Colchicine Inhibits Neutrophil Extracellular Trap Formation in Patients With Acute Coronary Syndrome After Percutaneous Coronary Intervention

Abstract

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.

The Emerging Role of Neutrophils in the Pathogenesis of Thrombosis in COVID-19

“…The athero-protective potential of colchicine is based on its effects on tubulin-colchicine-complex polymerization, as well as its ability to suppress proinflammatory cytokine (IL-1β and IL-18) release by interacting with the Nod-like receptor protein 3 inflammasome protein complex [118,119]. Moreover, colchicine inhibits NET formation in patients with Acute Coronary Syndrome (ACS) [120]. Based on its effects, colchicine was proposed for the prophylaxis of venous thromboembolism in patients with COVID-19 [121,122].…”

Neutrophil Extracellular Traps: A New Player in Cancer Metastasis and Therapeutic Target

“…In this respect, the primary role of NETs is advantageous, providing a rapid and disseminated means of controlling infection. On the other hand, it is to note that excessive NETs production induced by neutrophil dysregulation is counterproductive and have been implicated in many inflammatory disorders, including autoimmune diseases [ 21 ] , type 2 diabetes [ 22 ] , myocardial infarction [ 23 ] and cancer [ 24 , 25 ], which further exacerbate inflammation and cause cell damage.…”

Assessing the Impact of Colchicine on Coronary Plaque Phenotype After Myocardial Infarction with Optical Coherence Tomography: Rationale and Design of the COCOMO-ACS Study

“…In the setting of atherosclerotic plaque containing cholesterol crystals, NLRP3 inflammasome activation is dampened in colchicine-treated neutrophils and macrophages [ 29 ]. Colchicine also suppresses neutrophil extracellular traps (NETs) by restoring cytoskeletal dynamics in patients treated with percutaneous coronary intervention (PCI) following MI [ 30 ]. Comprising strands of DNA in the form of decondensed chromatin, and liberated by activated or dying neutrophils, NETs localize at the interface of blood and the intimal surface of diseased arteries [ 31 ].…”