Colchicine in Cardiovascular Disease: Mechanisms of Action and Therapeutic Potential

Abstract

Colchicine, a well-known anti-inflammatory agent, has recently garnered interest in the field of cardiovascular medicine. We provide an overview of the history of colchicine and its known biological effects. The discussion encompasses colchicine's applications in rheumatology and immunology, as well as other fields, highlighting its research value in cardiovascular diseases.

Modern diets high in fat and salt contribute to the accumulation of high cholesterol levels, leading to arterial wall damage and lipid deposition. Excess cholesterol injures the endothelium, resulting in the accumulation of lipids and activation of the NLRP3 inflammasome, which increases levels of pro-inflammatory mediators, such as IL-1β and IL-18 [1]. Chronic inflammation promotes atherosclerosis, rendering plaques unstable and prone to rupture, thereby causing thrombosis and myocardial infarction [1, 2].

Colchicine is an inexpensive and effective anti-inflammatory medication. It inhibits the release of IL-1β, IL-6, and TNFα by suppressing the NLRP3 inflammasome and also inhibits microtubule growth and activity [1, 2]. In terms of immune modulation, colchicine increases prostaglandin E2 levels [1], inhibits neutrophil adhesion, aggregation, and migration [1-3], suppresses the release of inflammatory cytokines (leukotriene B4, thromboxane A2, and cyclooxygenase 2), and reduces platelet function and endothelial activation [2, 3], thereby decreasing thrombosis [1]. Colchicine is absorbed in the gastrointestinal tract, metabolized by hepatic cytochrome P450 3A4, and ultimately excreted via bile [2].

Therefore, colchicine exerts its anti-inflammatory effects through relevant immune modulation pathways, making it effective in treating gout, Behcet's disease, familial Mediterranean fever [1], pericarditis [1, 2], reducing ischemic and hemorrhagic stroke in patients with diabetes [4], serving as additional therapy for hypopharyngeal cancer [5], preventing recurrent keloids [6], and being effective for osteoarthritis, recurrent aphthous stomatitis, and chronic urticaria [7].

Table 1 highlights the potential clinical applications of cholchicine in various inflammatory disease.

In acute gout attacks without tophi, colchicine should be taken daily at a dose of 0.6–1.2 mg for at least 3 months until serum uric acid is < 5–6 mg/dL. If tophi are present, the treatment duration should be extended to 6 months [8].

Colchicine has garnered significant attention in recent years for its therapeutic potential in acute pericarditis, coronary artery disease (CAD) [9], atrial fibrillation, and post-pericardiotomy syndrome [3]. Studies have shown that among 941 patients with acute gouty inflammation, the risk of major adverse cardiovascular events was 1.7-times higher during the post-discharge period [10]. The mechanisms of colchicine, including inhibition of inflammatory cytokines release, hold promise for the treatment of CAD and myocardial infarction (MI).

In CAD, colchicine has been shown to enhance the stability of atherosclerotic plaques, reducing the risk of plaque rupture and thrombus formation. The Australian COPS study involving 396 individuals treated with colchicine 0.5 mg twice daily demonstrated a reduction in stroke, death, and revascularization in acute coronary syndrome (ACS) [3]. Colchicine also reduces the risk of urgent hospitalization for coronary revascularization and decreases coronary plaque volume on computed tomography angiography [1-3].

Colchicine mitigates myocardial injury as well. A 2020 NEJM study involving 2762 individuals using low-dose colchicine (0.5 mg once daily) demonstrated a reduction in MI, stroke, ischemia-driven revascularization, and high-sensitivity C-reactive protein (CRP) levels from 1.52 to 1 mg/L [3]. The low-dose colchicine (LoDoCo) study showed a decrease in urgent hospitalization for angina leading to revascularization [1]. This effect is attributed to colchicine's inhibition of the inflammatory response, reducing infiltration of inflammatory cells and release of inflammatory mediators post-MI, thereby slowing cardiac tissue damage and fibrosis processes.

Patients with gout often have comorbidities, such as hypertension, diabetes, and obesity, which contribute to cardiovascular disease [1, 10]. Taking hypertension as an example, studies have shown that colchicine can reduce the extent of vascular inflammation, decrease inflammatory cell infiltration into the vessel wall, and inhibit the release of inflammatory mediators, thereby improving vascular elasticity and blood pressure regulation. This is attributed to colchicine's protective effect on endothelial cells, which can reduce endothelial cell damage and vascular constriction response, potentially lowering the risk of hypertension occurrence and progression.

Similarly, colchicine can suppress the release of inflammatory mediators from adipocytes, reduce adipose tissue inflammation, and improve lipid metabolism abnormalities, thereby lowering lipid levels and improving glucose metabolism. These effects help reduce the damage of hyperlipidemia and diabetes to the cardiovascular system, thereby reducing the risk of related cardiovascular diseases.

Patients with CAD often take aspirin and clopidogrel post-percutaneous coronary intervention to prevent acute myocardial infarction (AMI). Colchicine has been shown to reduce the risk of urgent hospitalization due to AMI within 30 days [1-3], with no observed increase in the risk of cerebral hemorrhage.

Gout is characterized by chronic inflammation and episodes of acute intense inflammation [10]. Although colchicine is used for controlling chronic inflammation, nonsteroidal anti-inflammatory drugs (NSAIDs) are typically used for acute pain relief. However, NSAIDs may increase the risk of subsequent MI [1], cardiovascular disease (CVD), and stroke [11]. Switching to cyclooxygenase-2 inhibitors (COX-2i), such as celecoxib and etoricoxib [11], as used in patients with rheumatoid arthritis, may reduce the risk of CAD, thrombosis, and CVD [11].

Excessive alcohol consumption in patients with gout leads to purine accumulation, exacerbating the condition. Alcohol is metabolized by cytochrome P450 in the liver, and excessive alcohol intake can lead to liver cirrhosis. Colchicine is absorbed in the gastrointestinal tract and metabolized in the liver, so reducing alcohol intake is necessary to avoid excessively high colchicine levels in the bloodstream.

This editorial highlight the mechanisms of action, clinical applications, and research progress of colchicine in cardiovascular diseases. It emphasizes the importance of colchicine as a therapeutic agent in cardiovascular medicine. Future research can explore its potential benefits in controlling hypertension, hyperlipidemia, and diabetes.

S.-T. S., Y-H. L. and J. C.-C. W. had full access to the study data and verified the underlying study data. J. C.-C. W. led the conception. S.-T. S. wrote the original draft of this paper. S.-T. S., Y.-H. L. and J. C.-C. W. contributed to the conception and writing with review and editing of this paper. All authors had final responsibility for the decision to submit for publication.

The authors declare no conflicts of interest.