The lowering of level of LDL by therapyof statin and ezetimibe, used as aprevention of atherosclerosis.AbstractAtherosclerosis is a chronic disease of thearterial walls, which leads to complication such asmyocardial inflammation and strake. By understanding the results and conclusion from experimentalclinical trials, it may be possible to preventatherosclerosis. Most important is to understand thebiological principles behind atherosclerosisgenesis because it provides us with information ofpossible ways to overcome obstacles and bring the solution of lowering LDL-lower densitylipoprotein which is cholesterol, which is responsible for atherosclerosis.IntroductionGeneral conception of atherosclerosis genesis.Libby P. et.al, in the Nature article, described atherosclerosis as the development of plaque in theinner membrane of arteries (fig. 1). The normal muscular artery and the cell changes that occur duringdisease progression to thrombosis are shown. a, The normal artery contains three layers. The inner layer, the tunica intima, islined by a monolayer of endothelial cells that is in contact with blood overlying a basement membrane. b, The initial stepsof atherosclerosis include adhesion of blood leukocytes to the activated endothelial monolayer. c, Lesion progressioninvolves the migration of SMCs from the media to the intima, the proliferation of resident intimal SMCs and media-derivedSMCs, and the heightened synthesis of extracellular matrix macromolecules such as collagen, elastin and proteoglycans. d,Thrombosis, the ultimate complication of atherosclerosis, often complicates a physical disruption of the atheroscleroticplaque.Furthermore, they proved that by examinationof humans and animalswas a show changes in themonolayer of endothelial cells, which poses attachment to white blood cells. This evidencesuggested that changes such as this allow LDL entry by permeable endothelial cells to the arterywall. Cholesterol is there chemically modification by intima express scavenger receptors in theoxidation process.Davis Jr. H.R. et.al, in Atherosclerosis articles from 2011 had been suggested thatprimary events of atherosclerosis were inhibiting Apo-apolilipoprotein modification which wastriggered of modification, inflammatory immune system and accumulation of lipoprotein like LDL.Inaddition, Libby P. et.al, believed that cholesterol undergoes endocytosis process by monocyte- whiteblood cell occurred in plague, what leads to cholesterol accumulation and migration to feather level
of artery, called tunica intima, where changed into macrophages and when engulfsmore lipoproteinin foam cell. They explained that atheroma, region where atherosclerosis begins formation,produced the migration of muscles from media to intima. In fact, this made extracellular matrixmolecules: including collagen and elastin, which together with platelet, mediated by smooth musclesform fibrous cap. Libby P. et.al, point out, thatin this cap foam cells realised: lipids and macrophagesbodies, which eventually die and accumulated in there in the process of not efficient clearancecalled efferocytosis. Above all,accumulation of cellular derbies and extracellular lipids are formedrich of fat pool called by the authors’ necrotic core of plague. In result,that plaque becomes biggerand bigger, which eventual produced thrombi, caused limiting flow of blood. (Libby P. et.al; 2011)MethodsMouse model, as an understanding of potential drug therapy .In order to prove theory of Altmannet.al published in Science article from 2004, which identifiedcholesterol transporter called Niemann- Pick like protein in short NPC1L1, placedon the membraneof intestine, as a target of new agent called ezetimibe (fig. 3), which can inhibit that transporter,Davis Jr. H.R. et.al, in Atherosclerosis articles from 2011 had been usedmice models as a tool tounderstand a complex of pathways involved in atherosclerosis disease, which developed evaluationof potential ezetimibe therapy. In first experiment, they was used the two mouse one with npcl nullandsecond-wild type mice. In comparison with wild type mice,mice with null npc1l1 show 86%reduction in cholesterol absorption and 72% of inhibition of intestinal cholesterol uptake. Inadditional results was proved that a wild type mouse was insensitive to treatment with ezetimibe. Inthis wayDavis Jr. H.R. et.al had been defined direct interaction between ezetimibe and NPC1L1 andidentification of mechanism of high affinity binding ezetimibe to NPC1L1, which is 61- amino acidsite of extracellular loop C in NPC1L1. These findings lead to the conclusion that ezetimibe preventsNPC1L1 from cholesterol uptake. fig. 3. Mechanism of actionfor reduction of atherogenicApoB-containing lipoproteins by ezetimibe, and potential effects on atheroscleroticburden.ApoB = apolipoprotein B, CE = cholesteryl ester, CETP = cholesteryl ester transfer protein, FFA = free fatty acid,HDL = high density lipoprotein, IDL = intermediate density lipoprotein, LCAT = lecithin-cholesterol acyltransferase,LDL = low density lipoprotein, LPL = lipoprotein lipase, NPC1L1 = Niemann-Pick C1 Like 1 sterol transporter, SR-B1 = scavenger receptor type B1, TG = triglyceride, VLDL = very low density lipoprotein.
