Immature neutrophil response is associated with cardiac complications after non-traumatic subarachnoid hemorrhage

Acute non-traumatic subarachnoid hemorrhage (SAH) is complicated by systemic inflammation and cardiac dysfunction that contribute to the high rates of morbidity and mortality. To better define the mechanistic relationship between immune response and cardiac complications, we evaluated subpopulations of circulating immune cells and their associations with abnormalities of cardiac rhythm, injury biomarkers, and mechanical function after hemorrhage. In this single-site prospective observational study, we screened all adult patients presenting to our neurocritical care unit with non-traumatic SAH who required external ventricular drain (EVD) placement for treatment of hydrocephalus. Following informed consent, peripheral blood samples were obtained at post-bleed days (PBDs) 1, 3, 5, 7, and 10. Subjects were separated into groups based on evidence of cardiac abnormalities (cAbn(+))" versus "no cardiac abnormalities (cAbn(-))," and flow cytometric analysis was used to identify and quantify immune cell subpopulations. Circulating neutrophil-secreted factors, including myeloperoxidase (MPO), were measured in plasma using ELISA. We measured associations between these immune factors and cardiac abnormalities. Sixty patients were enrolled between January 2018 and August 2023. Our patient cohort was 65% female with a median age of 58 (IQR 51-68). Poor grade SAH (Hunt Hess = 4-5) occurred in 52% (n = 31) of patients. In the overall cohort 47 (78%) required prolonged mechanical ventilation (> 24-hours), and 52 (87%) underwent coil embolization/clipping of their aneurysm. The average ICU and hospital lengths of stay (LOS) were 18.5 (IQR 12.2-22) and 23 (IQR 18.2-33.8) days, respectively. In-hospital mortality for enrolled patients was 11.8% and overall mortality 6 months after discharge was 25% (n = 15). 40% (n = 24) of patients were discharged home, 37% (n = 22) to acute rehabilitation, 8% (n = 5) to SNF, and 3% (n = 2) to hospice. Cardiac abnormalities after SAH were associated with increased circulating neutrophil counts but not monocyte or lymphocyte levels. Circulating neutrophils in patients with cardiac abnormalities also had reduced cell-surface expression of maturation markers CD10, CD14, and CD16 in patients with cardiac abnormalities. Elevated levels of immature neutrophils and circulating levels of lipocalin-2, and myeloperoxidase (MPO) correlated with increased Hunt-Hess score, ICU, and hospital length of stay. Higher grade SAH was associated with increased immature neutrophil response, which was associated with cardiac abnormalities. These cardiac abnormalities tracked with increased levels of pro-inflammatory lipocalin-2 and MPO, and worse outcomes.