Endotoxin depresses heart rate variability in mice: cytokine and steroid effects.
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 TNFalpha 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 TNFalpha 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.
Fairchild
Karen D
KD
Departments of Pediatrics, University of Virginia School of Medicine, Charlottesville, Virginia 22908, USA. Kdf2n@virginia.edu
Saucerman
Jeffrey J
JJ
Raynor
Laura L
LL
Sivak
Joseph A
JA
Xiao
Yuping
Y
Lake
Douglas E
DE
Moorman
J Randall
JR
D000818:Animals; D001794:Blood Pressure; D001831:Body Temperature; D016207:Cytokines / Q000008:administration & dosage / Q000097:blood*; D003907:Dexamethasone / Q000494:pharmacology*; D004195:Disease Models, Animal; D015716:Electrocardiography, Ambulatory; D005938:Glucocorticoids / Q000494:pharmacology*; D006339:Heart Rate / Q000187:drug effects*; D008070:Lipopolysaccharides; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018805:Sepsis / Q000139:chemically induced / Q000188:drug therapy / Q000276:immunology / Q000503:physiopathology* / Q000517:prevention & control; D013686:Telemetry; D013997:Time Factors; D014409:Tumor Necrosis Factor-alpha / Q000097:blood; D015854:Up-Regulation
D016207:Cytokines; D005938:Glucocorticoids; D008070:Lipopolysaccharides; D014409:Tumor Necrosis Factor-alpha; C482199:lipopolysaccharide, E coli O55-B5; D003907:Dexamethasone