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

We stratified previously banked serum from children with septic shock by Pediatric Sepsis Biomarker Risk Model (PERSEVERE) II mortality probability as low, intermediate, or high risk. We treated iPSC-CM spheroids with 10% v/v diluted risk-stratified septic serum and defined contractile and mitochondrial functional and transcriptomic responses.

High-risk septic serum reversibly depressed iPSC-CM contractility as measured by percent shortening and spontaneous beat frequency, while low-risk septic serum had no impact. Further, high-risk septic serum depressed measures of mitochondrial function and drove distinct patterns of gene expression. These findings validate mortality risk-stratified septic serum exposure of iPSC-CMs as a human-relevant translational platform to interrogate mechanisms of myocardial dysfunction in septic shock.