Acute myocardial infarction (AMI) is a leading contributor to morbidity and mortality worldwide [1]. Inflammation plays a pivotal role in the development of atherosclerotic plaques, as well as acceleration of plaque rupture and local thrombosis [2]. Inflammation is a double-edged sword. Although the post-AMI inflammatory response is prerequisite for normal healing of damaged heart tissue, excessive inflammation is associated with maladaptive left ventricular (LV) remodeling, progressive heart failure, and ultimately adverse clinical outcomes [3]. Thus, inflammation in AMI has potential as a therapeutic target.

Interleukin-1 (IL-1) plays a central role as a mediator propagating the inflammatory response and is considered the main target in atherosclerotic thromboprotection [4]. Two proteins, IL-1$\alpha$ and IL-1$\beta$, induce potent inflammatory responses [5]. IL-1 receptor antagonists (IL-1Ra) and IL-1 receptor type 2 (IL-1R2) are separate mechanisms for inhibiting IL-1-mediated inflammation [6]. The binding of IL-1 to IL-1 receptor type 1 (IL-1R1) is blocked by IL-1Ra. IL-1R2 acts as a decoy receptor on the cell surface or in a soluble form (sIL-1R2) in the circulation, inhibiting the IL-1-mediated inflammatory response (Fig. 1) [7]. Maintaining a balance between agonist and antagonist levels avoids exaggerated inflammatory responses. Recently, the Canakinumab Anti-inflammatory Thrombosis Outcomes Study (CANTOS) showed that blocking inflammation with the anti-IL-1$\beta$ monoclonal antibody canakinumab reduced heart attacks, strokes and new-onset diabetes among patients with prior myocardial infarction (MI) [8]. Other clinical trials have shown that the IL-1 receptor antagonist anakinra exhibits anti-inflammatory properties in patients with MI [9, 10]. However, little is known about the levels of sIL-1R2, which significantly affect net activity in IL-1-related pathways in the setting of AMI.

Fig. 1.

The IL-1 system. Activation. The main extracellular soluble activators IL-1$\alpha$ and IL-1$\beta$ bind to IL-1R1. IL-1RAcP is necessary for the formation of the signal transduction complexes. Inhibition. IL-1R$\alpha$ prevents IL-1 from interacting with IL-1R1. Membrane IL-1R2 acts as a decoy receptor binding to IL-1, but not initiating signaling. Soluble IL-1R2 exhibits anti-inflammatory activity by sequestering IL-1 in the circulation. IL, interleukin; R, receptor; AcP, accessory protein; s, soluble. Figure created with https://BioRender.com.

We hypothesize that sIL-1R2 may be an inflammatory indicator associated with LV remodeling after AMI. Using blood sampling and repeated echocardiography, we aim to assess the possible associations between sIL-1R2 and LVEF, ventricular remodeling and adverse clinical events.

Circulating levels of sIL-1R2 were elevated in AMI patients as compared to healthy controls. Circulating sIL-1R2 measured early in AMI patients was associated with recovery of LV function and with clinical events during 12 months of follow-up. These findings support the notion that sIL-1R2 may play a crucial role in postinfarction inflammation, and that sIL-1R2 may be clinically useful as a predictor of increased risk of new events in AMI patients.