Second experiment was based on the work of Mahley R.W. et.al, publishes in Annual ReviewGenomics Human Genetics, from 2000 and Plump A.S. et.al, published in Cell from 1992, whichsuggested that ApoE- lipoprotein E genotype was essential for normal catabolism of trigriceride–richprotein consistent (fig. 2). In that publication ApoE was mapped in 19 chromosome and proteinproduced from that is targeting X receptor liver, which play important role inregulation ofmetabolism of cholesterol.Davis Jr. H.R. et.al, show that Apo E knockout mouse was developed thehypercholestelemia and premature atherosclerosis similar in characteristic to human; indeed theytreated those mice with ezetimibe.Apo E knockout mice was received; a high-fat western diet (40kal% butter fat, 0.15% cholesterol), or low-fat diet (10 kal% butter fat, 0.15% cholesterol), or semi-synthetic, cholesterol free diet (10 kal% corn oil) with or without ezetimibe treatment.ResultsAs a consequence of that treatment was reduced the plague for about 57%, coronary arterialocclusion 68%, myocardial fibrosis 57% and cardiomegaly 12 % with compered in untreated controlmice. Davis Jr. H.R. et.al, in brief proved that ezetimibe was inhibit absorption by 90 % andsignificantly lower plasma cholesterol. Conclude from this experiment ezetimibe was producedreduction in atherosclerotic lesion surface area of the entire aorta from 20% to 4% in mice feed thewestern diet and from 24% to 7% in the low-fat cholesterol diet. (Davis Jr. H.R. et.al; 2011) fig.2. Representative −/−aortic arch images from male apoE mice following 6 months of diet ± ezetimibe Davis et al.
Result of clinical test of ezetimibe and statinIntroductionHigh level of LDL is correlated with high risk of cardiovascular complication such asatherosclerosis.Clinical trials from 2009 and 2010 prove that new agent called ezetimibe can inhibitthat transporter and reduce level of LDL of about 20% in individuals being treats with statin for longperiod. Statin are popular inhabitants of hydroxymethyl grutaryl co-enzyme a reductase in shortHMG CoA reductase inhibitor which regulate pathway of LDL production in liver. Research foundthat statin is most effective in therapy with cardiovascular disease as well as prevention of thatdisease for people with CVD family history. Statins are have side effects of muscular damage andresearch also found that statin lowering LDL level but risk of cardiovascular disease still high.Ezetimibe commercial name is Zetia or Ezetrol together with statin called Vytorin and Inegu.MethodsResearch from 2009 and 2010 shows that ezetimibe did not improve outcomes significantly,however in 2010 clinical trials was show that together with statin results significantly improved.Studies of trials ENHANCE and ARBITER-6 was suggested that ezetimibe effectively lowering LDLplasma, but doesn’t effect on atherosclerosis (tab. 1 and tab. 2). Recent studies from April 2011 inArteriosclerosis was proved that adding ezetimibe to statin could regress atherosclerotic plague thatwas measured by MRI. A study was involved 67 PAD-with peripheral arterial disease patients. Therewere 16 patients whose was treated by simvastatin 40 mg, 18 patients whose was treated bysimvastatin 40 mg and 10 mg ezetimibe and 33 patients whose was chosen with LDL-C level above80 mg/dL and was treated with open –labelled ezetimibe 10 mg on top of statin therapy before. Inthe therapy patient was treated regularly and the plunge picture was taken in first and second yearafter therapy.(West et.al, 2011)ResultsResults was showed that with the statin treatment baseline was at beginning 118 mg/dL and wasreduced to 91 mg/dL in first year and 83 mg/dL in second year volume of plague. Results wasshowed that with the statin+ezetimibe treatment baseline was at beginning 118 mg/dL and wasreduced to 67 mg/dL in first year and then start increase to 68 mg/dL in second year volume ofplague. Results was showed that with the ezetimibe treatment baseline was at beginning 100 mg/dLand was reduced to 80 mg/dL in first year and 71 mg/dL in second year of volume of plague. (Westet.al, 2011)
LDL levels (tab1)LDL cholesterol (mg/dL) Simvastatin Simvastatin/ezetimibe Ezetimibe (on top of current statin)Baseline 118 118 100Year 1 91 67 80Year 2 83 68 77Plaque volume (tab2)Plaque volume (cm3) Simvastatin Simvastatin/ezetimibe Ezetimibe (on top of current statin)Baseline 11.0 11.5 10.0Year 1 10.3 11.1 10.4Year 2 10.5 10.5 10.8ConclusionDefinitively benefit of statin and ezetimibe in seen when studied this trials. Conclusion of ezetimibeworking alone doesn’t exist yet, but with proving of reduction low –density lipoprotein make goodcontribution to conclusion that may take place in 2013 on trial called- IMPROVEIT- IMProvedReduction of Outcomes: Vytorin Efficacy International Trial.Reference1. Atherosclerosis215 (2011) 266-278 “Effects of ezetimibe on atherosclerosis in preclinical models”Harry R., Davis Jr., Robert S. Lowe, David R. Neff; Available online 17 February 20112. Nature473, 317-325 19 May 2011 “Progress and challenges in translating the biology ofatherosclerosis” Peter Libby, Poul M. Ridker, Goran K. Hansson; Published online 18 of May 2011.3.Atheriosclerosis 218(1), 156-62 2011 Sep; Online publication Jan 2012“The effect of ezetimibe onperipheral arterial atherosclerosis depends upon statin use at baseline” West AM., Anderson JD.,Meyer CH., Epstein FH., Wang H., Hagspiel KD., Berr SS., Harthun NL., DiMaria JM., Hunter JR.,Christopher JW., Chew JD., Winberry GB., Kramer CM.