Lipids and atherosclerosis PDF

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Delivered by Professor Chris Packard. The link between lipid lowering and atherosclerosis....

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C Packard typed Both triglyceride and cholesterol are lipids, both contained within lipoproteins Triglycerides are a source of energy stored in the adipose tissue - Can be used for energy production if no glucose or food source is available Cholesterol is used for composition of cell membranes, steroid synthesis and bile acid production Prospective studies collaboration by Lancet in 2007 - As. The usual HDL-cholesterol increases in mg/gl, the hazard ratio i.e. risk for ischaemic heart disease decreases, although the decrease seen is best in younger age groups versus older age groups - The opposite is true for the usual non-HGL-C and total cholesterol but LDL Molecule has fatty acid and side chain interacting with lipid. The pseudomicellar structure of LDL of this oil droplet contains hydrophobic cholesterol esters and triglycerides (triglyceride and cholesterol esters) inside LDL. ApoB containing lipoproteins; chylomicrons, Lp(a), IDL, VLDL and their remnants also. ApoA containing lipoproteins: HDL - ApoB lipoproteins transport lipid from liver and intestine to peripheral tissue such as skeletal muscle whereas ApoA containing lipoproteins transport lipid from the periphery to the liver for excretion. ApoA containing lipoproteins are in fact cardioprotectant as they can safely deliver any HDL from plaques too, towards the liver. HDL also promoted efflux of cholesterol from macrophages after binding, delivering safely to liver, HDL also inhibits oxidation of cholesterol in the arterial wall and inhibits monocyte binding to the arterial wall, something common in inflammation during atherosclerosis. ApoA or ApoB on surface, that governs functionality of plasma lipoproteins. LDL-C carries most cholesterol out of all ApoB lipoproteins hence the marker status of cholesterol Pathogenesis of atherosclerosis – superoxide oxidises LDL, monocytes recruited. Decades long process to form lesions in the coronary artery. If LDL-C accumulates then lesions form. Rupture of these lesions which are unstable causes a clinical event. It is here that HDL can exert its cardio protectant effect when plaque ruptures. In plaques, foam cell macrophages which accumulate in the shoulder region can contribute to instability of the plaque depending on the degree of the LDL’s oxidation and if very small, hence dense – oxLDL can make the macrophage very atherogenic and increased ability to permeate the arterial wall. Initially you need t observe endothelium injury for chemokines (chemoattractant proteins) to recruit monocytes to the damaged wall – it is here where the monocytes transform to macrophages and can then engulf oxLDL (in case of oxidative stress where Ros are high). This occurs in inflamed states of vessels which drives atherosclerosis, the first stage of atheroma formation is fatty streak formation and this is at what stage they occur. CRP reflects the inflammation, which is correlated to the extent of macrophage accumulation. CRP actually increases cellular adhesion molecules – something NO inhibited/downregulated usually. In fact, T cell activation stimulates macrophages to deposit Matrix metalloproteinases which can cause plaque rupture

(inflammation causing thrombi formation). CRP has actually been correlated to deposition and build up of macrophage too in vessels where they are recruited. Endogenous lipid metabolism – what controls bloodstream LDL levels Free fatty acid pours into the liver and VLDL is produced by liver, lipoprotein lipase converts this into IDL which goes back to the liver where hepatic lipase produces LDL. LDL can then act on LDL receptor or scavenger receptor. LDL receptor molecule Can be uptook upon request by a cell, cell will make negatively charged domain on LDL-receptor which the positive domains on LDLApoB will bind  Internalise Apo BLDL. Cholesterol is hence delivered into cell. LDL-R will also not be made any further if sufficient cholesterol s within. Any excess ApoB LDLcan be uptook by scavenger receptor or scavenger macrophage pathways.

Redundant of LDL-R? via defect - Autosomal dominant inheritance, only one copy of defective allele/gene required - LDL accumulates across tendons and leads to tendon xanthomata and eventually coronary disease as increased risk for it. Severe premature CHD can also occur if individual is homozygous, hpercholesterolaemia is initiated at young age (not just increased risk for development CHD). - This deposition of cholesterol across tendons = tendon xanthomata, due to familial hypercholesterolemia - Familial hypercholesterolaemia is extremely elevated LDL-C which can cause plaque/lesion deposition in coronary artery walls In FH, the most prevalent CVD is CAD - Presents as ACS; angina/MI - FH actually can occur due to heterozygous mutation in either ApoB, LDLR or PCSK9 genes  Increased risk for CAD - Most common genetic cause, most common variation in gene is for LDLR gene variant in which heterozygous FH occurs - Heterozygous FH requires patient to have inheritance of just one defective copy of an FH gene e.g. ApoB, PCSK9 or LDLR - Homozygous = have inherited 2 defective genes – one from each parent i.e. meaning both partents were heterozygous for FH in 1st instance ApoB gene variant in causing FH composes ~10% of the cases if the gene has variant - USUALLY, ApoB lipoproteins will bind LDLR in which they are up took into lier to reduce cholesterol in blood – doesn’t happen if gene mutates PCSK9 gene variation = composes only minimum of FH cases as reason - Standard PCSK9 function would allow enzyme production which would degrade LDL-Rs after their use - However, see a mutation which is gain of function – hence excessive degradation of receptor by overproduction of degrading enzymes = prolong LDL-C in blood

