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type=\u0022text\/css\u0022 rel=\u0022stylesheet\u0022 href=\u0022\/\/d282kpwvnogo5m.cloudfront.net\/sites\/default\/files\/cdn\/css\/http\/css_Xg7z6oCTVgud_Q0huYz9x9iiD5H_2YPSJ5z2ZViSWdY.css\u0022 media=\u0022all\u0022 \/\u003E\n\u003Clink rel=\u0027stylesheet\u0027 type=\u0027text\/css\u0027 href=\u0027\/sites\/all\/modules\/contrib\/panels\/plugins\/layouts\/onecol\/onecol.css\u0027 \/\u003E\u003C\/head\u003E\u003Cbody\u003E\u003Cdiv class=\u0022panels-ajax-tab-panel panels-ajax-tab-panel-sageoa-tab-art\u0022\u003E\u003Cdiv class=\u0022panel-display panel-1col clearfix\u0022 \u003E\n  \u003Cdiv class=\u0022panel-panel panel-col\u0022\u003E\n    \u003Cdiv\u003E\u003Cdiv class=\u0022panel-pane pane-highwire-markup\u0022 \u003E\n  \n      \n  \n  \u003Cdiv class=\u0022pane-content\u0022\u003E\n    \u003Cdiv class=\u0022highwire-markup\u0022\u003E\u003Cdiv xmlns=\u0022http:\/\/www.w3.org\/1999\/xhtml\u0022 id=\u0022content-block-markup\u0022 xmlns:xhtml=\u0022http:\/\/www.w3.org\/1999\/xhtml\u0022\u003E\u003Cdiv class=\u0022article fulltext-view \u0022\u003E\u003Cspan class=\u0022highwire-journal-article-marker-start\u0022\u003E\u003C\/span\u003E\u003Cdiv class=\u0022section abstract\u0022 id=\u0022abstract-1\u0022\u003E\u003Ch2\u003ESummary\u003C\/h2\u003E\n            \u003Cp id=\u0022p-1\u0022\u003EInflammation plays a critical role in all phases of atherosclerosis, and it is triggered in part by lipid entry and retention and subsequent oxidation in the vessel walls. Most of the factors that contribute to plaque instability are related to lipid accumulation and subsequent inflammatory pathway activation. Changing the phenotype of the atherosclerotic lesions could increase plaque stability and reduce clinical events. This article discusses several interventions to reduce inflammation, as well as selected studies regarding the reduction of risk factors.\u003C\/p\u003E\n         \u003C\/div\u003E\u003Cul class=\u0022kwd-group\u0022\u003E\u003Cli class=\u0022kwd\u0022\u003Einflammatory disease\u003C\/li\u003E\u003Cli class=\u0022kwd\u0022\u003Elipid disorders\u003C\/li\u003E\u003C\/ul\u003E\u003Cdiv class=\u0022section\u0022 id=\u0022sec-1\u0022\u003E\n         \n         \u003Cp id=\u0022p-2\u0022\u003EInflammation plays a critical role in all phases of atherosclerosis, and it is triggered in part by lipid entry and retention and subsequent oxidation in the vessel walls (\u003Ca id=\u0022xref-fig-1-1\u0022 class=\u0022xref-fig\u0022 href=\u0022#F1\u0022\u003EFigure 1\u003C\/a\u003E). However, while lipids are essential, they are not sufficient to stimulate atherosclerosis. Lipids induce inflammation, in part, by activating the innate immune signaling pathway, involving toll-like receptor (TLR) 4 and myeloid differentiation primary response gene 88 (MyD88) [Michelson KS et al. \u003Cem\u003EProc Nat Acad Sci\u003C\/em\u003E 2004].\u003C\/p\u003E\n         \u003Cdiv id=\u0022F1\u0022 class=\u0022fig pos-float  odd\u0022\u003E\u003Cdiv class=\u0022highwire-figure\u0022\u003E\u003Cdiv class=\u0022fig-inline-img-wrapper\u0022\u003E\u003Cdiv class=\u0022fig-inline-img\u0022\u003E\u003Ca href=\u0022http:\/\/d282kpwvnogo5m.cloudfront.net\/content\/spmdc\/10\/2\/25\/F1.large.jpg?width=800\u0026amp;height=600\u0026amp;carousel=1\u0022 title=\u0022Inflammation: A Key Determinant of Plaque Development and Progression\/Stability.\u0022 class=\u0022fragment-images colorbox-load\u0022 rel=\u0022gallery-fragment-images-1827617510\u0022 data-figure-caption=\u0022Inflammation: A Key Determinant of Plaque Development and Progression\/Stability.