Pioglitazone Modulates Vascular Inflammation in Atherosclerotic Rabbits

• Published in: JACC. Cardiovascular imaging Vol. 4; no. 10; pp. 1100 - 1109
• Main Authors: Vucic, Esad, MD, Dickson, Stephen D., MS, Calcagno, Claudia, MD, PhD, Rudd, James H.F., MD, PhD, Moshier, Erin, MS, Hayashi, Katsumi, MD, Mounessa, Jessica S., BS, Roytman, Michelle, BS, Moon, Matthew J., BS, Lin, James, MS, Tsimikas, Sotirios, MD, Fisher, Edward A., MD, PhD, Nicolay, Klaas, PhD, Fuster, Valentin, MD, PhD, Fayad, Zahi A., PhD
• Format: Journal Article
• Language: English
• Published: 01.10.2011
• Subjects: Cardiovascular; dynamic contrast-enhanced magnetic resonance imaging; AUC 2 min; magnetic resonance imaging; area under the curve quantified at 1 minute; MRI; SUV max; FDG; arbitrary unit; AUC; AUC 1 min; inflammation; 18F-fluorodeoxyglucose positron emission tomography/computed tomography; SUV mean; mean standard uptake value; PPAR-γ; atherosclerosis; computed tomography; DCE; standard uptake value; dynamic contrast-enhanced; area under the curve; fluorodeoxyglucose; CT; maximal standard uptake value; pioglitazone; AU; SUV; area under the curve quantified at 2 minutes; positron emission tomography; peroxisome proliferator-activated receptor gamma; PET
• ISSN: 1936-878X
• DOI: 10.1016/j.jcmg.2011.04.020

Objectives We sought to determine the antiatherosclerotic properties of pioglitazone using multimethod noninvasive imaging techniques. Background Inflammation is an essential component of vulnerable or high-risk atheromas. Pioglitazone, a peroxisome proliferator-activated receptor-gamma agonist, possesses potent anti-inflammatory properties. We aimed to quantify noninvasively the anti-inflammatory effects of pioglitazone on atheroma using18 F-fluorodeoxyglucose (18 F-FDG) positron emission tomography (PET)/computed tomography (CT) and dynamic contrast-enhanced (DCE) magnetic resonance imaging (MRI). Methods Atherosclerotic plaques were induced in the aorta of 15 New Zealand white rabbits by a combination of a hyperlipidemic diet and 2 balloon endothelial denudations. Nine rabbits continued the same diet, whereas 6 rabbits received pioglitazone (10 mg/kg orally) in addition to the diet. Twelve animals underwent18 F-FDG-PET/CT, and 15 animals underwent DCE-MRI at baseline, 1 month, and 3 months after treatment initiation. Concomitantly, serum metabolic parameters were monitored. After imaging was completed, aortic histologic analysis and correlation analysis were performed. Results The18 F-FDG-PET/CT imaging detected an increase in average standardized uptake value in the control group (p < 0.01), indicating progressive inflammation, whereas stable standardized uptake values were observed in the treatment group, indicating no progression. The DCE-MRI analysis detected a significant decrease in the area under the curve for the pioglitazone group (p < 0.01). Immunohistologic examination 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. Strong positive correlations between standardized uptake value and macrophage density and between area under the curve and neovessels were detected ( r2 = 0.86 and p < 0.0001, and r2 = 0.66 and p = 0.004, respectively). Conclusions Both18 F-FDG-PET/CT and DCE-MRI demonstrate noninvasively the anti-inflammatory effects of pioglitazone on atheroma. Both imaging methods seem suited to monitor inflammation in atherosclerosis.