Blocking interleukin-6 trans-signaling in AF: Promises and challenges

Atrial fibrillation (AF) stands as the most prevalent cardiovascular disease, posing significant risks of stroke, heart failure (HF), and other complications that contribute to morbidity and mortality. While traditional research on AF has primarily focused on electrophysiological components such as ionic currents and Ca²⁺ handling system, treatment strategies have mainly revolved around the rate-limiting b-blockers and Ca²⁺ channel blockers or rhythm-control methods such as cardioversion, antiarrhythmic drugs, and catheter ablation. Even though these interventions can be initially effective, the recurrence rate remains high, necessitating the need for new therapies targeting the underlying causes, inducers, or triggers of AF. Emerging areas of interests in AF pathogenesis include inflammation and oxidative stress, as both mechanisms can induce electrical and structural remodeling in atria, which is fundamental in AF progression. Inflammation, in particular, is drawing attention because of its close association with various risk factors such as obesity, hypertension, and aging. In cardiac milieu, inflammation fosters fibrosis and immune cells–atrial myocardium interactions via cytokines, positioning inflammatory signaling pathways the focal point in AF development.¹ Yet, the standard anti-inflammatory drugs, such as colchicine, have not proven successful in AF treatment.²

Cytokines, as primary messengers in the immune system, have the capacity to activate immune cells and fibroblasts. Despite AF being sterile, elevated cytokine levels can trigger macrophages, amplifying inflammation, as well as activate fibroblasts, causing fibrotic remodeling. Among various inflammatory cytokines, interleukin 6 (IL-6) stands out as a key player. Produced by a range of cell types, including cardiomyocytes, IL-6 is involved in immune regulation and tissue homeostasis. Elevated levels of IL-6 correlate with AF progression and the outcomes of AF ablation.³ IL-6 exerts its effects by binding to the IL-6 receptor (IL-6R), which exists in 2 forms: a membrane-bound form (mIL-6R) present on certain immune cells and a soluble form (sIL-6R) generated through proteolytic cleavage. The classical IL-6 signaling pathway involves the binding of IL-6 to mIL-6R, leading to the activation of intracellular signaling cascades. Although promising, blocking IL-6 alone has faced challenges. For instance, the clinical trial of the IL-6 blocker for patients with leukemia was discontinued because of its severe side effects.⁴ Alternatively, the selective blockade of IL-6 trans-signaling introduces an innovative approach to targeting inflammation and cardiac dysfunction.⁵ In trans-signaling, IL-6 binds first to sIL-6R and then to the signal-transducing glycoprotein 130. Unlike classic signaling, trans-signaling allows IL-6 to exert its effects on a broader range of cells, including those lacking mIL-6R.⁵ This selective blockade strategy aims to inhibit the pro-inflammatory effects of IL-6 while preserving its beneficial roles in tissue repair and immune response.

In this issue of Heart Rhythm Journal, Li et al⁶ investigated the impact of IL-6 trans-signaling on AF. They found the elevated IL-6 and sIL-6R levels in patients with AF. Given that the binary IL-6–sIL-6R complex is inactivated by soluble glycoprotein 130 (sgp130) through the formation of the ternary IL-6–sIL-6R–sgp130 complex, the authors used the binary-to-ternary complex ratio (B/T) to determine the relative levels of IL-6 trans-signaling. B/T was elevated in the AF group, revealing an association between IL-6 trans-signaling and AF occurrence. To evaluate the efficacy of the selective IL-6 trans-signaling blockade, the authors assessed the AF inducibility in a murine HF model induced by the pressure overload. As expected, HF mice showed increased AF susceptibility, along with increased IL-6 levels, decreased mIL-6R levels, and increased phosphorylated ‘signal transducer and activator of transcription 3’ (STAT3) levels, which are indicative of trans-signaling activation. The authors then blocked the trans-signaling pathway by administering sgp130Fc. Also known as olamkicept, sgp130Fc is a selective IL-6 trans-signaling blocker that binds to IL-6–sIL-6R and/or IL-6–mIL-6R complexes while preserving the classic IL-6 pathway intact.⁵ sgp130Fc reduced AF inducibility in HF mice. This reduction was accompanied by improvement in activation time, conduction velocity, and conduction homogeneity. Connexin 40 (Cx40) and Cx43 are crucial gap junctions necessary for proper electrical signal propagation in the heart. Dysregulation of these proteins is commonly associated with AF. In HF mice, dysregulation of Cx43 and phosphorylated Cx43 was evident, but this was ameliorated by sgp130Fc. Building on these findings, both Masson’s trichrome staining and picrosirius red staining revealed that structural remodeling and fibrosis were attenuated in sgp130Fc-treated HF mice. These mice also exhibited decreased macrophage infiltration and lowered monocyte chemoattractant protein 1 expression, correlating with the diminished inflammatory factors of oxidative stress and apoptosis in the atria.

While the concept of selective IL-6 trans-signaling blockade is relatively new, the data support the potential of sgp130Fc as a treatment for AF. Olamkicept (sgp130Fc) has successfully completed 2 clinical trials: a phase IIa trial for patients with inflammatory bowel disease and a phase IIb trial for patients with ulcerative colitis.⁷ Olamkicept also can reduce arterial wall inflammation in a patient with a heightened risk of atherosclerotic cardiovascular disease, illustrating its potential application in treating cardiovascular disorders.⁸ Li et al have laid the groundwork for the potential use of anti–IL-6 trans-signaling in treating AF. Their work suggests that spg130Fc strikes a balance in mediating inflammation in patients by maintaining the classical IL-6 pathway and its positive regulatory effects. Additionally, the authors presented preliminary evidence linking elevated B/T as a diagnostic marker for AF. B/T, when monitored alongside the administration of sgp130Fc, could offer a preventive therapy approach for AF and other related diseases by curbing inflammation before it causes irreparable damage.

With every innovative therapeutic approach, challenges and considerations arise. Although the pressure overload–induced HF mouse model exhibited an increased susceptibility to AF, its representation of AF risk factors is limited. Further research involving large animal models of AF is essential to evaluate the efficacy of anti–IL-6 trans-signaling in preventing either the onset or progression of AF. Moreover, the control patient population consisted of patients with paroxysmal supraventricular tachycardia, who might have underlying proarrhythmic alterations. This merits additional studies using proper sinus rhythm control patients. As clinical evidence continues to emerge, there is a pressing need for rigorous evaluation of the safety, efficacy, and long-term effects of IL-6 trans-signaling blockade across diverse patient populations to optimize the benefits of this strategy. It is worth noting that blocking IL-6 trans-signaling can have immunosuppressive effects and may not be suitable for all patients. A better understating of the intricate interplay of IL-6 signaling pathways is imperative, along with the development of strategies for atrial-specific targeting, to minimize both known and unknown off-target effects.

AF poses a multifaceted challenge, with inflammation playing a pivotal role in its onset and progression. Targeting inflammation associated with elevated IL-6 levels, particularly through the selective IL-6 trans-signaling blockade, could offer a dual advantage: reducing inflammation and safeguarding cardiac tissue. As research advances and future clinical trials develop, the therapeutic potential of selective IL-6 trans-signaling blockade will become fully apparent.