Interleukin-6 in Cardiogenic Shock

Abstract

Purpose of Review: Cardiogenic shock (CS) is one of the leading causes of mortality in patients with acute cardiac disease, and systemic inflammation plays a critical role in its pathophysiology. This review explores the role of interleukin-6 (IL-6) in CS, with a focus on its biological pathways, prognostic value, and potential as a therapeutic target, highlighting the importance of addressing inflammation in this context.

Recent Findings: Recent evidence highlights systemic inflammation implied in CS progression. Among the various cytokines involved, IL-6 is a major pro-inflammatory cytokine associated with organ dysfunction, and high mortality rates in acute myocardial infarction complicated by CS. Mechanistic studies exhibited an involvement of IL-6 since the first stages of CS onset, suggesting its role as both a biomarker and likely a mediator of CS.

Summary: IL-6 emerges as a key inflammatory mediator in CS pathophysiology, serving as a prognostic biomarker and a potential therapeutic target. Future research should focus on further understanding the underlying mechanism linking acute inflammation and CS, patient phenotyping, and optimizing anti-inflammatory strategies investigating IL-6-targeted therapies to improve outcomes in this poor prognosis condition. Clinical trials of IL-6 blockade in cardiogenic shock are lacking.

Keywords: Cytokines; Heart failure; Inflammation; Interleukin-6; Myocardial infarction.

Fig. 1

Progression from acute myocardial infarction to cardiogenic shock and the role of systemic inflammatory response. During acute myocardial infarction (AMI), the occlusion of the epicardial coronary artery leads to cardiomyocyte necrosis. The necrosis is associated with a release of damage-associated molecular patterns, directly contributing to the activation of the innate immune system. Necrosis and systemic inflammation cause a decrease in cardiac contractile mass, ventricular function, and cardiac output, which lead to systemic hypoperfusion, vasoconstriction, and end-organ dysfunction. The latter further decreases cardiac output, creating a negative feedback loop. Additionally, decreased cardiac output results in volume overload, pulmonary congestion, and hypoxemia, further impacting cardiac function and activating the renin-angiotensin-aldosterone system (RAAS). The RAAS activation, triggered by reduced renal perfusion, causes vasoconstriction, sodium and water retention, and aldosterone release, exacerbating fluid overload. This cascade results in a systemic inflammatory response characterized by the release of inflammatory cytokines such as interleukin (IL)-1α, IL-1β, IL-6, and tumor necrosis factor (TNF)-α. These three cytokines contribute to further systemic inflammation and organ dysfunction, perpetuating the cycle of cardiac and systemic deterioration during AMI and cardiogenic shock, potentially leading to death. They also stimulate the production of angiotensinogen in the liver, upregulate renin release, and angiotensin II production. Angiotensin II, in turn, promotes more cytokine release, creating a vicious cycle. (Created in BioRender. Golino, M. (2025) https://BioRender.com/ao97t7j)

Fig. 2

Interleukin-6 pathway and the drugs targeting its modulation. Interleukin (IL)-6 plays a central role in the inflammatory response associated with cardiogenic shock. IL-6 binds to its membrane-bound IL-6 receptor (IL-6R), and this complex associates with gp130, initiating intracellular signaling (classical signaling). In trans-signaling, IL-6 binds to soluble IL-6R (sIL-6R), and this complex interacts with gp130 on cells that do not express membrane-bound IL-6R. The IL-6/IL-6R/gp130 complex activates Janus kinases (JAKs), which phosphorylate and activate the signal transducer and activator of transcription 3 (STAT3). Phosphorylated STAT3 dimerizes and translocates to the nucleus to induce pro-inflammatory gene transcription. The complex can also activate the Ras/Raf/Mitogen-Activated Protein Kinase (MAPK) cascade, activating transcription factors like Activator Protein 1 (AP-1). Additionally, activation of gp130 can lead to Inhibitor of nuclear factor kappa B (IκB) degradation, releasing NF-κB to enter the nucleus and promote pro-inflammatory gene expression. Tocilizumab, a monoclonal antibody, blocks IL-6R, while ziltivekimab, also a monoclonal antibody, targets and inhibits IL-6 ligand. (Created in BioRender. Golino, M. (2025) https://BioRender.com/t51d676)