Plasma proteomics identifies S100A8/A9 as a novel biomarker and therapeutic target for fulminant myocarditis

INTRODUCTION: Fulminant myocarditis (FM) is a lethal inflammatory myocardial disease characterized by rapid progression and poor prognosis. Investigating plasma proteins linked to FM may elucidate underlying pathological mechanisms, identify novel biomarkers for early detection in high-risk populations, and advance the development of targeted therapeutic strategies. OBJECTIVES: This study aimed to investigate the proteomic profiles of FM patients and identify potential biomarkers and therapeutic targets, focusing on S100A8/S100A9. METHODS: We conducted a comprehensive proteomic analysis of an extensive plasma sample collection derived from FM patients across three clinical cohorts. Our approach included screening for proteins correlated with cardiac dysfunction and disease severity. Key findings were validated in an independent cohort. In parallel, we employed a CVB3-induced FM mouse model to evaluate the expression of these biomarkers in myocardial tissue and assessed the effects of targeted interventions. Specifically, we investigated the therapeutic impacts of blocking the S100A8/A9 heterodimer using the inhibitor ABR-238901. RESULTS: The analysis revealed significant innate immune activation and severe metabolic disturbances in FM patients. Through proteomic profiling and correlation analysis, proteins S100A8 and S100A9 emerged as significant biomarkers linked to cardiac dysfunction and FM severity. S100A8/A9 heterodimer was validated as a crucial diagnostic marker for FM, with elevated plasma levels correlating with increased rates of cardiac death, heart transplantation, and hospitalizations due to heart failure or myocarditis. In CVB3-induced FM mouse models, myocardial tissues showed increased levels of S100A8 and S100A9. Treatment with ABR-238901 significantly reduced mortality by alleviating acute inflammation and improving cardiac function. CONCLUSION: S100A8/A9 emerged as an essential biomarker and a promising therapeutic target for FM. These findings offer new insights into FM diagnosis and suggest potential intervention strategies. These results pave the way for further research to validate the clinical application of S100A8/A9-targeted therapies, potentially improving outcomes for patients suffering from this severe cardiac condition. TRIAL REGISTRATION: ClinicalTrials.gov NCT03268642.