Circulating histones are major mediators of cardiac injury in patients with sepsis

Objective: To investigate the impact of circulating histones on cardiac injury and dysfunction in a murine model and patients with sepsis. Design: Prospective, observational clinical study with in vivo and ex vivo translational laboratory investigations. Setting: General intensive care unit and University research laboratory. Subjects: Sixty-five septic patients and 27 healthy volunteers. Twelve-week-old male C57BL/6N mice. Interventions: Serial blood samples from 65 septic patients were analyzed and left ventricular (LV) function was assessed by echocardiography. Patients’ sera were incubated with cultured cardiomyocytes in the presence or absence of anti-histone antibody and cellular viability was assessed. Murine sepsis was initiated by intra-peritoneal E.coli injection (108 colony-forming unit/mouse) in 12-week old male C57BL/6N mice and the effect of anti-histone antibody (10 mg/kg) was studied. Murine blood samples were collected serially and LV function was assessed by intra-ventricular catheters and electrocardiography. Measurements and Main Results: Circulating histones and cardiac troponins in human and murine plasma were quantified. In 65 septic patients, circulating histones were significantly elevated compared to healthy controls (n=27) and linearly correlated with cardiac troponin T levels (rs=0.650,