. Familial hypercholesterolaemia (FH) Genetic disorder causing very high LDL levels Leads to early onset CHD and atherosclerosis Caused by mutations in the LDL receptor pathway leading to impaired LDL clearance Types of FH Heterozygous FH Autosomal dominant inheritance One mutated copy of the LDLR gene Homozygous FH Two defective LDLR gene copies either the same or different mutation , it is more rare Causes extremely high LDL and early CVD Treatment includes: ​ Statins (lower LDL cholesterol). ​ PCSK9 inhibitors (prevent LDL receptor degradation). ​ Lifestyle modifications (healthy diet, exercise). ​ Lipid apheresis (for severe cases of HoFH). Corneal arcus Basically a grey-white yellowish circle like shape (an arc) that surrounds the periphery of the cornea due to lipid deposition in the corneal stroma Familial hypercholesterolaemia is one of the causes if the patient is under 40 CVD risk in younger individuals it may be linked to an increased risk of CVD Xanthelasma Yellowish soft and slightly raised plaques typically appear around the eyelids Particularly the medial canthus Composed of lipid laden macrophages and are a form of xanthoma Cases Hyperlipidaemia which is often linked to high cholesterol levels in younger patients CVD risk matter as it is associated with atherosclerosis Tendon xanthomas Deposition of cholesterol in the tendons Achilles tendon xanthomas Deposition of cholesterol in the achilles tendon For someone who has homozygous FH the chart clears that they might develop CHD at the age of 12 if not treated earlier For someone who has Heterozygous FH they can develop CHD by the age of 35 That's on comparison with someone who has high cholesterol levels but doesn't have FH They can develop heart disease at an age of 55 The role of LDL in the development of atherosclerosis Higher LDL = higher risks of developing CVD that when the relationship between LDL-C levels and CHD risk is plotted on a log scale, the relationship becomes linear. It demonstrates that excess hazard and risk of IHD starts as low as 40 mg/dl which equates to 1.0 mmol/L Different pharmacological treatments for high LDL levels 1)small molecules -statins Reduces cholesterol synthesis and increases LDLR expression -bempedoic acid Works upstream of statins to reduce cholesterol levels -ezetimibe Blocks cholesterol absorption in the intestines 2)PCSK9 inhibition -pcsk9 monoclonal antibodies The block pcsk9 binding to LDLR extracellularly preventing LDLR degradation Which increases LDLR availability for LDL uptake and clearance 3)cholesterol depletion mechanism Intracellular cholesterol depletion triggers increased LDLR synthesis enhancing LDL uptake Statins : Inhibitors of HMG CoA reductase Lower LDL cholesterol by 25-50% Reduces CVD Safe and generally well tolerated Side effects : muscle pain Pravastatin and simvastatin are fungal derived inhibitors of HMG CoA reductase Atorvastatin , rosuvastatin and fluvastatin are fully synthetic compounds The structures can be divided up into 3 parts:  An analogue of the target enzyme substrate, HMG-CoA A complex hydrophobic ring structure that is covalently linked to the substrate analogue and is involved in the binding of the statin to the reductase enzyme Side groups on the rings that define the solubility properties of the drugs and therefore many of their pharmacokinetic properties.