Colchicine treatment after severe ischemia and reperfusion attenuates myocardial inflammatory response demonstrated by C-14-methionine imaging and subsequent ventricular remodeling

Objectives: Colchicine is a substance with pleiotropic anti-inflammatory effect and has been usually used for treatment and prevention of gouty attacks in daily clinical practice. The medicine is reported to reduce inflammatory cytokines and this anti-inflammatory effect might be cardioprotective after acute myocardial infarction. This study aimed to explore how colchicine administration after reperfusion affects myocardial inflammatory response using C-14-methionine as an inflammatory marker and subsequent ventricular dimention and function measured by gated SPECT in a rat model of severe ischemia and reperfusion.

Methods: The left coronary artery was occluded for 30 min followed by reperfusion. In control rats, 3 and 7 days after reperfusion, C-14-methionine (0.74 MBq) was injected 20 min before sacrifice. One min before sacrifice the left coronary artery was re-occluded and Tc-99m-MIBI was injected to verify the area at risk. In rat with colchicine, 0.4 mg/kg/day of colchicine was intraperitoneally administered every day from 1 day after reperfusion to the day before methionine injection (Day 3 and day 7). Dual-tracer autoradiography of the left ventricular short axis slices was performed. The first autoradiographic exposure on an imaging plate was performed for 15-20 min to visualize the area at risk expressed by Tc-99m-MIBI distribution. Three days later the second exposure was made for 1-2 weeks to visualize the methionine uptake. The methionine uptake ratio in an ischemic area was calculated by dividing the count density in an ischemic area by that of a normally perfused area. For the analysis of ventricular function, gated Tc-99-m-MIBI SPECT was performed at 2, 4, and 8 weeks after reperfusion in both control (n=5) and colchicine treatment (n=5) rats (colchicine was administered daily from day1 to 6 after reperfusion). A QGS software algorithm was used to assess end diastolic volume (EDV), end systolic volume (ESV) and left ventricular ejection fraction (LVEF).

Results: In control rats (n=12), methionine uptake ratios at day 3 and 7 were 1.85 ± 0.15 and 1.38 ± 0.13, respectively. With colchicine (n=12), methionine uptake was reduced significantly at both day 3 (1.59 ± 0.24, p< 0.05) and at day 7 (1.25 ± 0.098, p< 0.05). In colchicine, uptake area of methionine to area at risk was similar to control at day 3 (0.67 ± 0.077 (control) vs 0.65 ± 0.048 (with colchicine), p = ns) and at day7 (0.57 ± 0.15 (control) vs 0.58 ± 0.048 (colchicine), p = ns). Compared with control rats, colchicine treatment rats showed more smaller EDV, ESV, and higher EF, however, statistically significant in only at 8 weeks. At 2 weeks, EDV (μL), ESV (μL), LVEF (%) in control rats were 632 ± 120, 385 ± 116, 40.2 ± 7.4 and those in colchicine rats were 485 ± 45, 266 ± 48, 45.4 ± 6.2 (p = 0.07, 0.11, 0.31), respectively. At 4 weeks, those in control rats were 686 ± 118, 452 ± 96, 34.2 ± 5.6 and those in colchicine rats were 585 ± 77, 360 ± 76, 38.8 ± 7.1 (p = 0.20, 0.17, 0.34), respectively. At 8 weeks, those in control rats were 864 ± 103, 620 ± 90, 28.4 ± 2.2, and those in colchicine rats were 665 ± 67, 390 ± 87, 42.2 ± 7.6 (p = 0.015, 0.0061, 0.020), respectively.

Conclusions: Administration of colchicine after severe ischemia and reperfusion attenuated methionine uptake both at day 3 and day 7, and attenuated ventricular remodeling at 8 weeks after reperfusion. The result suggested that, after myocardial infarction, colchicine treatment early after infarction suppressed inflammatory response and subsequent excessive ventricular remodeling. It is concluded that methionine imaging and gated perfusion SPECT would be feasible to monitor the effectiveness of the anti-inflammatory therapy and ventricular function after acute myocardial infarction.