Cardiac Electrical and Structural Changes During Bacterial Infection: An Instructive Model to Study Cardiac Dysfunction in Sepsis.
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.
Department of Physiology and Cell Biology, Dorothy M. Davis Heart and Lung Institute, Wexner Medical Center, College of Medicine, The Ohio State University, Columbus, OH.
Michael A
MA
Makara
Department of Microbial Infection and Immunity, Center for Microbial Interface Biology, Wexner Medical Center, College of Medicine, The Ohio State University, Columbus, OH.
Ky V
KV
Hoang
Department of Physiology and Cell Biology, Dorothy M. Davis Heart and Lung Institute, Wexner Medical Center, College of Medicine, The Ohio State University, Columbus, OH.
Latha P
LP
Ganesan
Division of Pulmonary Critical Care and Sleep Medicine, Department of Internal Medicine, Wexner Medical Center, College of Medicine, The Ohio State University, Columbus, OH.
Elliot D
ED
Crouser
Department of Microbial Infection and Immunity, Center for Microbial Interface Biology, Wexner Medical Center, College of Medicine, The Ohio State University, Columbus, OH.
John S
JS
Gunn
Department of Microbial Infection and Immunity, Center for Microbial Interface Biology, Wexner Medical Center, College of Medicine, The Ohio State University, Columbus, OH.
Joanne
J
Turner
Department of Microbial Infection and Immunity, Center for Microbial Interface Biology, Wexner Medical Center, College of Medicine, The Ohio State University, Columbus, OH.
Larry S
LS
Schlesinger
Department of Physiology and Cell Biology, Dorothy M. Davis Heart and Lung Institute, Wexner Medical Center, College of Medicine, The Ohio State University, Columbus, OH.
Peter J
PJ
Mohler
Department of Microbial Infection and Immunity, Center for Microbial Interface Biology, Wexner Medical Center, College of Medicine, The Ohio State University, Columbus, OH Murugesan.Rajaram@osumc.edu.
Murugesan V S
MV
Rajaram
D000818:Animals; D017209:Apoptosis; D016207:Cytokines / Q000378:metabolism; D004195:Disease Models, Animal; D004562:Electrocardiography; D006321:Heart / Q000503:physiopathology*; D000076249:Heat Shock Transcription Factors / Q000378:metabolism; D053583:Interleukin-1beta / Q000378:metabolism; D016209:Interleukin-8 / Q000378:metabolism; D051379:Mice; D035683:MicroRNAs / Q000378:metabolism; D009206:Myocardium / Q000378:metabolism / Q000473:pathology*; D032383:Myocytes, Cardiac / Q000473:pathology; D018805:Sepsis / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology*; D013482:Superoxide Dismutase / Q000378:metabolism; D014406:Tularemia / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology*; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism; D000099156:Superoxide Dismutase 2
D016207:Cytokines; D000076249:Heat Shock Transcription Factors; D053583:Interleukin-1beta; D016209:Interleukin-8; D035683:MicroRNAs; D013482:Superoxide Dismutase; D014409:Tumor Necrosis Factor-alpha; D000099156:Superoxide Dismutase 2; C490017:Hsf1 protein, mouse; C587672:IL1B protein, mouse; C532623:Mirn155 microRNA, mouse
cardiac damage; electrocardiogram; immunology; microRNA; myocardial inflammation; myocyte apoptosis and necrosis; pathogenesis; sepsis