IL-1 signaling disorders after myocardial infarction can affect infarction healing, cause collateral damage, deteriorate cardiac function and lead to adverse clinical outcomes [18]. IL-1 activity is controlled by the activation of the receptors [4]. Soluble IL-1R2 can competitively bind to IL-1 with high affinity in the circulation and exclude it from the signal transduction complex, so that excessive IL-1 cannot exert its biological function [7]. Moreover, intracellular sIL-1R2 can directly bind to the IL-1$\beta$ precursor pro-IL-1$\beta$, preventing the further conversion of pro-IL-1$\beta$ into mature IL-1$\beta$, inhibiting the IL-1 signaling pathway, and attenuating inflammation [19]. Thus, sIL-1R2 acts as a natural inhibitor of IL-1. However, the role of sIL-1R2 in the inflammatory response accompanying ischemia/reperfusion myocardial damage remains to be explored. Yao et al. [20] recently found that the expression of IL-1R2 in AMI patients was higher than that in healthy controls, and a three-gene signature comprising IL1R2, C-C motif chemokine ligand 20 (CCL20), and Intelectin-1 (ITLN1) exhibited outstanding performance in MI diagnosis. Similarly, a previous study demonstrated a persistent increase in sIL-1R2 levels in the acute phase and during 4 months of follow-up in a population of STEMI patients [21]. In the present study, we found that plasma levels of sIL-1R2 were elevated the day after AMI, consistent with previous findings, and suggesting that elevated sIL-1R2 expression might be detected in the circulation and may provide novel therapeutic opportunities for atheroprotection. A previous study demonstrated that elevated sIL-1R2 levels were significantly associated with adverse LV remodeling following STEMI, as assessed as changes in indexed LVEDV and indexed LVESV from the acute phase to 4 months, even after adjustment for relevant clinical variables [21]. Their explanation for the association was that increased sIL-1R2 levels in the acute phase could potentially affect adaptive remodeling induced by IL-1, and thus promote adverse remodeling during follow-up. However, we did not observe this in our study. When comparing our results to those of other studies, it should be noted that there is no unified definition of adverse LV remodeling after AMI [22]. Although sIL-1R2 levels were not associated with adverse LV remodeling outcomes in the present study, the significantly higher frequency of impaired ventricular contractibility after 12 months observed in patients with low sIL-1R2 levels suggests that sIL-1R2 may be involved in their deteriorated LV function. One explanation could be that elevated sIL-1R2 levels represent the activation of a pathway suppressing the activity of IL-1 to protect cardiomyocytes from ischemia/reperfusion injury and to limit the extent of left ventricle remodeling, and that low sIL-1R2 levels may facilitate IL-1 signaling. It is also possible that insufficient sIL-1R2 release promotes atherosclerotic plaque activation and increases the risk of recurrent events. In a previous study, IL-1R2 expression was reduced in monocytes from hyperlipidemic patients and in human atherosclerotic lesions, suggesting a potential role for low IL-1R2 expression in atherosclerosis progression [23]. Although myocardial damage and infarction size are the major determinants of left ventricular remodeling and impaired recovery of LV function, excessive local and systemic inflammation may accelerate this process.

Recently, IL-1R2 has been identified as a pivotal mediator of a broad spectrum of inflammatory cytokines involved in the development of coronary atherosclerosis [24]. In animal models of arthritis [25], IL-1-induced inflammation [26] and cardiac allograft surgery [27], overexpression of IL-1R2 has anti-inflammatory profiles. In transgenic mice, phorbol ester-induced dermal and epidermal inflammation is ameliorated by overexpressing IL-1R2 in the epidermis [28]. The conventional view holds that IL-1R2 is mainly expressed in neutrophils, monocytes and macrophages [5]. Recent research has indicated that there is release of soluble IL-1R2 from injured cardiomyocytes subjected to ischemia/reperfusion conditions. In addition, myocardial ischemia/reperfusion-induced apoptosis is abrogated by IL-1R2 overexpression in cardiomyocytes [29]. Some studies have suggested that IL-1R2 plays a role in regulating monocyte accumulation during myocardial ischemia/reperfusion injury [17]. These findings suggest that IL-1R2 is probably more than redundant in endogenous IL-1 antagonist systems and could be a promising mediator of the inflammatory response in AMI.

