Cytokines as potential novel therapy targets in inflammatory cardiomyopathy

Background

Inflammatory cardiomyopathy (iCMP) is an important cause of heart failure and frequently progresses despite immunosuppressive therapy. (1). Cytokines are frequently elevated in iCMP, yet their contribution to heart failure progression and their potential as novel therapeutic targets remain incompletely understood. (2-4).

Purpose

To identify potential therapeutic targets in severe inflammatory cardiomyopathy by combining cytokine profiling from large clinical cohorts with mechanistic studies in human cardiomyocytes and exploratory analyses of real-world clinical data.

Methods

Cytokine levels were analyzed in blood samples from patients with severe biopsy-proven inflammatory cardiomyopathy (iCMP) from our center (local cohort, n=63; LVEF ≤35%) and validated in an independent national cohort (n=425). Cytokines associated with severe iCMP were subsequently selected for mechanistic studies in human induced pluripotent stem cell–derived cardiomyocytes (iPSC-CMs) and human aortic endothelial cells (HAECs), using concentrations observed in the clinical cohorts. Following cytokine exposure, reactive oxygen species (ROS) production and calcium homeostasis were assessed. Additionally, exploratory real-world analyses were performed in patients treated with cytokine pathway inhibitors targeting the investigated cytokines to evaluate potential cardioprotective effects.

Results

Across the local and the national cohort, multiple cytokines were associated with reduced LVEF and severe iCMP (Fig. 1). Among these, COLEC-12, CRIM-1, and IL-6 were selected for mechanistic evaluation based on the strength of association and biological plausibility. In iPSC-CMs, exposure to these cytokines increased ROS production (H2DCFDA assay, Fig. 1) and intracellular Ca2+ levels (Fluo-4AM assay, Fig. 2) consistent with cellular stress and impaired calcium homeostasis. These effects were less pronounced in HAECs, suggesting a predominantly cardiomyocyte-specific response.

Together, these findings link cytokine elevations observed in severe iCMP to functional cardiomyocyte stress pathways that may contribute to myocardial dysfunction and heart failure progression. Exploratory real-world analyses further suggested a potential cardioprotective effect in patients receiving IL-6 pathway inhibitors (e.g., tocilizumab) or Janus kinase inhibitors targeting downstream IL-6–associated JAK/STAT signaling, with significantly lower NT-proBNP and high-sensitivity troponin T levels observed (5, 6).

Conclusion

COLEC12, CRIM1, and IL-6 are associated with severe iCMP and represent potential novel therapeutic targets. Integrated clinical, mechanistic, and exploratory therapeutic data suggest that cytokine-driven oxidative stress and calcium dysregulation contribute to myocardial dysfunction in myocarditis and highlight these pathways as promising targets for future therapeutic strategies.Figure 2Figure 1