Colchicine treatment early after infarction attenuates myocardial inflammatory response demonstrated by 14C-methionine imaging and subsequent ventricular remodeling by quantitative gated SPECT

Abstract

Objective: Colchicine has been used as an anti-inflammatory agent and may be cardioprotective after acute myocardial infarction (AMI). We investigated how colchicine administration after AMI affects the myocardial inflammatory response using ¹⁴C-methionine and subsequent ventricular remodeling using single-photon emission computed tomography (SPECT) in a rat model of AMI.

Methods: The left coronary artery (LCA) was occluded for 30 min followed by reperfusion. ¹⁴C-methionine was injected at 20 min before sacrifice. The LCA was re-occluded at 1 min before sacrifice and ^99mTc-methoxyisobutylisonitrile (^99mTc-MIBI) was injected. Colchicine was administered intraperitoneally from day 1 to the day before ¹⁴C-methionine injection. Dual-tracer autoradiography of the left ventricular short-axis slices was performed. The methionine uptake ratio in an ischemic area was calculated. ^99mTc-MIBI gated SPECT assessed end-diastolic volume (EDV), end-systolic volume (ESV) and left ventricular ejection fraction (LVEF). On Cluster of Differentiation 68 with 4',6-diamidino-2-phenylindole (CD68/DAPI) staining the positive myocardial cell percentage in an ischemic area was calculated.

Results: In control rats, ¹⁴C-methionine uptake ratios on day 3 and 7 were 1.87 ± 0.15 and 1.39 ± 0.12, respectively. With colchicine, the uptake was reduced on days 3 (1.56 ± 0.26, p = 0.042) and 7 (1.23 ± 0.10, p = 0.030). Colchicine treated rats showed smaller EDV, ESV, and higher LVEF compared with control rats. At 8 weeks, those in control rats were 864 ± 115 μL, 620 ± 100 μL, 28.4 ± 2.5%, and in colchicine rats 665 ± 75 μL, 390 ± 97 μL, 42.2 ± 8.5% (p = 0.012, 0.0061, 0.0083), respectively. In control rats, CD68/DAPI positive myocardial cell percentages on days 3 and 7 were 38.4 ± 1.9% and 24.0 ± 2.4%, respectively. With colchicine, the percentages were reduced significantly on both days 3 (31.5 ± 2.0%, p < 0.0001) and 7 (12.0 ± 1.6%, p < 0.0001) as compared with the control.

Conclusions: Short-term colchicine treatment after AMI attenuated the post-AMI inflammatory response and subsequent ventricular remodeling and dysfunction. ¹⁴C-methionine imaging and gated ^99mTc-MIBI SPECT would be feasible to monitor the effectiveness of anti-inflammatory therapy and left ventricular function.

Keywords: 99mTc-MIBI; Macrophage; Methionine; Myocardial infarction; SPECT.