Suspects – for driving athero plaques/lesions formation Chylomicrons or large LDL molecules are subject to lipolysis by lipoprotein lipase (fatty acid and glycerol production) and production of smaller more cholesterol rich particles - Of course in plaques, the oxLDL that is most atherogenic and able to permeate arterial wall to cause damage (or damage when rupture) - LDL remnants and chylomicron remnants have a high cholesterol composition too and are large enough to penetrate arterial wall  atherosclerosis - IDL is also elevated in those with coronary disease – yet LDL elevation isn’t seen surprisingly in some cases Copenhagen City Heart Study - Emphasised that LDLC as well as remnant cholesteol is highly atherogenic - Both LDL-C and remnant cholesterol increases in mmol/L increased the HR i.e. the risk for succumbing to an MI - Was a completely random sample of ~20000 mean and women aged 20-93 - So atherogenuc lipoproteins in bloodstream are LDL-C and chylomicron, LDL remnants and chylomicron remnants as well as IDL Diabetics and dyslipidaemia - T2D patients have atherogenic lipoprotein phenotype - Raised VLDL causes hypercoagulation in these patients as plaques/clots of fibrin form due to Plasminogen activator inhibitor 1 increaseing, hence tissue plasminogen activator is inhibited (plasminogen activated into plasmin hence degradation fibrin clot) - Also see remnants of chylomicrons and VLDL elevated in T2D - Smallerer and hence more dense LDL which is more readily oxidised by superoxide and hence retained in artery wall as it permeates it is present in these diabetics too - The cardioprotectant features of HDL are minimal (mentioned above) as HDLC is actually low - Thereby, T2D at high risk from CVD events due to the atherogenesis increased risk of it forming due to the dyslipidaemia – die more from CVD versus high sugar itself All remnant and LDL-C deposition contributes to the foam cell formation as when oxidised they will be engulfed hence the inflammation. - Inflammation such as ICAM and CRP elevation, endothelial stress, VLDL remnants and LDL increase and HDL reduction Procam Münster heart study highlighted that lipoproteins such as HDL-C decreasing, raises the incidence % of coronary events per 1000 people over 8 years follow up (in men aged 40 and above). It was also demonstrated that the incidence of coronary events can be mitigated by having a high HDL-cholesterol value mg/dl despite having high total cholesterol – almost as if HDL-C mitigates the effect of ApoB “bad” cholesterol. This was in comparison to those individuals with high cholesterol and low HDL-C mg/dl who seen a high incidence of events

LDL-C lowering clinical trials STATINS Mechanism: Competitively inhibit HMG-CoA reductase enzyme which is RLS for cholesterol synthesis in liver as otherwise the enzyme will produce activated isoprenes from mevalonate. In response to decreased production, compensatory increased uptake of cholesterol into liver from blood enabled by increased LDL-R expression at hepatocytes, hence LDL-C and ApoB lipoproteins are decreased in plasma. WOSCOPS - Primary prevention Pravastatin versus placebo - Men over middle age with high LDL, at high risk but had no prior CHD events - Asymptomatic individuals, 5 year study. Redution SS of Primary endpoint – non-fatal MI and CHD death versus placebo - Even a 15 year follow up continuously followed the difference along the whole way in event incidence - The success of statin actually warranted 1/3 of placebo cohort onto statin treatment after 5 years - However, a non SS reduction in total mortality was seen - Individually MI, CV mortality, PTCA and CABG requirement all SS by pravastatin - Non-CV events being identical almost between both groups proves how safe it is to use statins Primary interventions below – JUPITER AND ASCOT LLA The JUPITER trial investigated the role of rosuvastatin VERSUS PLACEBO in primary prevention of vascular events. The patients had high levels of hs-CRP (inflammation marker) but low LDL-cholesterol. In this study with ~18000 patients the primary endpoint containing non-fatal MI, stroke, need for revascularisation after angina symptoms and death of a CV cause being reduced significantly led to trial termination only a year into 4 year schedule. Lowering of the already low LDL-C and CRP allowed such a reduction to be seen. Although a difficulty could be that early termination did not allow a safety profile to be determined. The trial could be regarded peculiar, as statins are used to lower lipids, which were below the threshold that warrants statin use in first instance. Rationale of using despite no elevated LDLC was that despite LDL-C increasing chance of ASCVD event, ~1.7M of heart attacks/strokes occur in those who have low cholesterol – so despite no hyperlipidaemia (JUPITER Trial Results, controversies, and implications for prevention Paul Ridker) ASCOT Trial Lipid lowering arm tested whether the use of atorvastatin would decrease coronary heart disease vascular events in hypertensives who had low cholesterol levels. Over 10000 patients predominantly male with age~60 – approximate median age. So the patients had not sufferd from previous ACS events. LDL-C and total cholesterol were lowered versus placebo. The significant non-fatal MI and fatal CHD reduction (Primary endpoint) warranted an early stoppage of lipid lowering arm. Atorvastatin also lowering the fatal/nonfatal stroke rate significantly versus placebo was observed. This whole arm had hypertensives but low cholesterol individuals.

