Vascular inflammation and low‐density lipoproteins: is cholesterol the link? A lesson from the clinical trials

Abstract

For long time, the role of LDL and inflammation in the pathogenesis of atherosclerosis have been studied independently from each other and only more recently a common platform has been suggested. Accumulation of excess cholesterol due to the presence of increased circulating LDL promotes endothelium dysfunction and activation, which is associated with increased production of pro-inflammatory cytokines, overexpression of adhesion molecules, chemokines and C-reactive protein (CRP), increased generation of reactive oxygen species and reduction of nitric oxide levels and bioavailability. All these processes favour the progressive infiltration of inflammatory cells within the arterial wall where cholesterol accumulates, both extracellularly and intracellularly, and promotes vascular inflammation. According to this, lipid-lowering therapies should improve inflammation and, indeed, statins decrease circulating inflammatory markers such as CRP and improve endothelial function and plaque burden. Pleiotropic activities have been proposed to explain this effect. However, mendelian randomization studies ruled out a direct role for CRP on coronary artery disease and studies with other lipid lowering drugs, such as ezetimibe showed that the beneficial effect of LDL-cholesterol-lowering therapies on systemic inflammatory status, as monitored by changes in CRP plasma levels, could be achieved, independently of the mechanism of action, only in patients presenting with baseline inflamed conditions. These observations strengthen the direct link between cholesterol and inflammation and indicate that decreasing LDL levels is one of the key goals for improving cardiovascular outcome. LINKED ARTICLESThis article is part of a themed section on Targeting Inflammation to Reduce Cardiovascular Disease Risk. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v174.22/issuetoc and http://onlinelibrary.wiley.com/doi/ 10.1111/bcp.v82.4/issuetoc Abbreviations CAD, coronary artery disease; CETP, cholesteryl ester transfer protein; CHD, coronary heart disease; CRP, C-reactive protein; CV, cardiovascular; FMD, flow-mediated dilatation; HMG-CoA, 3-hydroxy-3-methylglutaryl-CoA; hs-CRP, highsensitivity CRP; IVUS, intravascular ultrasound; LDL-C, LDL-cholesterol; LDLR, LDL receptor; Lp(a), lipoprotein(a); NLRP3, nucleotide-binding domain, leucine-rich-containing family, pyrin domain-containing-3; OxLDL, oxidized LDL; PAV, percent atheroma volume; PCSK9, proprotein convertase subtilisin/kexin type 9; SNP, single nucleotide polymorphism; TG, triglycerides; VLDL, very low density lipoprotein IntroductionInflammation and hypercholesterolemia are linked in a vicious cycle in which the excess of cholesterol that accumulates in the arterial wall induces an inflammatory response that, in turn, accelerates cholesterol deposition and amplifies inflammation.The role of LDL and inflammation in the pathogenesis of atherosclerosis have been, for a long time, studied independently from each other and only more recently a...

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