| Background and PurposeThe atherosclerotic plaque that has a potential risk to rupture or erosion withsuperimposed atherothrombosis is defined as vulnerable plaque, which may causesevere clinical sequelae such as myocardial and cerebral infarctions. The rationalinterventions of this atherosclerotic disease underscore the importance ofameliorating plaque vulnerability. Currently, the inflammatory state has been wellrecognized as a determinant of plaque vulnerability. Overwhelming majority ofinflammatory cells infiltrate into the plaque core—especially macrophages—makingfocal metabolism over-active and plaque propensity to rupture.Pioglitazone, an activation of the Peroxisome Proliferator-Activated Receptor-γ(PPAR-γ), is the most widely used thiazolidinedione. Beyond its insulin sensitizingeffect, recently, more and more studies have shed light on its cardioprotective effectsand anti-atherosclerosis properties. However, the question remains whetherpioglitazone can decrease plaque rupture and thrombosis formation through plaquestabilization, and therefore reduce incidence of cardio-cerebrovascular events. In thisstudy, we established an atherosclerotic rabbit model by a high cholesterol diet andendothelial denudation, with pioglitazone served as medicine intervention, andperformed pharmacological triggering to induce plaque rupture and thrombosisformation. Multi-modality imaging technique—18F-fluorodeoxyglucose positronemission tomography/computed tomography (18F-FDG PET/CT) was utilized todynamically monitor and evaluate the inflammatory changes in atherosclerotic plaqueunder pioglitazone intervention. Plaque morphology, macrophages and neovesselswere analyzed by standard histopathology and immunohistochemistry techniques. Bycomparing PET/CT parameters and histopathological results between pioglitazoneintervention group and control group, we aimed at investigating the feasibility of PET/CT in monitoring the therapeutic effect of pioglitazone on plaque inflammation,and clarifying the underlying mechanisms of pioglitazone on reducing plaquevulnerability.Methods20male New Zealand white rabbits were randomly divided into2groups:pioglitazone intervention group (Group A, n=10) and control group (Group B, n=10).Atherosclerosis was induced in all rabbits by intermittent high-cholesterol diet andendothelial denudation. From the very beginning, rabbits in group A receivedpioglitazone (10mg·kg-1·d-1) in addition to the diet, till the end of the experiment. Allsurvival rabbits at18wks underwent2pharmacological triggerings to induce plaquerupture. Serum samples were obtained at8wks and18wks for analysis of glucose,cholesterol, triglycerides, insulin, hs-CRP and MMP-9concentration.17rabbitsunderwent mid-stage PET/CT scan at8wks, whereas15rabbits underwent end-stagePET/CT scan at18wks before pharmacological triggering. Concomitantly, PET/CTparameters—SUVmean （mean standardized uptake value）and SUVmax（maxstandardized uptake value）—were measured and documented. After pharmacologicaltriggering, all rabbits were euthanatized, and aortic histopathological analysis andcorrelation analysis were performed.ResultsSerum samples analysis showed both a lower MMP-9concentration inpioglitazone group at8wks (2.25±0.11vs.2.60±0.19, p=0.040) and18wks (2.27±1.17vs.2.70±0.37, p=0.010). In pioglitazone intervention group, the SUVmean andSUVmax documented at mid-stage were0.665±0.076and0.850±0.072respectively,and at end-stage were0.492±0.116and0.612±0.082respectively. In control group,the SUVmean and SUVmax documented at mid-stage were0.800±0.084and0.997±0.065respectively, and at end-stage were1.033±0.621and1.335±0.113respectively. The PET/CT scan parameters revealed a decline in SUVmean andSUVmax at18wks in pioglitazone intervention group (p=0.020and0.004,respectively), indicating no progressive inflammation, whereas increasing SUVmeanand SUVmax were observed in control group (p=0.004and0.005, respectively), indicating progressive inflammation. The mid-stage imaging showed a higherSUVmean and SUVmax in control group (p=0.073and0.023, respectively) withrespect to pioglitazone intervention group, despite no statistical difference inSUVmean. And the end-stage imaging showed an obviously higher SUVmean andSUVmax in control group (p=0.000and0.000, respectively) with respect topioglitazone intervention group, indicating the anti-inflammatory effect bypioglitazone was initiated at the mid-stage, maintained and strengthened till theend-stage. Histopathological examination demonstrated a significant decrease inplaque rupture and thrombosis in pioglitazone intervention group by chi-square test(χ2=9.862, p=0.002). Morphological assay showed plaque area was quite smaller inpioglitazone intervention group than control group (0.029±0.018vs.0.186±0.093，p=0.033), Besides, macrophages (8.800±3.936vs.30.130±4.188) and neovessels(80.267±13.094vs.162.637±73.112) were also markedly reduced (p=0.003and0.022,respectively) in pioglitazone intervention group compared with control group. Strongpositive correlations between SUVmean and plaque area, SUVmax and plaque area,SUVmean and macrophages, and between SUVmax and macrophages were observed(r=0.863，p=0.000; r=0.793，p=0.000; r=0.564，p=0.001and r=0.550，p=0.001,respectively), whereas no correlations between SUVmean and neovessels or betweenSUVmax and neovessels (r=-0.081，p=0.687and r=-0.156，p=0.438) were detected.ConclusionsPioglitazone can decrease the incidence of plaque rupture and attenuate plaquevulnerability by ways of modulating vascular inflammation and inhibitinginflammatory progression. PET/CT, as a non-invasive, multi-modality imagingtechnique, seems capable of monitoring inflammation in atherosclerosis underpioglitazone intervention. |
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