Multimodal Analysis of Sepsis-induced Cardiomyopathy in a Baboon Model

Abstract

Sepsis-induced cardiomyopathy (SIC) significantly contributes to sepsis-related morbidity and mortality, necessitating a deeper understanding of its mechanisms. This study used a post-hoc, multimodal approach--including single-nucleus RNA sequencing (snRNA-seq), echocardiography, mitochondrial function, and histopathology--to characterize SIC in a non-human primate model. Archived data and samples from six baboons challenged with 37.5 mg/kg of purified peptidoglycan were analyzed. Vital signs and echocardiography were monitored for 8 hours; the endpoint was survival at 168 hours or euthanasia for irreversible organ failure. Septic shock--defined by hypotension, tachycardia, and elevated lactate--was associated with poor outcomes. Echocardiography showed reduced intravascular volume, contraction, stroke volume, and cardiac index. SnRNA-seq revealed distinct transcriptomic profiles: non-survivors exhibited inflammation, mitochondrial dysfunction, and maladaptive remodeling; survivors showed activation of pathways supporting contraction, metabolism, and repair. Cell-type analysis highlighted metabolic dysfunction in cardiomyocytes, TNF/NF-{kappa}B-driven inflammation in endothelial cells, and stress responses in fibroblasts and pericytes. Mitochondrial analysis showed impaired electron transport and disrupted metabolism. Histopathology revealed inflammation and myofibrillar damage, more severe in non-survivors. This model recapitulates key SIC features and supports mechanistic and therapeutic discovery.