Circulating Histone Concentrations Differentially Affect the Predominance of Left or Right Ventricular Dysfunction in Critical Illness
Circulating Histone Concentrations Differentially Affect the Predominance of Left or Right Ventricular Dysfunction in Critical Illness
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DOI：
10.1097/ccm.0000000000001413
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发表时间：
2016-05-01
影响因子：
8.8
通讯作者：
Toh, Cheng-Hock
中科院分区：
文献类型：
--
作者：
Alhamdi, Yasir;Zi, Min;Toh, Cheng-Hock
目的：心脏并发症在危重病中常见，且后果严重。在这种情况下，循环组蛋白水平升高与实验模型和脓毒症患者的心脏损伤和功能障碍有关。组蛋白诱导的心脏毒性的机制和对左心室和右心室的功能影响尚不清楚。本研究的目的是检查临床相关浓度下循环组蛋白对左心室和右心室功能的剂量依赖性作用。设计：体外和体内研究的前瞻性实验室研究。设置：大学研究实验室。受试者：12周龄雄性C57 BL/6 N小鼠。干预措施：将培养的心肌细胞与临床相关的组蛋白浓度孵育，组蛋白输注小鼠模型也被用于通过超声心动图和左心室/右心室导管衍生变量表征血流动力学变化。循环组蛋白和心肌肌钙蛋白水平从serial blood samples. Measures和主要结果：IV组蛋白输注引起时间依赖性心肌肌钙蛋白升高，表明心脏损伤。在中等亚致死剂量组蛋白（30 mg/kg）下，左心室收缩功能障碍是射血分数降低和舒张时间延长的显著异常。在高剂量（>= 60 mg/kg）下，肺血管阻塞引起右心室压力升高和扩张，但由于肺部血液回流减少，左心室舒张末期容积有所改善。在机械上，组蛋白诱导培养的心肌细胞中的深刻的钙内流和过载，对细胞内钙瞬时振幅、收缩性和节律具有剂量依赖性的有害作用，这表明组蛋白直接不利地影响心肌细胞功能。然而，增加组蛋白诱导的中性粒细胞充血，中性粒细胞细胞外陷阱的形成，和血栓形成的肺微血管在右心室功能障碍的高潮。抗组蛋白抗体治疗废除组蛋白cardiotoxic.Conclusions：循环组蛋白显着损害左心室和右心室功能，通过不同的机制，依赖于组蛋白浓度。这为解释和靶向危重病中心功能不全的光谱表现提供了翻译基础。(Crit Care Med 2016; 44：e278-e288）
Objectives: Cardiac complications are common in critical illness and associated with grave consequences. In this setting, elevated circulating histone levels have been linked to cardiac injury and dysfunction in experimental models and patients with sepsis. The mechanisms underlying histone-induced cardiotoxicity 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/6N mice.Interventions: Cultured cardiomyocytes were incubated with clinically relevant histone concentrations, and a histone infusion mouse 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 timedependent cardiac troponin elevation to indicate cardiac injury. At moderate sublethal histone doses ( 30 mg/kg), left ventricular contractile dysfunction was the prominent abnormality with reduced ejection fraction and prolonged relaxation time. At high doses (>= 60 mg/kg), pulmonary vascular obstruction 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 calcium influx and overload in cultured cardiomyocytes with dose-dependent detrimental effects on intracellular calcium transient amplitude, contractility, and rhythm, suggesting that histones directly affect cardiomyocyte function adversely. However, increasing histone-induced neutrophil congestion, neutrophil extracellular trap formation, and thrombosis in the pulmonary microvasculature culminated in right ventricular dysfunction. Antihistone antibody treatment abrogated histone cardiotoxicity.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 cardiac dysfunction in critical illness. (Crit Care Med 2016; 44: e278-e288)