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.

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Our findings suggest, for the first time, that low-dose colchicine therapy favorably modifies coronary plaque, independent of high-dose statin intensification therapy and substantial low-density lipoprotein reduction. The improvements in plaque morphology are likely driven by the anti-inflammatory properties of colchicine, as demonstrated by reductions in hsCRP, rather than changes in lipoproteins. Colchicine may be beneficial as an additional secondary prevention agent in patients post-ACS if validated in future studies.

Rationale: Inflammasome activation, with subsequent release of pro-inflammatory cytokines IL-1β and IL-18, has recently been implicated in atherosclerosis-associated inflammation.Objective: To assess in acute coronary syndrome (ACS) patients (1) inflammasome activation in circulating monocytes and (2) whether short-term oral colchicine, a recognised anti-inflammatory agent that has been shown to be cardio-protective in clinical studies, might acutely suppress inflammasome-dependent inflammation. Methods and Results:ACS patients (n=21) were randomised to oral colchicine (1 mg followed by 0.5 mg 1 hour later) or no treatment, and compared with untreated healthy controls (n=9). Peripheral venous blood was sampled pre-(day 1) and 24 hours 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 to controls but only with ATP stimulation. Untreated ACS patients secreted significantly higher levels of IL-18 vs healthy controls independent of ATP stimulation (p< 0.05). Colchicine treatment in ACS patients markedly reduced intracellular and secreted levels of IL-1β vs 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 % vs untreated patients (p<0.05 for both). Conclusions: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. SUMMARY STATEMENTInflammasome activation in monocytes is elevated in ACS patients versus healthy subjects.Acute colchicine therapy dramatically suppresses this activation, via inhibition of caspase-1 gene transcription leading to reduced secretion of IL-1β, supporting a beneficial role for colchicine in atherosclerosis.

Dysglycemia, in this survey defined as impaired glucose tolerance (IGT) or type 2 diabetes, is common in patients with coronary artery disease (CAD) and associated with an unfavorable prognosis. This European survey investigated dysglycemia screening and risk factor management of patients with CAD in relation to standards of European guidelines for cardiovascular subjects. RESEARCH DESIGN AND METHODS The European Society of Cardiology's European Observational Research Programme (ESC EORP) European Action on Secondary and Primary Prevention by Intervention to Reduce Events (EUROASPIRE) V (2016-2017) included 8,261 CAD patients, aged 18-80 years, from 27 countries. If the glycemic state was unknown, patients underwent an oral glucose tolerance test (OGTT) and measurement of glycated hemoglobin A 1c. Lifestyle, risk factors, and pharmacological management were investigated. RESULTS A total of 2,452 patients (29.7%) had known diabetes. OGTT was performed in 4,440 patients with unknown glycemic state, of whom 41.1% were dysglycemic. Without the OGTT, 30% of patients with type 2 diabetes and 70% of those with IGT would not have been detected. The presence of dysglycemia almost doubled from that selfreported to the true proportion after screening. Only approximately one-third of all coronary patients had completely normal glucose metabolism. Of patients with known diabetes, 31% had been advised to attend a diabetes clinic, and only 24% attended. Only 58% of dysglycemic patients were prescribed all cardioprotective drugs, and use of sodium-glucose cotransporter 2 inhibitors (3%) or glucagon-like peptide 1 receptor agonists (1%) was small. CONCLUSIONS Urgent action is required for both screening and management of patients with CAD and dysglycemia, in the expectation of a substantial reduction in risk of further cardiovascular events and in complications of diabetes, as well as longer life expectancy.

SummaryCirculating tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL) levels are reduced in patients with cardiovascular disease, and TRAIL gene deletion in mice exacerbates atherosclerosis and inflammation. How TRAIL protects against atherosclerosis and why levels are reduced in disease is unknown. Here, multiple strategies were used to identify the protective source of TRAIL and its mechanism(s) of action. Samples from patients with coronary artery disease and bone-marrow transplantation experiments in mice lacking TRAIL revealed monocytes/macrophages as the main protective source. Accordingly, deletion of TRAIL caused a more inflammatory macrophage with reduced migration, displaying impaired reverse cholesterol efflux and efferocytosis. Furthermore, interleukin (IL)-18, commonly increased in plasma of patients with cardiovascular disease, negatively regulated TRAIL transcription and gene expression, revealing an IL-18-TRAIL axis. These findings demonstrate that TRAIL is protective of atherosclerosis by modulating monocyte/macrophage phenotype and function. Manipulating TRAIL levels in these cells highlights a different therapeutic avenue in the treatment of cardiovascular disease.

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.

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