The Role of Colchicine in Acute Coronary Syndromes.

Because inflammation is a key process implicated in the pathogenesis of atherosclerosis at all stages, including plaque formation, progression, instability, and rupture, and because colchicine has unique anti-inflammatory properties, this review article summarizes the pathophysiologic mechanisms underpinning inflammation in atherosclerosis and acute coronary syndrome (ACS), outlines anti-inflammatory therapeutic approaches that have been tested thus far, and evaluates the evidence supporting the potential role of colchicine in improving outcomes and reducing cardiovascular morbidity and mortality in patients after ACS. PubMed was searched for publications on colchicine and ACSs and atherosclerosis, and www.clinicaltrials.org was searched for completed and ongoing trials of colchicine use in ACSs. Despite contemporary optimal medical therapy, patients remain at a high risk of future events after an ACS because of residual inflammation at culprit and nonculprit sites. Several attempts have been made to address this with targeted anti-inflammatory therapies, but until the recent promising results of canakinumab (an anti-interleukin-1β monoclonal antibody), most have failed to find any prognostic benefit in large clinical trials with hard end points. The pathogenic role of neutrophils and monocytes in atheroinflammation is well established, and a fundamental component in this process is the activation of the NOD-like receptor protein 3 inflammasome, a cytosolic multiprotein complex that, when activated by a stress signal such as cholesterol crystals, drives caspase-1-dependent release of 2 key proinflammatory cytokines, which are predictive of future adverse cardiovascular events: interleukin-1β and interleukin-18. Colchicine is a widely available, inexpensive, and well-tolerated medication that, among several anti-inflammatory mechanisms of action, inhibits activation of the NOD-like receptor protein 3 inflammasome complex. A seminal trial has found the beneficial properties of colchicine in reducing adverse cardiovascular events in the stable coronary artery disease population. Despite promising results in small prospective observational and randomized trials, there is a need for more evidence evaluating the role of colchicine as a secondary preventive agent after ACSs.

Vaidya K ，Martínez G ，Patel S 《-》

Why Colchicine Should Be Considered for Secondary Prevention of Atherosclerosis: An Overview.

Colchicine is a widely available, inexpensive drug with a range of antiinflammatory properties that may make it suitable for the secondary prevention of atherosclerosis. This review examines how past and contemporary approaches to antiinflammatory therapy for atherosclerosis have led to a better understanding of the nature of the disease and sets out the reasons why colchicine has the potential to become a cornerstone therapy in its management. We performed a literature search using PubMed, the Cochrane library, and clinical trial registries to identify completed and ongoing clinical studies on colchicine in coronary artery disease, and a PubMed search to identify publications on the mechanism of action of colchicine relevant to atherosclerosis. A large body of data confirms that inflammation plays a pivotal role in atherosclerosis. The translation of this extensive knowledge into improved clinical outcomes has until recently been elusive. Findings from statin trials support the possibility that targeting inflammation may be beneficial, but this evidence has been inconclusive. Direct inhibition of atherosclerotic inflammation is being explored in current clinical trials. Targeted inhibition of interleukin 1β with canakinumab provided the proof of principle that limiting inflammation can improve outcomes in atherosclerotic vascular disease, but long-term treatment with a monoclonal antibody is unlikely to have widespread uptake. Other approaches using agents with a wider set of targets are being explored. Findings from observational studies suggest that methotrexate may reduce cardiovascular risk in patients with rheumatoid arthritis, but CIRT (Cardiovascular Inflammation Reduction Trial) demonstrated that methotrexate provided no cardiovascular benefit in patients with atherosclerotic vascular disease. Recent demonstration that cholesterol crystals trigger the NLRP3 (nucleotide oligomerization domain-, leucine-rich repeat-, and pyrin domain-containing protein 3) inflammasome and the release of inflammatory cytokines that also drive uric acid crystal-induced inflammation indicates that the multiple actions of colchicine that make it effective in gout may be relevant to preventing inflammation and limiting inflammatory injury in atherosclerosis. The ongoing LoDoCo2 (Low Dose Colchicine2) and COLCOT (Colchicine Cardiovascular Outcomes Trial) trials and several other planned large-scale rigorous trials will determine the long-term tolerability and efficacy of low-dose colchicine for secondary prevention in patients with coronary disease. Colchicine holds promise as an important, accessible drug that could be successfully repurposed for the secondary prevention of atherosclerotic cardiovascular disease should its tolerability and cardiovascular benefits be confirmed in ongoing clinical trials.

