Role of inflammation and evidence for the use of colchicine in patients with acute coronary syndrome

Abstract

Acute Coronary Syndrome (ACS) significantly contributes to cardiovascular death worldwide. ACS may arise from the disruption of an atherosclerotic plaque, ultimately leading to acute ischemia and myocardial infarction. In the pathogenesis of atherosclerosis, inflammation assumes a pivotal role, not solely in the initiation and complications of atherosclerotic plaque formation, but also in the myocardial response to ischemic insult. Acute inflammatory processes, coupled with time to reperfusion, orchestrate ischemic and reperfusion injuries, dictating infarct magnitude and acute left ventricular (LV) remodeling. Conversely, chronic inflammation, alongside neurohumoral activation, governs persistent LV remodeling. The interplay between chronic LV remodeling and recurrent ischemic episodes delineates the progression of the disease toward heart failure and cardiovascular death. Colchicine exerts anti-inflammatory properties affecting both the myocardium and atherosclerotic plaque by modulating the activity of monocyte/macrophages, neutrophils, and platelets. This modulation can potentially result in a more favorable LV remodeling and forestalls the recurrence of ACS. This narrative review aims to delineate the role of inflammation across the different phases of ACS pathophysiology and describe the mechanistic underpinnings of colchicine, exploring its purported role in modulating each of these stages.

Keywords: NETosis; acute coronary syndrome; colchicine; inflammasome; myocardial infarction.

Figure 1

Role of colchicine in atherothrombosis. Colchicine exerts three main effects preventing atherosclerotic plaque build-up and disruption. Effect on monocytes: colchicine inhibits monocyte migration and the NLRP3 inflammasome, thus limiting the activation of the potent proinflammatory cytokine IL-1β and downstream IL-6 and C-reactive protein. Effect on neutrophils: colchicine inhibits neutrophil chemotaxis, and endothelial adhesion, and reduces deformability and motility, thus hindering recruitment and extravasation. Additionally, colchicine reduces NETosis. Both effects on neutrophils contribute to plaque stability. Effect on platelets: colchicine reduces platelet aggregation both directly and through NETs reduction. Created with Biorender.com.

Figure 2

Effect of colchicine in infarct size/acute left ventricular remodeling. Following acute coronary obstruction, infarct size and acute LV remodeling are directly related to both ischemic injury and reperfusion injury (referred here as PCI-related MI). Ischemic injury: colchicine shows reduced infiltration of neutrophils and monocytes, with attenuated M1 (Pro-inflammatory)-monocyte and increased M2 (Reparative)-monocyte response. This translates into reduced myocardial tissue destruction, with less release of proteinases, and inflammatory cytokines and reduced phagocytosis/efferocytosis by activated monocytes; and enhanced tissue repair, with increased release of fibrogenic and angiogenic mediators leading to granulation tissue formation. Reperfusion injury: colchicine lowered NETosis and platelet aggregation, which translated into reduced endothelial dysfunction, leukocyte-platelet aggregates, and microvascular obstruction. Therefore, by reducing the magnitude of ischemic and reperfusion injury, colchicine administration during the acute phase of ACS has been shown to reduce infarct size, as assessed by levels of myocardial enzyme release and LV scar size; and acute LV remodeling, as assessed by LV volumes and ejection fraction. LV, left ventricle; PCI, percutaneous coronary intervention; NET, neutrophil extracellular traps; ACS, acute coronary syndrome. Icons from Servier Medical Art, licensed under CC BY 4.0.

Figure 3

A general framework of the effect of colchicine in ACS. ACS most commonly derives from atherosclerotic plaque disruption (Initial event), leading to acute ischemia and MI. Acute inflammation along with time to reperfusion and other hemodynamic factors, mediates ischemic and reperfusion injury and determines infarct size and acute LV remodeling. Chronic inflammation, alongside neurohumoral activation, determines chronic LV remodeling. Both chronic LV remodeling and recurrent ischemic events determine the progression to heart failure and cardiovascular death. Colchicine exerts its anti-inflammatory effects both in the myocardium and the atherosclerotic plaque. At the myocardial level, colchicine attenuates acute inflammation -both ischemic and reperfusion injury-, thus limiting infarct size and acute remodeling. Subsequently, colchicine attenuates chronic low-grade inflammation, limiting chronic LV remodeling (i.e., chamber dilation and reduced EF). At the atheroma level, colchicine reduces plaque instability features, thus preventing plaque disruption and recurrent events. Theoretically, it may also prevent the occurrence of an initial ACS in patients with chronic coronary syndromes. Finally, the effects of colchicine in both attenuating acute and chronic LV remodeling after an ACS, in addition to the prevention of recurrent ACS, may translate into reduced heart failure and CV death. Icons from Servier Medical Art, licensed under CC BY 4.0.