Elevated Cytokine Levels Linked to Future Development of Myocardial Infarction

Elevated levels of the plasma biomarkers interleukin-6 (IL-6) and the IL-6 binary complex have been linked to the increased risk of myocardial infarction (MI) found in smokers and individuals with hypertension.

IL-6 acts as both a pro-inflammatory cytokine and an anti-inflammatory myokine. It is secreted by macrophages in response to specific microbial molecules, referred to as pathogen-associated molecular patterns (PAMPs). These PAMPs bind to an important group of detection molecules of the innate immune system, called pattern recognition receptors (PRRs), including Toll-like receptors (TLRs). These are present on the cell surface and intracellular compartments and induce intracellular signaling cascades that give rise to inflammatory cytokine production. IL-6 is an important mediator of fever and of the acute phase response. The importance of IL-6 trans-signaling associated with risk of future myocardial infarction has not been studied to any great extent. Furthermore, whether elevation in IL-6 explains part of the association between traditional risk factors and future MI has not been explored.

In this regard, investigators at Örebro University (Sweden) sought to evaluate the association of plasma concentrations of IL-6 and IL-6 binary complex with the potential for future development of MI. IL-6 binary complex is a novel biomarker estimated from plasma concentration of IL-6, sIL-6R (soluble IL-6 receptor), and sgp130 (soluble-glycoprotein130) that reflects the extent of systemic IL-6 trans-signaling.

For this study, the investigators conducted a nested case-control study including a total of 584 participants (292 cases and 292 controls). At baseline, plasma cholesterol levels were measured, and clinical characteristics of participants were collected. The investigators measured the plasma concentration of IL-6, sIL-6R, and sgp130 and estimated the concentration of the IL-6 binary complex.

Results revealed that IL-6 binary complex concentration was significantly elevated in participants who experienced MI compared with those who did not. Furthermore, exposure to traditional cardiovascular disease risk factors contributed to elevated concentration of IL-6 binary complex. Univariate analyses showed that a 10-fold increase in IL-6 binary complex was associated with a 3.6 times higher risk of future MI. In addition, the investigators found a statistically significant indirect effect of smoking and hypertension on future MI that was mediated through increased IL-6 binary complex or plasma IL-6.

"What is unique about this study is that we have only studied the inflammatory aspects of IL-6. We have measured the levels of inflammatory IL-6 in the blood," said senior author Dr. Liza Ljungberg, senior lecturer in medical sciences at Örebro University. "Focusing on solely reducing the inflammatory characteristics of IL-6 could reduce inflammation without other important functions in the body being impaired. This means that serious side effects of the medication can be avoided."

The link between IL-6 and MI was discussed in the April 2021 issue of the journal Atherosclerosis, Thrombosis and Vascular Biology.

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Örebro University