Abstract Wed151: Multi-Omics Profiling of iPSC-Cardiomyocytes Identifies Novel Drivers and Therapeutics of Sepsis-Induced Cardiomyopathy

Introduction: Sepsis cardiomyopathy is a fatal acute ventricular dysfunction unrelated to myocardial ischemia and is associated with a significant increase in the mortality rate of up to 70-90%. Sepsis survivors who undergo myocardial remission after similar cardiomyopathies are at higher risk of developing severe cardiovascular morbidities in the future. ~40% of septic patients develop cardiomyopathies, while others do not, despite both having normal baseline cardiac function. Sepsis-induced cardiomyopathy is associated with sex, age, and hemoglobin levels; however, its mechanisms remain unclear. This is due to the inability of in vivo sepsis models to accurately mimic the cardiomyocyte responses observed in patients. These gaps should ideally be studied in the heart tissues of sepsis patients; however, human cardiac tissue is essentially unavailable for such analysis. Human induced pluripotent stem cells (hiPSC) are a powerful platform for addressing these gaps. Goal: To establish a human-specific sepsis cardiomyopathy model using hiPSC-cardiomyocytes that faithfully recapitulates the response of patients’ cardiomyocytes to sepsis. Method and Result: To develop a clinically relevant human sepsis-cardiomyopathy model, hiPSC-cardiomyocytes were treated with serum isolated from sepsis patients. The samples were characterized by quantifying 26 sepsis-related cytokines in each sample and only significantly correlated samples were pooled and used to treat the cardiomyocytes. The sepsis serum treatment resulted in impaired mitochondrial respiration, decreased viability, elevated ROS and apoptosis, altered beating rates, disrupted electrical conduction, dysregulated calcium handling, and sarcomere disorganization. RNAseq identified 3945 significantly differentially expressed genes. Moreover, gene set enrichment analysis identified many known sepsis-regulated enriched pathways. Following this, we analyzed ATACseq data and identified 3800 significantly differential accessible chromatin loci emphasizing the important regulatory role of chromatin remodeling in sepsis cardiomyopathy. Integrated ATAC-seq and RNA-seq analyses uncovered novel therapeutic targets linked to the regulatory mechanisms underlying cardiomyopathy pathogenesis. Conclusion: To the best of our knowledge this is the first human-specific model of sepsis cardiomyopathy that successfully recapitulate clinical features of sepsis cardiomyopathy and lay the foundation for subsequent mechanistic studies.