Persistent and excessive inflammation unrelated to infarct size has been considered an important contributor to increased risk of ventricular remodeling and adverse clinical events following MI [30]. Abnormal inflammatory status after myocardial infarction is associated with adverse LV remodeling and underlies heart failure pathogenesis [31]. We excluded patients with infectious diseases, chronic inflammatory diseases or cancer to eliminate the effects of other disease processes on the association between low levels of sIL-1R2 and adverse outcomes. The major finding in this study was that low levels of sIL-1R2 during the acute phase of AMI were significantly associated with impaired LV contractibility defined as a decrease in LVEF ˃10% from hospitalization to 12 months and LVEF 50% at 12 months. The association between acute-phase sIL-1R2 levels and poor prognosis remained after adjustment for NT-proBNP, showing that low levels of sIL-1R2 may reflect disadvantageous aspects beyond heart failure itself. Our findings also suggest that IL-1 blockade by sIL-1R2 may have a potential therapeutic effect during the acute phase. This hypothesis should be verified in a future larger cohort of patients with AMI.

Randomized trial data have consistently demonstrated persistent inflammation to be as important a potential therapeutic target for atheroprotection [32, 33]. The CANTOS trial provided proof of concept that attenuating IL-1 inflammation reduces the risk for acute cardiovascular events [8]. Due to the clinical usage of anakinra, the recombinant human IL-1Ra analog, the beneficial effects of IL-1Ra during MI are well documented [34]. In contrast, the role of IL-1R2 in AMI has not been well elucidated. Although anakinra is a valuable therapeutic tool, it has a short in vivo half-life, necessitating daily injection [35]. IL-1R2 has a longer half-life, low affinity for IL-1Ra and high affinity for IL-1$\beta$, and thus may be a promising therapeutic candidate [36]. In the present study, the association between low sIL-1R2 and adverse clinical outcomes enhances the likelihood of a therapeutic potential of targeting sIL-1R2 in AMI, and will warrant being more thoroughly addressed in future studies.

The limitations of this study should be acknowledged. The results of this study provide no evidence of a causal relationship involving sIL-1R2 and LV function or adverse clinical outcomes. The reported number of adverse events in the present cohort was relatively small. Moreover, we used echocardiography to assess adverse remodeling in the present study, which needs to be considered when interpreting the results. Furthermore, we lacked follow up measurements and the temporal profile of sIL-1R2 on the AMI patients between days 1 and 12 months. Other inflammatory markers, such as IL-1$\alpha$, IL-1$\beta$, IL-1R1, and IL-1RAcP, which might reflect the inflammatory status more accurately, were not evaluated in the study. Future studies, including experimental studies, are necessary to further evaluate the role of sIL-1R2 in AMI. Nonetheless, our data demonstrate that sIL-1R2 could be an unrecognized mediator of recovery of LV function in AMI patients.

The present study demonstrated that low levels of sIL-1R2 in the acute phase of AMI patients were associated with impaired recovery of LV function and increased future adverse clinical events. The results indicated that sIL-1R2 may be a clinically useful biomarker for risk prediction in AMI patients, and sIL-1R2 itself may be a novel target for atherothrombotic protection.

SFL and FG designed the study and drafted the manuscript. SL and QTY collected the data. TGG and YZ analyzed the data. SFL, JYC and SL contributed to patient management. CWJ and YNZ performed coronary angiography and percutaneous coronary intervention. SFL and FG performed the statistical analysis. All authors revised the manuscript critically for important intellectual content and approved the submitted manuscript. All authors contributed to editorial changes in the manuscript. All authors read and approved the final manuscript.

The study was conducted in accordance with the Declaration of Helsinki and the Ethics Committee of Zhongshan Hospital of Xiamen University (No. 2021-141). Written informed consent was obtained from all patients prior to inclusion.

We thank Haiqiang Chen for valuable assistance with the statistical analyses. We appreciate the help and support of study nurses, echocardiography technicians, and the staff at the Intensive Coronary Care Unit, Zhongshan Hospital of Xiamen University.

This research was funded by the Xiamen Science and Technology Program Project (3502Z20209023 and 3502Z20214ZD1049), Science and Technology Plan Project of Fujian Provincial Health Commission (2022GG01010075).

The authors declare no conflict of interest.