\u0022 data-icon-position=\u0022\u0022 data-hide-link-title=\u00220\u0022\u003E\u003Cimg class=\u0022fragment-image\u0022 alt=\u0022Figure 1.\u0022 src=\u0022http:\/\/d282kpwvnogo5m.cloudfront.net\/content\/spmdc\/10\/2\/25\/F1.medium.gif\u0022\/\u003E\u003C\/a\u003E\u003C\/div\u003E\u003C\/div\u003E\u003Cul class=\u0022highwire-figure-links inline\u0022\u003E\u003Cli class=\u00220 first\u0022\u003E\u003Ca href=\u0022http:\/\/d282kpwvnogo5m.cloudfront.net\/content\/spmdc\/10\/2\/25\/F1.large.jpg?download=true\u0022 class=\u0022highwire-figure-link highwire-figure-link-download\u0022 title=\u0022Download Figure 1.\u0022 data-icon-position=\u0022\u0022 data-hide-link-title=\u00220\u0022\u003EDownload figure\u003C\/a\u003E\u003C\/li\u003E\u003Cli class=\u00221\u0022\u003E\u003Ca href=\u0022http:\/\/d282kpwvnogo5m.cloudfront.net\/content\/spmdc\/10\/2\/25\/F1.large.jpg\u0022 class=\u0022highwire-figure-link highwire-figure-link-newtab\u0022 target=\u0022_blank\u0022 data-icon-position=\u0022\u0022 data-hide-link-title=\u00220\u0022\u003EOpen in new tab\u003C\/a\u003E\u003C\/li\u003E\u003Cli class=\u00222 last\u0022\u003E\u003Ca href=\u0022\/highwire\/powerpoint\/11218\u0022 class=\u0022highwire-figure-link highwire-figure-link-ppt\u0022 data-icon-position=\u0022\u0022 data-hide-link-title=\u00220\u0022\u003EDownload powerpoint\u003C\/a\u003E\u003C\/li\u003E\u003C\/ul\u003E\u003C\/div\u003E\u003Cdiv class=\u0022fig-caption attrib\u0022\u003E\u003Cspan class=\u0022fig-label\u0022\u003EFigure 1.\u003C\/span\u003E \n               \u003Cp id=\u0022p-3\u0022 class=\u0022first-child\u0022\u003EInflammation: A Key Determinant of Plaque Development and Progression\/Stability.\u003C\/p\u003E\n            \u003Cq class=\u0022attrib\u0022 id=\u0022attrib-1\u0022\u003EReproduced with permission from PK Shah, MD.\u003C\/q\u003E\u003Cdiv class=\u0022sb-div caption-clear\u0022\u003E\u003C\/div\u003E\u003C\/div\u003E\u003C\/div\u003E\n         \u003Cp id=\u0022p-4\u0022\u003EMost of the factors that contribute to plaque instability (eg, increased necrotic lipid core, reduced collagen content, increased cap-inflammation, etc.) are related to lipid accumulation and subsequent inflammatory pathway activation. Changing the phenotype of the atherosclerotic lesions could increase plaque stability and reduce clinical events. Prediman K. Shah, MD, Cedars Sinai Heart Institute, Los Angeles, CA, suggested several interventions to alter the phenotype and thus reduce inflammation: low-density lipoprotein (LDL) lowering, increasing high-density lipoprotein (HDL)-based interventions, and anti-inflammatory and immunomodulatory interventions.\u003C\/p\u003E\n         \u003Cp id=\u0022p-5\u0022\u003ECarotid plaque in patients with symptomatic carotid artery stenosis who received 40 mg\/day pravastatin (n=11) versus no lipid-lowering therapy (n=13) for 3 months before scheduled carotid endarterectomy displayed decreased lipids, lipid oxidation, inflammation, metalloproteinase activity, and cell death and increased tissue inhibitor of metalloproteinase 1 and collagen [Crisby M et al. \u003Cem\u003ECirculation\u003C\/em\u003E 2001]. These data show that statins can change human plaque phenotype in a favorable way.