Abstract 4366003: Anti-inflammatory effects of colchicine after myocardial infarction

Abstract

Background: The molecular mechanisms underlying colchicine’s benefits after myocardial infarction (MI) remain unclear. This study aimed to investigate the impact of colchicine on the plasma proteome. Methods: Plasma samples were collected from a subset of 203 COLCOT trial participants at baseline and at six months. Proteomic profiling was performed using a targeted multiple-reaction monitoring mass spectrometry assay, while inflammatory biomarkers were quantified using electrochemiluminescence-based multiplex and enzyme-linked immunosorbent assays. The changes from baseline to six months were analyzed using analysis of covariance models adjusted for baseline values either using the original data or log-transformed data, depending on the distribution. The mean percentage reductions by colchicine are presented for in vitro assays and the logarithm of the ratio of LPS+colchicine/LPS were tested against zero. Results: Reductions in the plasma concentrations of interleukin-12p70 (IL-12p70), IL-12/IL-23p40 (p40) subunit, IFN-γ, and IL-17A were observed in the colchicine group compared with the placebo group (adjusted geometric mean % changes of -42.8% vs. 0.4%, p = 0.007 for IL-12p70 and -23.7% vs. -4.1%, p = 0.053 for IFN-γ; adjusted mean changes of -12.8 pg/ml vs. 7.5 pg/ml, p = 0.003 for IL-12/IL-23p40 and -2.1 pg/ml vs. 0.2 pg/ml, p = 0.038 for IL-17A). Decreases over time in plasma IL-6 and IL-1α concentrations also occurred in the colchicine group compared with placebo (adjusted geometric mean % changes of -51.1% vs. -40.8%, p = 0.055 and -18.9% vs. 7.6%, p = 0.052, respectively). These effects were supported by in vitro assays that demonstrated colchicine-induced reductions of secretion of IL-12 (-41.8%, p=0.023), IL-23 (-21.0%, p=0.014) and IL-6 (-46.7%, p<0.001) by lipopolysaccharide-stimulated THP-1 macrophages. The proteomic panel showed that colchicine, compared with placebo, reduced additional inflammation-related biomarkers including alpha-1-acid glycoprotein, complement factor D and lysozyme C (adjusted geometric mean % changes of -35.6% vs. -28.1%, p = 0.026; -13.2% vs. -0.2%, p = 0.020; and -10.8% vs. -3.3%, p = 0.041, respectively). Conclusions: Low-dose colchicine treatment after MI substantially reduced IL-12 and IL-23 signaling, suggesting important effects on Th1 and Th17 inflammatory pathways. The effects of colchicine on IL-6 and IL-1α also demonstrate its effects on NLRP3 inflammasome activity.