Nidorf SM ，Thompson PL 《-》

The Beneficial Therapy with Colchicine for Atherosclerosis via Anti-inflammation and Decrease in Hypertriglyceridemia.

Lipid-lowering therapy and control of cardiovascular risk factors are the current recommendations of atherosclerotic disease management. Despite optimal treatment the rate of acute coronary syndrome events remains high. Inflammation plays an essential role in the pathophysiology of atherosclerotic plaque formation, progression and rupture, which conclusively causes acute clinical episodes. This review aims to give a conceptual description of the potential therapeutic benefits and effects of colchicine in inflammation-mediated atherosclerotic disease and hypertriglyceridemia. A complete literature survey was performed using the PubMed database search to collect available information regarding colchicine, atherosclerosis, and hypertriglyceridemia. A total of 42 studies met the selection criteria for inclusion in the review. Inflammation is a well-known key mediator of atherogenesis in coronary artery disease. Colchicine has direct antiinflammatory effects by inhibiting critical inflammatory signaling networks as the inflammasome, pro-inflammatory cytokines, and expression of adhesion molecules, preventing both local chemoattraction of inflammatory cells such as neutrophils and systemic inflammation including the decrease of the release of IL-1β by the neutrophils. Colchicine reduces the levels of inflammatory markers, stabilizes the coronary plaque, leads to more favorable cardiac healing after damage, and reduces the acute coronary syndromes event recurrence. Colchicine reduces the myocardial infarct size, myocardial fibrosis, and improves the hemodynamic parameters. Several studies report the potential attenuating role of colchicine on triglyceride levels. Current evidence though regarding the pathophysiological mechanism of colchicine's triglyceride-lowering effect remains scarce.

Spartalis M ，Spartalis E ，Tzatzaki E ，Tsilimigras DI ，Moris D ，Kontogiannis C ，Kaminiotis VV ，Paschou SA ，Chatzidou S ，Siasos G ，Voudris V ，Iliopoulos DC ... -  《-》

The NLRP3 inflammasome and the emerging role of colchicine to inhibit atherosclerosis-associated inflammation.

Atherosclerosis is considered a chronic inflammatory disease of the arterial wall. Recently, compelling evidence has arisen for the role of monocytes and neutrophils and a particular protein complex that resides within these cells - the NLRP3 inflammasome - in atherosclerosis-associated inflammation. It is now also known that cholesterol crystals are present through all stages of atherosclerosis and can activate the NLRP3 inflammasome within these inflammatory cells to produce interleukin 1β and interleukin 18 - key mediators in the inflammatory cascade that drive plaque progression and instability. In this review, we describe the role of monocytes/macrophages and neutrophils in atherosclerosis, outline mechanisms of activation of the NLRP3 inflammasome in the setting of atherosclerosis-associated inflammation and discuss potential therapies that specifically target the NLRP3 inflammasome and/or its downstream mediators in atherosclerosis, with a particular focus on the emerging role of colchicine.

Martínez GJ ，Celermajer DS ，Patel S 《-》

Colchicine for acute and chronic coronary syndromes.

Colchicine is an ancient drug, traditionally used for the treatment and prevention of gouty attacks; it has become standard of treatment for pericarditis with a potential role in the treatment of coronary artery disease. Atherosclerotic plaque formation, progression, destabilisation and rupture are influenced by active proinflammatory cytokines interleukin (IL)-1β and IL-18 that are generated in the active forms by inflammasomes, which are cytosolic multiprotein oligomers of the innate immune system responsible for the activation of inflammatory responses. Colchicine has a unique anti-inflammatory mechanism: it is not only able to concentrate in leucocytes, especially neutrophils, and block tubulin polymerisation, affecting the microtubules assembly, but also inhibits (NOD)-like receptor protein 3 (NLRP3) inflammasome. On this basis, colchicine interferes with several functions of leucocytes and the assembly and activation of the inflammasome as well, reducing the production of interleukin 1β and interleukin 18. Long-term use of colchicine has been associated with a reduced rate of cardiovascular events both in chronic and acute coronary syndromes, with an overall good safety profile. This review will focus on the influence of colchicine on the pathophysiology of coronary artery disease, reviewing essential pharmacology and discussing the most important and recent clinical studies. On the basis of current literature, colchicine is emerging as a possible new valuable, safe and cheap agent for the treatment of acute and chronic coronary syndromes.

Imazio M ，Andreis A ，Brucato A ，Adler Y ，De Ferrari GM ... -  《-》