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.

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.

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.

Objective To assess the influence of the trajectory of weight gain from birth to adolescence on cardiovascular and metabolic risk. We studied childhood body mass index (BMI) trajectories from birth to age 14 years and cardiometabolic risk factors at age 14 years. Study design In total, 410 children with weight and height measurements were assessed from birth throughout childhood, from the Childhood Asthma Prevention Study, a prospective community-based cohort. BMI trajectory groups were determined by latent basis growth mixture models. Of these subjects, 190 had detailed cardiometabolic risk factors assessed at age 14 years. Results Three BMI trajectory groups were identified; normal BMI, "early rising" excess BMI from 2 years, and "late rising" excess BMI from 5 years. Differences were found between normal and excess BMI in children at 14 years of age. In addition, children with an early rising BMI trajectory had statistically significantly higher central adiposity and a more atherogenic lipoprotein profile at age 14 years than children with a late rising BMI trajectory (P < .05). No differences between BMI trajectory groups in vascular structure or function was identified at age 14 years. Conclusions Earlier onset of an elevated BMI trajectory persisting from birth to age 14 years results in an unfavorable cardiometabolic risk profile at age 14 years, including central adiposity and more atherogenic lipoproteins, independent of achieved BMI.

period, hazard ratios were 1-26 (0.49 to 3.26) and 0*85 (0.41 to 1.79) respectively. For absence of a full confidant the figures were 093 (0-42 to 2.09) and 0-86 (0-38 to 1-93).Conclusion-These results give no support to the theory that psychosocial stress contributes to relapse of breast cancer.

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Background: The potential utility of microRNAs (miRNAs) in the diagnosis, prognosis, and treatment of multiple disease states has been an area of great interest since their discovery. In patients with cardiovascular disease, there is a large pool of literature amassed from the last decade assessing their diagnostic and prognostic potential. This systematic review sought to determine whether existing literature supports the use of miRNAs as prognostic markers after an Acute Coronary Syndrome (ACS) presentation. Methods: A systematic review of published articles from 2005–2019 using MEDLINE and EMBASE databases was undertaken independently by two reviewers. Studies addressing prognosis in an ACS population yielded 32 studies and 2 systematic reviews. Results/conclusion: 23 prospective studies reported significant differences in miRNA levels and 16 compared the predictive power of miRNAs. The most common miRNAs assessed included miR-133a, -208b, -21, -1, -34a, -150, and -423, shown to be involved in cell differentiation, apoptosis, and angiogenesis. Barriers to the use of miRNAs as prognostic markers include bias in miRNA selection, small sample size, variable normalization of data, and adjustment for confounders. Therefore, findings from this systematic review do not support the use of miRNAs for prognostication post-ACS beyond traditional cardiovascular risk factors, existing risk scores, and stratifications tools.

Background: Circulating microRNAs (miRNAs) may play a pathogenic role in acute coronary syndromes (ACS). It is not yet known if miRNAs dysregulated in ACS are modulated by colchicine. We profiled miRNAs in plasma samples simultaneously collected from the aorta, coronary sinus, and right atrium in patients with ACS. Methods: A total of 396 of 754 miRNAs were detected by TaqMan real-time polymerase chain reaction from EDTA-plasma in a discovery cohort of 15 patients (n = 3 controls, n = 6 ACS standard therapy, n = 6 ACS standard therapy plus colchicine). Fifty-one significantly different miRNAs were then measured in a verification cohort of 92 patients (n = 13 controls, n = 40 ACS standard therapy, n = 39 ACS standard therapy plus colchicine). Samples were simultaneously obtained from the coronary sinus, aortic root, and right atrium. Results: Circulating levels of 30 of 51 measured miRNAs were higher in ACS standard therapy patients compared to controls. In patients with ACS, levels of 12 miRNAs (miR-17, -106b-3p, -191, -106a, -146a, -130a, -223, -484, -889, -425-3p, -629, -142-5p) were lower with colchicine treatment. Levels of 7 of these 12 miRNA were higher in ACS standard therapy patients compared to controls and returned to levels seen in control individuals after colchicine treatment. Three miRNAs suppressed by colchicine (miR-146a, miR-17, miR-130a) were identified as regulators of inflammatory pathways. MicroRNAs were comparable across sampling sites with select differences in the transcoronary gradient of 4 miRNA. Conclusion: The levels of specific miRNAs elevated in ACS returned to levels similar to control individuals following colchicine. These miRNAs may mediate ACS (via inflammatory pathways) or increase post-ACS risk, and could be potentially used as biomarkers of treatment efficacy.