Cardiac Electrical and Structural Changes During Bacterial Infection: An Instructive Model to Study Cardiac Dysfunction in Sepsis.
Cardiac Electrical and Structural Changes During Bacterial Infection: An Instructive Model to Study Cardiac Dysfunction in Sepsis.
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DOI：
10.1161/jaha.116.003820
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发表时间：
2016-09-12
影响因子：
5.4
通讯作者：
Rajaram MV
中科院分区：
文献类型：
--
作者：
Makara MA;Hoang KV;Ganesan LP;Crouser ED;Gunn JS;Turner J;Schlesinger LS;Mohler PJ;Rajaram MV
脓毒症合并心功能不全患者死亡率明显增高。尽管有几种途径与脓毒症中的心肌损伤相关，但确切原因仍不清楚，治疗选择有限。本研究旨在建立一种新的模型来研究脓毒症进展过程中的早期心脏损害事件。 土拉热弗朗西丝菌杀新亚种（Ft.n）是一种革兰氏阴性细胞内病原体，可引起小鼠严重脓毒症综合征。BALB/c小鼠（N=12）进行假处理或通过鼻内途径感染Ft.n。在多个时间点记录连续心电图，直至96小时。然后收获心脏用于组织学和基因表达研究。与脓毒症患者相似，我们在我们的鼠Ft.n感染模型中说明了心脏电和结构表型，包括突出的R'波形成、延长的QRS间期和显著的左心室功能障碍。值得注意的是，在感染的动物中，我们检测到心肌中的许多微小病变，先前在医院链球菌感染和败血症患者中观察到。我们发现Ft.n介导的微病变归因于心肌细胞凋亡、免疫细胞浸润增加和炎症介质（肿瘤坏死因子、白细胞介素[IL]-1 β、IL-8和超氧化物歧化酶2）的表达。最后，我们确定心脏Ft.n感染后microRNA-155表达增加和热休克因子1快速降解是心肌炎症和细胞凋亡的主要原因。我们已经开发并表征了Ft.n感染模型，以了解脓毒症心脏失调的发病机制。我们的研究结果说明了新的在体内表型的基础上的心功能不全，在Ft.n感染与显着的翻译影响，我们的理解脓毒症的病理生理学。
Sepsis patients with cardiac dysfunction have significantly higher mortality. Although several pathways are associated with myocardial damage in sepsis, the precise cause(s) remains unclear and treatment options are limited. This study was designed to develop a new model to investigate the early events of cardiac damage during sepsis progression. Francisella tularensis subspecies novicida (Ft.n) is a Gram‐negative intracellular pathogen causing severe sepsis syndrome in mice. BALB/c mice (N=12) were sham treated or infected with Ft.n through the intranasal route. Serial electrocardiograms were recorded at multiple time points until 96 hours. Hearts were then harvested for histology and gene expression studies. Similar to septic patients, we illustrate both cardiac electrical and structural phenotypes in our murine Ft.n infection model, including prominent R' wave formation, prolonged QRS intervals, and significant left ventricular dysfunction. Notably, in infected animals, we detected numerous microlesions in the myocardium, previously observed following nosocomial Streptococcus infection and in sepsis patients. We show that Ft.n‐mediated microlesions are attributed to cardiomyocyte apoptosis, increased immune cell infiltration, and expression of inflammatory mediators (tumor necrosis factor, interleukin [IL]‐1β, IL‐8, and superoxide dismutase 2). Finally, we identify increased expression of microRNA‐155 and rapid degradation of heat shock factor 1 following cardiac Ft.n infection as a primary cause of myocardial inflammation and apoptosis. We have developed and characterized an Ft.n infection model to understand the pathogenesis of cardiac dysregulation in sepsis. Our findings illustrate novel in vivo phenotypes underlying cardiac dysfunction during Ft.n infection with significant translational impact on our understanding of sepsis pathophysiology.