Background: Interleukin ( 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 NLRP 3 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 Results: Forty 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). Conclusions: ACS patients exhibit increased local cardiac production of inflammatory cytokines. Short‐term colchicine administration rapidly and significantly reduces levels of these cytokines.

Inflammasome activation, with subsequent release of pro-inflammatory cytokines interleukin-1β (IL-1β) and IL-18, has recently been implicated in atherosclerosis-associated inflammation. This study aims to assess in acute coronary syndrome (ACS) patients (1) inflammasome activation in circulating monocytes and (2) whether short-term oral colchicine, a recognized anti-inflammatory agent that has been shown to be cardio-protective in clinical studies, might acutely suppress inflammasome-dependent inflammation. ACS patients (n=21) were randomized to oral colchicine (1 mg followed by 0.5 mg 1 h later) or no treatment, and compared with untreated healthy controls (n=9). Peripheral venous blood was sampled pre- (day 1) and 24 h post- (day 2) treatment. Monocytes were cultured and stimulated with ATP. Analysis of key inflammasome markers was performed by ELISA. IL-1β secretion increased by 580.4% (P<0.01) in ACS patients compared with controls but only with ATP stimulation. Untreated ACS patients secreted significantly higher levels of IL-18 compared with healthy controls independent of ATP stimulation (P<0.05). Colchicine treatment in ACS patients markedly reduced intracellular and secreted levels of IL-1β compared with pre-treatment levels (P<0.05 for both), as well as significantly reducing pro-caspase-1 mRNA levels by 57.7% and secreted caspase-1 protein levels by 30.2% compared with untreated patients (P<0.05 for both). Monocytes from ACS patients are ‘primed’ to secrete inflammasome-related cytokines and short-term colchicine acutely and markedly suppresses monocyte caspase-1 activity, thereby reducing monocyte secretion of IL-1β.

Background: Release of neutrophil extracellular traps (NETs) after percutaneous coronary intervention (PCI) in acute coronary syndrome (ACS) is associated with periprocedural myocardial infarction, as a result of microvascular obstruction via pro‐inflammatory and prothrombotic pathways. Colchicine is a well‐established anti‐inflammatory agent with growing evidence to support use in patients with coronary disease. However, its effects on post‐PCI NET formation in ACS have not been explored. Methods and Results: Sixty patients (40 ACS; 20 stable angina pectoris) were prospectively recruited and allocated to colchicine or no treatment. Within 24 hours of treatment, serial coronary sinus blood samples were collected during PCI. Isolated neutrophils from 10 patients with ACS post‐PCI and 4 healthy controls were treated in vitro with colchicine (25 nmol/L) and stimulated with either ionomycin (5 μmol/L) or phorbol 12‐myristate 13‐acetate (50 nmol/L). Extracellular DNA was quantified using Sytox Green and fixed cells were stained with Hoechst 3342 and anti‐alpha tubulin. Baseline characteristics were similar across both treatment and control arms. Patients with ACS had higher NET release versus patients with stable angina pectoris ( P <0.001), which was reduced with colchicine treatment (area under the curve: 0.58 versus 4.29; P <0.001). In vitro, colchicine suppressed unstimulated ( P <0.001), phorbol 12‐myristate 13‐acetate–induced ( P =0.009) and ionomycin‐induced ( P =0.002) NET formation in neutrophils isolated from patients with ACS post‐PCI, but not healthy controls. Tubulin organization was impaired in neutrophils from patients with ACS but was restored by colchicine treatment. Conclusions: Colchicine suppresses NET formation in patients with ACS post‐PCI by restoring cytoskeletal dynamics. These findings warrant further investigation in randomized trials powered for clinical end points. Registration: URL: https://anzctr.org.au ; Unique identifier: ACTRN12619001231134.