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Circulating Histones Are Major Mediators of Cardiac Injury in Patients With Sepsis.

Abstract：

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 ICU 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 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 RESULTS:Circulating 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. CONCLUSION:Circulating histones are novel and important mediators of septic cardiomyopathy, which can potentially be utilized for prognostic and therapeutic purposes.

journal_name

Crit Care Med

journal_title

Critical care medicine

authors

Alhamdi Y,Abrams ST,Cheng Z,Jing S,Su D,Liu Z,Lane S,Welters I,Wang G,Toh CH

doi

10.1097/CCM.0000000000001162

subject

Has Abstract

pub_date

2015-10-01 00:00:00

pages

2094-103

issue

eissn

0090-3493

issn

1530-0293

journal_volume

pub_type

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Circulating Histones Are Major Mediators of Cardiac Injury in Patients With Sepsis.