\u003C\/p\u003E\n         \u003Cp id=\u0022p-6\u0022\u003EHaving low HDL is also proinflammatory. Compared with normal individuals, individuals with familial hypoalphalipoproteinemia have increased levels of inflammation, as evidenced by higher hs-CRP levels, particularly if they also have coronary artery disease [Sampietro T et al. \u003Cem\u003ECirculation\u003C\/em\u003E 2002]. Animal studies have shown that plaque lipid content can be dramatically reduced with injections of recombinant HDL (Apo A-I Milano) [Shah PK et al. \u003Cem\u003ECirculation\u003C\/em\u003E 2001] or through gene transfer [Wang L et al. \u003Cem\u003EJ Am Col Cardiol\u003C\/em\u003E 2006]. In humans, infusion with human plasma-derived HDL has been shown to reduce plaque lipid and markers of plaque inflammation in plaques that have been removed from lower extremities and improve the cholesterol efflux-promoting capacity of serum [Shaw J et al. \u003Cem\u003ECirc Res\u003C\/em\u003E 2008].\u003C\/p\u003E\n         \u003Cp id=\u0022p-7\u0022\u003EThe feasibility of immunomodulating therapy for atherosclerosis has been shown in animal models. Immunization with homologous LDL [Ameli S and Shah PK et al. \u003Cem\u003EArterioscler Thromb Vasc Biol\u003C\/em\u003E 1996; Nilsson J and Shah PK et al. \u003Cem\u003EJ Am Col Cardiol\u003C\/em\u003E 1997] or Apo B-100-related peptide sequence [Chyu KY et al. \u003Cem\u003EBiochem Biophys Res Commun\u003C\/em\u003E 2005] has been shown to reduce aortic atherosclerosis. Human studies of Apo B-100-related peptide vaccine are expected to begin in the summer of 2010, pending investigational new drug approval by the United States Food and Drug Administration. Other novel approaches under investigation include inhibition of Lp-PLA2 with darapladib or sPLA2 using varespladib. Both of these compounds are in early human trials.\u003C\/p\u003E\n         \u003Cp id=\u0022p-8\u0022\u003EPoor control of cardiovascular risk factors, especially hyperlipidemia, diabetes mellitus, smoking, and the metabolic profile, alter the Virchow triad (rheology, substrate, and blood), a primary driver of arterial thrombosis. Their effects include worsening vasoconstriction that causes high shear force and increased platelet deposition; increased tissue factor, which leads to thrombin generation; and increased blood coagulability. James H. Chesebro, MD, University of Massachusetts Medical Center, Worcester, MA, provided data from selected studies, showing that the effect of controlling for even a single risk factor can be significant for reducing arterial thrombus formation.\u003C\/p\u003E\n         \u003Cp id=\u0022p-9\u0022\u003EReductions in low-density LDL-C levels dilate coronary arteries and microvessels and reduce endothelial dysfunction, platelet deposition, thrombin generation, arterial thrombus, and macrophage adhesion. Studies that used a Badimon perfusion chamber have shown that the use of statins to lower LDL-C is associated with a significant (p\u0026lt;0.05) reduction in arterial blood thrombogenicity and arterial thrombus formation. Lowering LDL-C from a median of 140 mg\/dL to 105 mg\/dL results in a 20% decrease in arterial thrombus formation [Rauch U et al. \u003Cem\u003EAtherosclerosis\u003C\/em\u003E 2000]. These results are similar to those that were achieved by adding clopidogrel to aspirin (23% decrease in arterial thrombus formation; p\u0026lt;0.05) [Helft G et al. \u003Cem\u003EArterioscler Thromb Vasc Biol\u003C\/em\u003E 2000].\u003C\/p\u003E\n         \u003Cp id=\u0022p-10\u0022\u003EAs shown in the ARMYDA-ACS [Patti G et al. \u003Cem\u003EJ Am Col Cardiol\u003C\/em\u003E 2007] and NAPLES II [Briguori et al \u003Cem\u003EJ Am Col Cardiol\u003C\/em\u003E 2009] trials, acute treatment with statins just prior to percutaneous coronary intervention (PCI) can reduce 30-day major adverse cardiac events. High-dose statin therapy is also associated with a reduction of coronary events, even in patients who are treated only medically (16% MIRACL; 25% A to Z, and 28% PROVE-IT). In the SAGE (Study Assessing Goals in the Elderly) study, which comprised older subjects (aged 65 to 85 years) with acute coronary syndromes, intensive statin therapy was associated with a significant reduction in all-cause death (HR, 0.33; 95% CI, 0.13 to 0.83; p=0.014) compared with moderate therapy, in addition to the reductions in ischemia that were observed with both therapies [Deedwania P et al. \u003Cem\u003ECirculation\u003C\/em\u003E 2007].