Endotoxin depresses heart rate variability in mice: cytokine and steroid effects

• Published in: American journal of physiology. Regulatory, integrative and comparative physiology integrative and comparative physiology, 2009-10, Vol.297 (4), p.R1019-R1027
• Main Authors: Fairchild, Karen D, Saucerman, Jeffrey J, Raynor, Laura L, Sivak, Joseph A, Xiao, Yuping, Lake, Douglas E, Moorman, J. Randall
• Format: Article
• Language: English
• Subjects: Animals; Blood Pressure; Body Temperature; Cytokines; Cytokines - administration & dosage; Cytokines - blood; Dexamethasone - pharmacology; Disease Models, Animal; Electrocardiography, Ambulatory; Gene expression; Glucocorticoids - pharmacology; Heart rate; Heart Rate - drug effects; Lipopolysaccharides; Male; Mice; Mice, Inbred C57BL; Rodents; Sepsis - chemically induced; Sepsis - drug therapy; Sepsis - immunology; Sepsis - physiopathology; Sepsis - prevention & control; Studies; Telemetry; Time Factors; Tumor Necrosis Factor-alpha - blood; Up-Regulation
• ISSN: 0363-6119; 1522-1490
• DOI: 10.1152/ajpregu.00132.2009

Departments of 1 Pediatrics, 2 Biomedical Engineering, 3 Internal Medicine, and 4 Statistics, University of Virginia School of Medicine, Charlottesville, Virginia Submitted March 6, 2009 ; accepted in final form July 28, 2009 Heart rate variability (HRV) falls in humans with sepsis, but the mechanism is not well understood. We utilized a mouse model of endotoxemia to test the hypothesis that cytokines play a role in abnormal HRV during sepsis. Adult male C57BL/6 mice underwent surgical implantation of probes to continuously monitor electrocardiogram and temperature or blood pressure via radiotelemetry. Administration of high-dose LPS ( Escherichia coli LPS, 10 mg/kg, n = 10) caused a biphasic response characterized by an early decrease in temperature and heart rate at 1 h in some mice, followed by a prolonged period of depressed HRV in all mice. Further studies showed that LPS doses as low as 0.01 mg/kg evoked a significant decrease in HRV. With high-dose LPS, the initial drops in temperature and HR were temporally correlated with peak expression of TNF 1 h post-LPS, whereas maximal depression in HRV coincided with peak levels of multiple other cytokines 3–9 h post-LPS. Neither hypotension nor hypothermia explained the HRV response. Pretreatment with dexamethasone prior to LPS significantly blunted expression of 7 of the 10 cytokines studied and shortened the duration of depressed HRV by about half. Interestingly, dexamethasone treatment alone caused a dramatic increase in both low- and high-frequency HRV. Administration of recombinant TNF caused a biphasic response in HR and HRV similar to that caused by LPS. Understanding the role of cytokines in abnormal HRV during sepsis could lead to improved strategies for detecting life-threatening nosocomial infections in intensive care unit patients. sepsis; lipopolysaccharide; dexamethasone; tumor necrosis factor alpha Address for reprint requests and other correspondence: K. D. Fairchild, Dept. of Pediatrics, Box 800386, Univ. of Virginia Health System, Hospital Drive, Charlottesville, VA 22908 (e-mail: Kdf2n{at}virginia.edu ).