PROVE-IT trial 90000 patients from 14 RCTs of statins in reducing LDL-C to prevent CHD events as well as any other vascular events - Over 5 years - ACM 12% RRR – SS

What about targeting HDL raising (cardioprotectant) HDL Molecule has cholesterol ester inside, ApoA1 outside as well as phospholipid Pravastatin pooling project

Pravastatin versus placebo - In the pooled data there were 3 RCTs and one included WOSCOPS which was primary prevention, other 2 studies were secondary prevention - Upon raising the HDL-C from 1mmol/L to ~1.5mmol/L – placebo had a higher event rate versus pravastatin - The risk decrease by pravastatin was due to LDL-C lowering, yet it showed a coinciding HDL-C increase as the risk was being lowered - Due to HDL-C promoting efflux cholesterol from foam (macrophage) cells - Also binding and delivering the cholesterol safely to liver if plaque ruptures and above mentioned cardioprotectant mechanism of HDL - Total deaths, fatal CHD and other fatal (CVD caused) all SS lowered by pravastatin, although total deaths no SS lowered versus placebo Even in placebo, increasing HDLC was good at decreasing their event rate Treat to new targets trial TNT trial So it was believed that risk would decrease ~30-40% if you increase HDL-C by 1-1.5mg/dl TNT trial was lowering of LDL-C with atorvastatin – low/high dose atorvastatin 10mg vs 80mg daily in patients with CHD already. In both of these LDL-C lowering doses a coincidental HDL-C increase was seen i.e. quintiles with greater HDL-C showed a trend of falling CV risk too. This was an example of how pursuing aggressive LDL-C reductions an even greater benefit can be seen despite having LDL-C at levels (beyond the minimum recommended threshold). So comparing vascular events incidence in group that ca reduce LDL-C to 2.6mmol/L and 1.9mmol/L respectively.

Other HDL mechanisms. By inhibiting adhesion molecule expression on vessel lumen, less monocytes can be recruited. This is reduction if inflammation as monocytes cant bind artery wall anymore. These monocytes would otherwise, be transformed into the macrophage in steps involves MCP-1 (produced by the modified oxLDL). Then the macrophage would engulf the oxLDL and act as a foam cell, or could cause cytokine release and further adhesion molecule production – self perpetuating the production of foam cells and macrophages which can engulf oxLDL. - HDL can inhibit initial oxidation of the LDL too - HDL can also cause efflux of cholesterol from foam cells, turning them into just macrophages again - Binds to cells and takes cholesterol to liver safely to liver

