Pioglitazone Modulates Vascular Inflammation in Atherosclerotic Rabbits

Abstract

Objectives We sought to determine the anti-atherosclerotic properties of pioglitazone using multi-modality non-invasive imaging techniques. Background Inflammation is an essential component of vulnerable or high risk atheromas. Pioglitazone, a peroxisome proliferator–activated receptor-gamma (PPAR-γ)agonist possesses potent anti-inflammatory properties. We aimed to non-invasively to quantify the anti-inflammatory effects of pioglitazone on atheroma using 18F-fluorodeoxyglucose (18F-FDG)-PET/CT and dynamic contrast enhanced MRI (DCE-MRI). Methods Atherosclerotic plaques were induced in the aorta of fifteen New Zealand White (NZW) rabbits by a combination of hyperlipidemic diet and two balloon endothelial denudations. Nine rabbits continued the same diet whereas six received pioglitazone (10mg/kg orally) in addition to the diet. Twelve animals underwent 18F-FDG-PET/CT and fifteen animals underwent DCE-MRI at baseline, one and three months after treatment initiation. Concomitantly, serum metabolic parameters were monitored. After imaging was completed aortic histological analysis and correlation analysis was performed. Results 18F-FDG-PET/CT detected an increase in average standardized uptake value (SUV) in the control group (p<0.01), indicating progressive inflammation, while stable SUV values were observed in the treatment group, indicating no progression. DCE-MRI detected a significant decrease in area under the curve (AUC) for the pioglitazone group (p<0.01). Immunohistology of the aortas demonstrated a significant decrease in macrophage and oxidized phospholipid immunoreactivity in the pioglitazone group (p=0.04 and p=0.01, respectively) with respect to control animals, underlining the imaging results. Serum metabolic parameters showed no difference between groups. A strong positive correlation between SUV and macrophage density and AUC and neovessels was detected ( r2=0.86, p<0.0001 and r2=0.66, p=0.004, respectively). Conclusions 18F-FDG-PET/CT and DCE-MRI demonstrate non-invasively the anti-inflammatory effects of pioglitazone on atheroma. Both imaging modalities appear suited to monitor inflammation in atherosclerosis.

The Advancing Clinical Impact of Molecular Imaging in CVD

“…Notably each group showed similar reductions in fasting plasma glucose and hemoglobin A1c levels. This study extends prior preclinical imaging evidence of decreased inflammation observed with pioglitazone (9,10) and may underlie the favorable clinical and ultrasound imaging results observed in the PROactive, CHICAGO, and PERISCOPE clinical trials.…”

The complementary roles of dynamic contrast-enhanced MRI and 18F-fluorodeoxyglucose PET/CT for imaging of carotid atherosclerosis

“…Kinetic parameters v p (fraction of vascular space), K trans (wash-in constant from plasma to tissue compartment), v e (fraction of extra-vascular extracellular space), and K ep (wash-out constant from tissue to plasma compartment) were calculated using standard non-linear least squares fittings (22) in Matlab. The non-model based parameter area under the concentration curve (AUC) (6,10–12) was also calculated at 1 (AUC1) and 2 minutes (AUC2) after injection of contrast agent (6) (Fig. 1).…”

Imaging the Permeable Endothelium

“…Using this same acquisition K trans was found to decrease in the carotid arteries of patients treated with statins 8 . In a rabbit model of atherosclerosis, the non-modeling parameter AUC calculated from 2D turbo spin echo (TSE) DCE-MRI was found to significantly correlate with plaque microvessel density 9–11 . Furthermore, DCE-MRI was used in this same model to quantify therapeutic efficacy of several FDA approved (atorvastatin 10 , pioglitazone 11 ) and novel therapeutics (liposome encapsulated glucocorticoids, liver-X-receptor agonists 10 ).…”

“…In a rabbit model of atherosclerosis, the non-modeling parameter AUC calculated from 2D turbo spin echo (TSE) DCE-MRI was found to significantly correlate with plaque microvessel density 9–11 . Furthermore, DCE-MRI was used in this same model to quantify therapeutic efficacy of several FDA approved (atorvastatin 10 , pioglitazone 11 ) and novel therapeutics (liposome encapsulated glucocorticoids, liver-X-receptor agonists 10 ). In the same model 12 K trans was demonstrated to increase during plaque progression, and to significantly correlate with plaque macrophages.…”