Colchicine Acutely Suppresses Local Cardiac Production of Inflammatory Cytokines in Patients With an Acute Coronary Syndrome

Abstract

BackgroundInterleukin (IL)-1β, IL-18, and downstream IL-6 are key inflammatory cytokines in the pathogenesis of coronary artery disease. Colchicine is believed to block the NLRP3 inflammasome, a cytosolic complex responsible for the production of IL-1β and IL-18. In vivo effects of colchicine on cardiac cytokine release have not been previously studied. This study aimed to (1) assess the local cardiac production of inflammatory cytokines in patients with acute coronary syndromes (ACS), stable coronary artery disease and in controls; and (2) determine whether acute administration of colchicine inhibits their production.Methods and ResultsForty ACS patients, 33 with stable coronary artery disease, and 10 controls, were included. ACS and stable coronary artery disease patients were randomized to oral colchicine treatment (1 mg followed by 0.5 mg 1 hour later) or no colchicine, 6 to 24 hours prior to cardiac catheterization. Blood samples from the coronary sinus, aortic root (arterial), and lower right atrium (venous) were collected and tested for IL-1β, IL-18, and IL-6 using ELISA. In ACS patients, coronary sinus levels of IL-1β, IL-18, and IL-6 were significantly higher than arterial and venous levels (P=0.017, <0.001 and <0.001, respectively). Transcoronary (coronary sinus-arterial) gradients for IL-1β, IL-18, and IL-6 were highest in ACS patients and lowest in controls (P=0.077, 0.033, and 0.014, respectively). Colchicine administration significantly reduced transcoronary gradients of all 3 cytokines in ACS patients by 40% to 88% (P=0.028, 0.032, and 0.032, for IL-1β, IL-18, and IL-6, respectively).ConclusionsACS patients exhibit increased local cardiac production of inflammatory cytokines. Short-term colchicine administration rapidly and significantly reduces levels of these cytokines.

Colchicine therapy in acute coronary syndrome patients acts on caspase-1 to suppress NLRP3 inflammasome monocyte activation

“…A corresponding decrease in pro-IL-1β mRNA was not observed, thus suggesting colchicine does not alter gene transcription of IL-1β and reduction in protein levels is due to a post-translational cleavage. Such findings are at least partially consistent with our previous study, where coronary levels of IL-1β and IL-18 were significantly reduced by colchicine therapy (15). In this study, the less marked effect on IL-18 secretion can be explained by the fact that IL-18 might also be secreted by non-monocyte resident cells in the vessel wall or other circulating leucocytes, on which colchicine could also inhibit, in contrast, the reduction in IL-1 secretion into the coronary circulation can be attributed, at least partly, to the action of colchicine on monocyte activation.…”

“…In this environment, ATP (the second stimulus required for complete inflammasome activation) might be secreted by inflammatory cells or aggregated platelets (26), alternatively it might be released from activated monocytes, leading to autocrine activation of the P2X7 receptor (27). We have previously shown release of inflammasome-related cytokines in the coronary circulation in ACS patients, supporting the concept of complete inflammasome activation in vivo (15).…”

“…For example, IL-1β deficient mice are characterised by reduced atherosclerotic lesions (13), while IL-1β infusions in Apo E -/-mice enhances aortic plaque development (14). Moreover, we have recently shown, in ACS patients, that trans-coronary IL-1β and IL-18 levels strongly correlate with disease activity (15).…”

Colchicine Improves Survival, Left Ventricular Remodeling, and Chronic Cardiac Function After Acute Myocardial Infarction

“…12, 13 In this study, colchicine tended to reduce the serum level of hs-cTnI at 24 h after MI, but this was not significantly different compared with the vehicle group. A previous study using a canine ischemia and reperfusion injury model concluded no myocardial protective effect of colchicine was observed, despite a reduction in neutrophil reactive oxygen species and accumulation in the myocardium.…”

“…11 Colchicine was reported to reduce inflammatory cytokines (including IL-1β and IL-18) and infarction size in MI. 12, 13 However, the sustained benefit of short-term colchicine treatment on survival, cardiac function, and ventricular remodeling after MI is unknown.…”