Colchicine and the Heart

Massimo Imazio; Mark Nidorf

Disclosures

Europace. 2021;42(28):2745-2760. 

In This Article

Abstract and Introduction

Abstract

Colchicine is a unique, sophisticated anti-inflammatory agent that has been used for decades for the prevention of acute inflammatory flares in gout and familial Mediterranean fever. In recent years, clinical trials have demonstrated its potential in a range of cardiovascular (CV) conditions. Colchicine is avidly taken up by leucocytes, and its ability to bind to tubulin and interfere with microtubular function affects the expression of cytokines and interleukins, and the ability of neutrophils to marginate, ingress, aggregate, express superoxide, release neutrophil extracellular traps, and interact with platelets. In patients with acute and recurrent pericarditis, clinical trials in >1600 patients have consistently shown that colchicine halves the risk of recurrence [relative risk (RR) 0.50, 95% confidence interval (CI) 0.42–0.60]. In patients with acute and chronic coronary syndromes, multicentre randomized controlled trials in >11 000 patients followed for up to 5 years demonstrated that colchicine may reduce the risk of CV death, myocardial infarction, ischaemic stroke and ischaemia-driven revascularization by >30% (RR 0.63, 95% CI 0.49–0.81). The use of colchicine at doses of 0.5–1.0 mg daily in CV trials has proved safe. Early gastrointestinal intolerance limits its use in ~10% of patients; however, ~90% of patients tolerate it well over the long term. Despite isolated case reports, clinically relevant drug interactions with moderate to strong CYP3A4 inhibitors/competitors or P-glycoprotein inhibitors/competitors are rare if this dosage of colchicine is used in the absence of advanced renal or liver disease. The aim of this review is to summarize the contemporary data supporting the efficacy and safety of colchicine in patients with CV disease.

Graphical Abstract: The central mechanism of the anti-inflammatory action of colchicine is the inhibition of microtubule function leading to the inhibition of granulocyte function, interference with selectin expression and neutrophil–platelet interactions, and non-specific inhibition of the assembly of the inflammasome in inflammatory cells. These actions could exert therapeutic effects in different cardiovascular diseases (e.g. pericarditis, acute and chronic coronary syndromes, atrial fibrillation, and heart failure).

Introduction

Colchicine is one of the oldest remedies still in use. It is derived from the bulb-like corms of the Colchicum autumnale plant, also known as autumn crocus. Its history as an herbal remedy for joint pain goes back to Egyptian times, and it was first mentioned in the medical literature in the Ebers Papyrus, an Egyptian medical manuscript written around 1500 BC (Figure 1).[1,2],1wColchicum extract was first described as a treatment for acute gout by Pedanius Dioscorides in De Materia Medica (first century AD). Use of colchicine continued over centuries and Colchicum corms were used by Avicenna, the famous Persian physician, and were recommended by Ambroise Paré in the 16th century. They were also mentioned in the London Pharmacopoeia in 1618.[1] The active ingredient, colchicine, was isolated in the early 1800 s by the French chemists Pierre-Joseph Pelletier and Joseph Bienaimé Caventou, and remains in use today as a purified natural product.2w The name 'colchicine' is derived from the ancient and legendary kingdom of Colchis from where Jason recovered the Golden Fleece and where C. autumnale plants were widespread.[1,2]

Figure 1.

Colchicine is the active principle derived from Colchicum autumnale plants. The drug has been cited as medical remedy for the first time in the ancient Ebers papyrus (1500 BC). The name 'colchicine' is after the ancient and legendary kingdom of Colchis, where Colchicum autumnale plants were widespread.

Despite its use over centuries, the exact mechanism of action of colchicine is still under investigation. In the 1950s and 1960s, the microtubule was identified as the primary cellular target. Microtubules are key constituents of the cellular cytoskeleton and are essential to several cellular functions, including maintenance of cell shape, intracellular trafficking, cytokine secretion, cell migration, and regulation of ion channels and cell division. Colchicine binds to tubulin heterodimers and alters the tubulin conformation, preventing any further growth of microtubules at low doses, but promoting their depolymerisation at high doses.[3] Anti-inflammatory effects of colchicine are derived from a combination of actions (Figure 2). The effect of colchicine on tubulin affects the assembly of inflammasome and the expression of interleukin (IL)-1β, and other ILs, including IL-18 by macrophages; and impairs neutrophil chemotaxis, adhesion, mobilization, recruitment, production and release of superoxide, and the expression of neutrophil extracellular traps (NETs). Moreover, colchicine decreases neutrophil L-selectin expression, and modulates E-selectin expression on the cell surface of endothelial cells, thereby impairing neutrophil recruitment. In addition, colchicine may interfere with neutrophil-platelet interactions, which play a role in atherothrombosis.[4–7] ,3w–5w

Figure 2.

Colchicine anti-inflammatory actions start with the interference with microtubule assembly and function and its capability to concentrate in inflammatory cells with limited expression of P-glycoprotein (e.g. granulocytes). Anti-inflammatory effects of colchicine are derived from a combination of different actions: (i) inhibition of granulocytes, (ii) interference with qualitative and quantitative expression of selectins on endothelial and inflammatory cells and platelet aggregation stimulated by inflammation, and (iii) non-specific inhibition of the inflammasome by interference with the assembly of its components when inflammation is stimulated.

The aim of this article is to critically review the usefulness of colchicine in the treatment of a range of cardiovascular (CV) conditions, focusing on the most relevant clinical studies. A literature review was performed including studies published up to January 2021. Bibliographic databases were searched (MEDLINE/PubMed, BioMed Central, the Cochrane Collaboration Database of Randomized Trials, Scopus, ClinicalTrials.gov, EMBASE, Google Scholar) using the search terms 'colchicine' AND 'cardiovascular disease' OR 'coronary artery disease' OR 'pericarditis' OR 'atrial fibrillation' OR 'heart failure'. The research was restricted to English language. The authors independently screened titles and abstracts of all studies, while potentially eligible studies were appraised as full text. The most relevant papers are included in the reference list (Supplementary material online, Figure).

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