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Am J Physiol Regul Integr Comp Physiol 297: R1019-R1027, 2009. First published August 5, 2009; doi:10.1152/ajpregu.00132.2009
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Articles

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

Karen D. Fairchild,1 Jeffrey J. Saucerman,2 Laura L. Raynor,1 Joseph A. Sivak,3 Yuping Xiao,3 Douglas E. Lake,3,4 and J. Randall Moorman3

Departments of 1Pediatrics, 2Biomedical Engineering, 3Internal Medicine, and 4Statistics, 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{alpha} 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{alpha} 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).






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