Cytokine-associated ROS and Ca2+ dysregulation in severe inflammatory cardiomyopathy.

AIMS: Inflammatory cardiomyopathy (iCMP) is a leading cause of heart failure, with limited therapeutic options. Excessive cytokine levels are implicated in adverse outcomes, but their pathomechanism in iCMP is poorly understood. We sought to identify key cytokines involved in severe iCMP and elucidate their potential contribution to cardiomyocyte injury. METHODS AND RESULTS: Cytokines were analysed in patients with severe biopsy-proven iCMP (n = 63; LVEF ≤ 35%) and validated in a national cohort (n = 425). In vitro experiments examined the effect of the top cytokines observed in severe iCMP with regards to production of reactive oxygen species (ROS) and calcium homeostasis in induced human pluripotent stem cell-derived cardiomyocytes (iPSC-CMs) and human aortic endothelial cells (HAECs). Three proteins (COLEC-12, CRIM-1, IL-6) were associated with severe iCMP. In iPSC-CMs, these proteins increased ROS (H2DCFDA assay) and intracellular Ca2+ levels (Fluo-4AM assay), indicating cellular stress. Effects were less pronounced in HAEC. Finally, real-world data from electronic medical records suggested a possible cardioprotective effect of clinically available inhibitors targeting these cytokines, although these findings remain exploratory and require confirmation in controlled studies. CONCLUSION: COLEC-12, CRIM-1, and IL-6 are elevated in severe iCMP and induce oxidative stress and calcium dysregulation in cultured cardiomyocytes. These findings highlight their potential as possible future therapeutic targets. CLINICAL TRIAL NUMBER: ClinicalTrials.gov Identifier: NCT04265040, NCT02187263.