• Yasir Alhamdi, Simon T Abrams, Zhenxing Cheng, Shengjie Jing, Dunhao Su, Zhiyong Liu, Steven Lane, Ingeborg Welters, Guozheng Wang, and Cheng-Hock Toh.
• 1Department of Clinical Infection, Microbiology and Immunology, Institute of Infection and Global Health, University of Liverpool, Liverpool, United Kingdom. 2The Medical School, Southeast University, Nanjing, China. 3Department of Biostatistics, Institute of Translational Medicine, University of Liverpool, Liverpool, United Kingdom. 4Institute of Aging and Chronic Disease, University of Liverpool, Liverpool, United Kingdom. 5Intensive Care Unit, Royal Liverpool University Hospital, Liverpool, United Kingdom. 6Roald Dahl Haemostasis & Thrombosis Centre, Royal Liverpool University Hospital, Liverpool, United Kingdom.
• Crit. Care Med. 2015 Oct 1; 43 (10): 2094-103.

ObjectiveTo investigate the impact of circulating histones on cardiac injury and dysfunction in a murine model and patients with sepsis.DesignProspective, observational clinical study with in vivo and ex vivo translational laboratory investigations.SettingGeneral ICU and university research laboratory.SubjectsSixty-five septic patients and 27 healthy volunteers. Twelve-week-old male C57BL/6N mice.InterventionsSerial blood samples from 65 patients with sepsis were analyzed, and left ventricular function was assessed by echocardiography. Patients' sera were incubated with cultured cardiomyocytes in the presence or absence of antihistone antibody, and cellular viability was assessed. Murine sepsis was initiated by intraperitoneal Escherichia coli injection (10(8) colony-forming unit/mouse) in 12-week-old male C57BL/6N mice, and the effect of antihistone antibody (10 mg/kg) was studied. Murine blood samples were collected serially, and left ventricular function was assessed by intraventricular catheters and electrocardiography.Measurements And Main ResultsCirculating histones and cardiac troponins in human and murine plasma were quantified. In 65 patients with sepsis, circulating histones were significantly elevated compared with healthy controls (n = 27) and linearly correlated with cardiac troponin T levels (rs = 0.650; p < 0.001), noradrenaline doses required to achieve hemodynamic stability (rs = 0.608; p < 0.001), Sequential Organ Failure Assessment scores (p = 0.028), and mortality (p = 0.008). In a subset of 36 septic patients without prior cardiac disease, high histone levels were significantly associated with new-onset left ventricular dysfunction (p = 0.001) and arrhythmias (p = 0.01). Left ventricular dysfunction only predicted adverse outcomes when combined with elevated histones or cardiac troponin levels. Furthermore, patients' sera directly induced histone-specific cardiomyocyte death ex vivo, which was abrogated by antihistone antibodies. In vivo studies on septic mice confirmed the cause-effect relationship between circulating histones and the development of cardiac injury, arrhythmias, and left ventricular dysfunction.ConclusionCirculating histones are novel and important mediators of septic cardiomyopathy, which can potentially be utilized for prognostic and therapeutic purposes.

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