OBJECTIVES: @entity299 are common in @entity3124 and associated with grave consequences. In this setting, elevated circulating histone levels have been linked to @entity299 and dysfunction in experimental models and @entity1 with @entity295 . The mechanisms underlying histone-induced @entity1370 and the functional consequences on left ventricle and right ventricle remain unclear. This study aims to examine dose-dependent effects of circulating histones on left ventricle and right ventricle function at clinically relevant concentrations. DESIGN: Prospective laboratory study with in vitro and in vivo investigations. SETTING: University research laboratory. SUBJECTS: Twelve-week old male C57BL/6 @entity19 . INTERVENTIONS: Cultured cardiomyocytes were incubated with clinically relevant histone concentrations, and a histone infusion @entity19 model was also used with hemodynamic changes characterized by echocardiography and left ventricle/right ventricle catheter-derived variables. Circulating histones and cardiac troponin levels were obtained from serial blood samples. MEASUREMENTS AND MAIN RESULTS: IV histone infusion caused time-dependent cardiac troponin elevation to indicate @entity299 . At moderate sublethal histone doses (30   mg/kg), @entity1002 was the prominent abnormality with reduced ejection fraction and prolonged relaxation time. At high doses (>=  60   mg/kg), @entity3885 induced right ventricular pressure increase and dilatation, but left ventricular end-diastolic volume improved because of reduced blood return from the lungs. Mechanistically, histones induced profound @entity460 influx and overload in cultured cardiomyocytes with dose-dependent detrimental effects on intracellular @entity460 transient amplitude, contractility, and rhythm, suggesting that histones directly affect cardiomyocyte function adversely. However, increasing histone-induced neutrophil congestion, neutrophil extracellular trap formation, and @entity715 in the pulmonary microvasculature culminated in right @entity67 . Antihistone antibody treatment abrogated histone @entity1370 . CONCLUSIONS: Circulating histones significantly compromise left ventricular and right ventricular function through different mechanisms that are dependent on histone concentrations. This provides a translational basis to explain and target the spectral manifestations of @entity299 in @entity3124 .

Circulating Histone Concentrations Differentially Affect the Predominance of Left or Right @entity67 in XXXX .

@entity1 :: ('9606', 'Species') :: ['patients'] @entity295 :: ('MESH:D018805', 'Disease') :: ['sepsis'] @entity19 :: ('10090', 'Species') :: ['mouse', 'N mice'] @entity3124 :: ('MESH:D016638', 'Disease') :: ['critical illness'] @entity3885 :: ('MESH:D008173', 'Disease') :: ['pulmonary vascular obstruction'] @entity460 :: ('MESH:D002118', 'Chemical') :: ['calcium'] @entity299 :: ('MESH:D006331', 'Disease') :: ['cardiac injury', 'cardiac dysfunction', 'Cardiac complications'] @entity715 :: ('MESH:D013927', 'Disease') :: ['thrombosis'] @entity67 :: ('MESH:D018754', 'Disease') :: ['ventricular dysfunction'] @entity1370 :: ('MESH:D066126', 'Disease') :: ['cardiotoxicity'] @entity1002 :: ('MESH:D018487', 'Disease') :: ['left ventricular contractile dysfunction']
@entity3124 :: (MESH:D016638,Disease) :: ['Critical Illness']
