Heart rate variability, cytokine, and brain responses to infection: insights from a mouse model
© BioMed Central Ltd 2009
Published: 11 November 2009
Continuous heart rate variability (HRV) monitoring can detect early sepsis in certain high-risk patient populations, but the mechanisms by which sepsis depresses HRV are not well understood. Our prior studies in rodents have shown that endo-toxin causes cytokine-related depression of HRV and activation of specific neuronal networks. The aim of the current studies was to identify pathogen-specific patterns of cytokine expression, HRV changes, and activation of central autonomic pathways in mice.
Materials and methods
Adult male C57BL/6 mice implanted with radiotelemetry probes for continuous ECG and temperature monitoring were inoculated intraperitoneally with Klebsiella pneumoniae (KP, n = 21), methicillin-resistant Staphylococcus aureus (MRSA-COL, n = 9) or Candida albicans (CA-SC5314, n = 2). Heart rate variability (standard deviation of RR intervals) was measured continuously for up to 3 days in K. pneumoniae and MRSA mice and up to 3 weeks in CA mice. Blood was obtained at two or more time points for culture and measurement of G-CSF, KC, MIP-1β, IFNγ, TNFα, IL-6, and IL-10. Neuronal activation was assessed in multiple brain regions of K. pneumoniae-infected mice by c-Fos staining.
Compared with sham-treated mice, infected mice had increases in multiple cytokines at 18 hours and 42 hours post inoculation. Cytokine profiles were similar among the three organisms except that CA-infected mice expressed less KC. Bacteria-inoculated mice with adverse outcome (positive blood culture and/or death, n = 8 of 21 K. pneumoniae and 3 of 9 MRSA) had significantly higher levels of all cytokines compared with mice with good outcome. Substantial depression of HRV was seen in all 11 bacteria-infected mice with adverse outcome and in only one of 19 mice with good outcome. Levels of G-CSF and IL-6 were negatively correlated with HRV (Spearman correlation coefficient = -0.36 and -0.37, respectively, P = 0.05 for each) and there was a trend toward a correlation with KC (-0.35, P = 0.07). Immunohistochemical studies revealed that, compared with sham-treated controls (n = 2), K. pneumoniae infection (n = 3) was associated with c-Fos induction in the dorsal vagal complex and ventrolateral medulla, paraventricular hypothalamic nucleus, preoptic area, subfornical organ, bed nucleus of the stria terminalis, and medial prefrontal and insular cortices. c-Fos immunoreactivity also occurred in ventricular ependymal cells and in cells associated with large blood vessels.
Infection with Gram-positive or Gram-negative bacteria invokes similar changes in cytokines and HRV in mice, whereas preliminary studies suggest Candida infection results in different patterns. K. pneumoniae infection causes widespread neuronal activation within the central autonomic network.