Following on from benefit of HDL raising, Cholesterol esterase transport inhibitors (CETB inhibitors) Basic mechanism of CEPT inhibitors is that the cholesterylesterse transfer protein usually facilitates transfer of cholesterol esterase from HDL-C to the VLDL/LDL atherogenic lipoproteins. Preventing this from occurring can prolong HDL high levels Dalcetrapib, Anacetrapib and Enacetrapib are all increasers of ApoA1 lipoprotein and HDL-C - They all increase HDL-C, dalcetrapib is weakest effect on this - Same with ApoA-1^ - LDL-C lowered by all, weaksest by da;cetrapib again - ApoB is decreased by only anacetrapib and evacetrapib – not by dalcetrapib - Triglyceride decreased only by anacetrapib and evacetrapib, not by dalcetrapib Dalcetrapib which mainly only increses HDL-C and ApoA1 was investigated by Dalcetrapib trial ACS in 2012 (NEJM) - In ~15000 ACS succumbed patients, were placed on dalcetrapib or placebo daly - HDL was increased from baseline with LDL largely unchanged as ecpexted versus placebo - But there was no alteration of the primry endpoint of CV events incidence despite the HDL raise. - Trial stopped early due to inadequacy Can attribute failure to the fact that dalcetrapib not having an effect on LDL-C and other Apo-B baring lipoproteins confers no benefit - Also has no effect on NO production – endothelial function – so no vasodilatory effcte, platelet aggregation reduction and leukocyte adherence as well as neutrophil attachment to ECs and to vessel lumen of artery. Also no inhibition of VSMC hypertrophy In the dal-OUTCOMES trial, this CETP inhibitor actually increased CRP also, which has been proven to concomitantly be decreased by statins as they lower LDL-C. Inflammation is an unchallenged driver of atherosclerosis and plaques as mentioned above (cytokines/adhesion molecules) – therefore was such a questionable function overlooked in the NEJM trial? Furthermore, as mentioned above the mechanism of HDL-C cardioprotectancy involves the cholesterol efflux from foam cells (allowing them to go into macrophages again) or plaques releasing cholesterol, safely to liver. This process is termed as “macrophages to feces” where the cholesterol expulsion from the foam cells which goes to HDL receptors (in HDL) and after esterification the cholesterol is transported from the HDL, safely to liver. - The CEPT inhibitor may not be enough in order to allow cholesterol efflux process

The measurement method i.e. HDL-C total concentration has been postulated to not be as a viable representation of CETPi effects. Indeed, number of HDL particles instead has been suggested as it is the small and dense particles which are more efficacious in being able to enhance the cholesterol efflux from foam cells and antiinflammation as well as antioxidant effects. Whereas – larger the particle size of HDL – apparently the lesser the ability to exert positive effects. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4790583/ - Above on why Dalcetrapib never worked Triglyceride (lipids) as target Evidence from mendelian randomisation; genes which result in individuals with high triglyceride, HDL and LDL - Those who have genetically higher LDL = higher risk for coronary disease - Genetically lower HDL of course increases risk

Triglycerides as targets, it’s the accumulation of remnants causing atherosclerosis – not triglyceride itself REDUCE-IT trial Derivative of fish oil, icosapent ethyl (Purified EPA) versus placebo ability to lower TGs - 2ndry prevention trial in those with either T2D or CVD - So this high dose fish oil allowed plasma TG levels to be lowered by ~20% whilst decreasing S.S patients having CV events such as CV death, non-fatal MI and non-fatal stroke. - Howeer decreased safety came at the cost of efficacy as serious major bleeding occurred more in ecosapent ethyl group versus placebo - Interestingly, even in patients with persistently elevated TG levels, still seen a beneficial reduction (over 150mg/dl) – so does the EPA have additional pleiotropic effects? Despite showing benefit in this trial, the STRENGTH Trial failed to replicate the benefit - The use of Epanova which is an omega3 carboxylic acid in high risk patients (dyslipidaemics) for CV events - The ptints with high TG moderate raised - Epanova was compared to a placebo corn oil It has been speculated that failure to replicate results is because icosapent ethyl has only EPA whereas strength used the combination of EPA and DHA, apparently the latter hampers the function of the highly purified EPA. Current clinical practice and issues Euroaspire IV - Audit of 24 countries – very high risk patients on statins - In reaching target of LDL-C reduction, only ~20% reaching reduction target whereas ~80% had LDL-C greater then 70mg/dl

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Could be due to reluctance to take statins in individuals who don’t like sid effects, have fear of it or because its chronic treatment they feel that its not really showing a benefit (hard to show as athero is decades long process)

Cholesterol absorption inhibitors - Ezetimibe = inhibition of intestinal uptake of cholesterol which was derived from diet and bile - Works at Np1cL1 (Niemann Pick C1 like protein 1) – cholesterol transport protein is inhibited by ezetimibe it so micelles are not up took into SI which contain the cholesterol - Less cholesterol will be up took into liver, of course with statins there is increased expression of LDL-R to increase LDL clearance from blood - The decline of LDL-C within hepatocytes means this works similarly to statins, as less cholesterol going to liver means the LDLRs on hepatocytes increase – SO AGAIN, LDL-C going into liver from blood/serum increases - Although differs to statins as doesn’t hamper the cholesterol synthesis pathway (https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5298356/) Cholesterol in serum 2 main sources include cholesterol produced in liver and the cholesterol from GI tract being absorbed Statins decrease cholesterol by inhibiting RLS of enzyme which makes cholesterol. But to counter this decreases haeptaic LDL-C, then LDL receptors on hepatocytes are upregulated so LDL-C transport from blood to liver rises IMPROVE-IT trial - 7 years, double blind RCT of ezetimibe and simvastatin versus simvastatin alone in patients already hospitalised for ACS. - Patients were already on statin/elevated LDL-C - Versus monother...