Multi-omics Alterations Associated with Tolerance and Response to Simulated Progressive Hemorrhage in Healthy Adult Humans

Hemorrhagic shock is a leading cause of preventable death among military and civilian trauma patients. While caused by severe hypovolemia, the threshold of blood volume reduction that triggers recruitment of compensatory mechanisms varies markedly. Individuals have been classified as having low (LT) or high (HT) tolerance to hypovolemia; however, molecular features contributing to tolerance remain unclear. Here we investigate multi-omics correlates of hypovolemia tolerance and molecular responses underlying physiologic compensating mechanisms of blood loss. Healthy adult human subjects (n=133) recruited from two sites underwent lower body negative pressure (LBNP) to simulate progressive hemorrhage. The primary outcome variable was hemodynamic instability accompanied by onset of decompensated shock defined by systolic blood pressure <80 mmHg. Participants were classified into HT (n=90) and LT (n=43) subjects using a Cumulative Stress Index quantifying maximal LBNP tolerance. Genome-wide mRNA, microRNA, whole-exome sequencing, and select protein abundances were assayed using blood samples collected immediately before and after LBNP procedure. LBNP produced extensive transcriptomic response at post- compared to pre-LBNP, including natural killer cell mediated immunity activation and gas transport processes inhibition. Differentially expressed miRNAs also regulated these enriched processes. Tolerance group specific signals include alpha-beta T cell activation and MHC class II protein complex assembly inhibition in HT group. Integrated analysis of multiple molecular layers demonstrated a role of cytokines and epigenetic regulators in molecular mechanisms of compensating to progressive hemorrhage. Overall, our results indicate that individual tolerances to central hypovolemia are associated with specific genomic mechanisms underlying the capacity to compensate for severe blood loss.