\u003C\/p\u003E\n         \u003Cp id=\u0022p-11\u0022\u003EControlling diabetes is also an important factor in decreasing thrombotic events. The CD-40 ligand is a mediator and risk marker for inflammation and thrombosis that is increased in individuals with diabetes. The use of insulin-sensitizing thiazolidinediones for controlling diabetes results in a decrease in CD-40 plasma levels and a 29% decrease in thrombotic events [Varo N et al. \u003Cem\u003ECirculation\u003C\/em\u003E 2003].\u003C\/p\u003E\n         \u003Cp id=\u0022p-12\u0022\u003EAs shown by the results of the Diabetes Control and Complications Trial (DCCT)\/Epidemiology of Diabetes Interventions and Complications (EDIC) study, intensive diabetes therapy has long-term beneficial effects on the risk of cardiovascular disease (CVD) in patients with type 1 diabetes. In this study, in which patients were followed for a mean of 17 years, intensive treatment reduced the risk of any CVD event by 42% (95% CI, 0.09 to 0.63; p=0.02) and the risk of nonfatal myocardial infarction (MI), stroke, or death from CVD by 57% (95% CI, 0.12 to 0.79; p=0.02). The decrease in glycosylated hemoglobin values during the DCCT was significantly associated with most of the positive effects of intensive treatment on the risk of CVD [Nathan DM et al. \u003Cem\u003EN Engl J Med\u003C\/em\u003E 2005].\u003C\/p\u003E\n         \u003Cp id=\u0022p-13\u0022\u003EMany patients aged under 60 years who present with acute MI are smokers. Smoking is associated with vasoconstriction, increases in TF in the arterial wall, and increases arterial (platelet-rich) thrombus formation. Just stopping smoking can be very beneficial in reducing future cardiovascular events.\u003C\/p\u003E\n         \u003Cp id=\u0022p-14\u0022\u003E\u201cAggressive risk factor reduction reduces the thrombotic factors of the Virchow triad and clinical events,\u201d said Dr. Chesebro.\u003C\/p\u003E\n      \u003C\/div\u003E\u003Cul class=\u0022copyright-statement\u0022\u003E\u003Cli class=\u0022fn\u0022 id=\u0022copyright-statement-1\u0022\u003E\u00a9 2010 MD Conference Express\u003C\/li\u003E\u003C\/ul\u003E\u003Cspan class=\u0022highwire-journal-article-marker-end\u0022\u003E\u003C\/span\u003E\u003C\/div\u003E\u003Cspan id=\u0022related-urls\u0022\u003E\u003C\/span\u003E\u003C\/div\u003E\u003Ca href=\u0022http:\/\/mdc.sagepub.com\/content\/10\/2\/25.abstract\u0022 class=\u0022hw-link hw-link-article-abstract\u0022 data-icon-position=\u0022\u0022 data-hide-link-title=\u00220\u0022\u003EView Summary\u003C\/a\u003E\u003C\/div\u003E  \u003C\/div\u003E\n\n  \n  \u003C\/div\u003E\n\u003C\/div\u003E\n  \u003C\/div\u003E\n\u003C\/div\u003E\n\u003C\/div\u003E\u003Cscript type=\u0022text\/javascript\u0022 src=\u0022http:\/\/mdc.sagepub.com\/sites\/all\/modules\/highwire\/highwire\/plugins\/highwire_markup_process\/js\/highwire_figures.js?nzmtg2\u0022\u003E\u003C\/script\u003E\n\u003Cscript type=\u0022text\/javascript\u0022 src=\u0022http:\/\/mdc.sagepub.com\/sites\/all\/modules\/highwire\/highwire\/plugins\/highwire_markup_process\/js\/highwire_openurl.js?nzmtg2\u0022\u003E\u003C\/script\u003E\n\u003C\/body\u003E\u003C\/html\u003E"}