Mortality Risk-Stratified Septic Serum Depresses Contractility and Mitochondrial Function in Human Induced Pluripotent Stem Cell-Derived Cardiomyocytes

Abstract

BackgroundSepsis-associated myocardial dysfunction (SAMD) is common in children with septic shock, is independently associated with mortality, and has no disease-modifying treatments. Differences in murine cardiomyocyte biology and repeated failures to translate discoveries into novel therapies for septic shock underscore a key translational need for human-relevant disease modeling. We sought to investigate human induced pluripotent stem cell-derived cardiomyocytes (iPSC-CMs) exposed to mortality risk-stratified septic serum as a model of SAMD. MethodsSerum from children with septic shock (n=120) was stratified by Pediatric Sepsis Biomarker Risk Model (PERSEVERE) II mortality probability as low, intermediate, or high risk. We conducted aptamer-based proteomic analysis of septic serum to determine differentially expressed proteins in children with high compared to low mortality risk. We treated iPSC-CMs with risk-stratified septic serum and defined contractile and mitochondrial functional and transcriptomic responses. ResultsWe found 612 differentially expressed proteins in children with high mortality probability, most prominently interleukins (IL)-6 and -8. High-risk septic serum reversibly depressed iPSC-CM contractility as measured by percent shortening, while low-risk septic serum had no impact. Further, high-risk septic serum depressed basal mitochondrial respiration, maximum uncoupled respiration, and coupled oxidative phosphorylation in iPSC-CMs relative to low-risk serum. We identified distinct patterns of gene expression due to risk-stratified serum with 5,293 differentially expressed genes, including upregulation of acute phase reactants and apolipoproteins and downregulation of chemokines, as well as transcriptional changes reflective of chronic IL-6 and IL-8 signaling. ConclusionsSeptic serum from children with high mortality risk exhibited distinct proteomic signatures, notably enriched for IL-6 and IL-8. Human iPSC-CMs differentially responded to risk-stratified septic serum, recapitulating phenotypic features of SAMD including reversible contractility depression and mitochondrial dysfunction with high-risk septic serum. These findings establish mortality risk-stratified septic serum exposure of iPSC-CMs as a human-relevant translational platform to interrogate mechanisms of myocardial dysfunction in septic shock.