Abstract
BACKGROUND: The molecular mechanisms of protective effect of metformin (Met) on ischemic myocardium have not been fully understood. This study aims to evaluate the cardioprotective effect of metformin on myocardial ischemia-reperfusion injury (MIRI) in rat models at different time points using dynamic (18)F-FDG micro-PET/CT imaging. METHODS: The I/R injury model in SD rats was established by ligation of left anterior descending coronary artery near the pulmonary arch root for 30 min. SD rats (n = 12) were randomly divided into 2 groups: Control group (n = 6) without any intervention and Met group (n = 6) with oral administration of metformin (50 mg/kg) twice a day. Gated (18)F-FDG (40Mbq) micro-PET/CT imaging was performed for 10 min at different time points (day 1st, day 7th, day 14th and day 30th after operation). Volumes of interest were drawn to identify different myocardium regions (ischemia center, peri-ischemia area and remote area). Standardized uptake values (SUVs) (SUV(mean) and SUV(max)) were analyzed to evaluate the FDG uptake activity, and then the center/remote ratio was calculated. In addition, the left ventricular (LV) end-diastolic volume (EDV), end-systolic volume (ESV) and LV ejection fraction (LVEF) were obtained. On the 30th day, all rats were scarified and myocardial ischemia was analyzed by HE staining and confirmed by pathology. RESULTS: In the Control group, the center/remote ratio showed no obvious change trend at each time point after reperfusion, while the LV EDV increased gradually over time, and they were significantly negatively correlated (r = - 0.507, p < 0.05). In the Met group, the center/remote ratio gradually increased with time, there was no significant correlation between center/remote ratio and LV EDV (r = - 0.078, p > 0.05). On the 30th day, the center/remote ratio of the Met group was significantly higher than that of the Control group (0.81 ± 0.06 vs. 0.65 ± 0.09, p < 0.05), while LV EDV in Met group was significantly lower than in Control group (358.21 ± 22.62 vs. 457.53 ± 29.91, p < 0.05). There was no significant difference of LVEF between Met group and Control group at different time points after reperfusion (p < 0.05). HE staining showed that the myocardial infarction and fibrosis in ischemic center area of the Control group was more serious than that of the Met group. CONCLUSIONS: Met could attenuate the severity of MIRI, delay and prevent the progress of LV remodeling. The cardioprotective progress could be dynamically assessed by (18)F-FDG micro-PET/CT imaging.