Pathogen-induced heart rate changes associated with cholinergic nervous system activation

Am J Physiol Regul Integr Comp Physiol. 2011 Feb;300(2):R330-9. doi: 10.1152/ajpregu.00487.2010. Epub 2010 Nov 10.


The autonomic nervous system plays a central role in regulation of host defense and in physiological responses to sepsis, including changes in heart rate and heart rate variability. The cholinergic anti-inflammatory response, whereby infection triggers vagal efferent signals that dampen production of proinflammatory cytokines, would be predicted to result in increased vagal signaling to the heart and increased heart rate variability. In fact, decreased heart rate variability is widely described in humans with sepsis. Our studies elucidate this apparent paradox by showing that mice injected with pathogens demonstrate transient bradyarrhythmias of vagal origin in a background of decreased heart rate variability (HRV). Intraperitoneal injection of a large inoculum of Gram-positive or Gram-negative bacteria or Candida albicans rapidly induced bradyarrhythmias of sinus and AV nodal block, characteristic of cardiac vagal firing and dramatically increased short-term HRV. These pathogen-induced bradycardias were immediately terminated by atropine, an antagonist of muscarinic cholinergic receptors, demonstrating the role of vagal efferent signaling in this response. Vagal afferent signaling following pathogen injection was demonstrated by intense nuclear c-Fos activity in neurons of the vagal sensory ganglia and brain stem. Surprisingly, pathogen-induced bradycardia demonstrated rapid and prolonged desensitization and did not recur on repeat injection of the same organism 3 h or 3 days after the initial exposure. After recovery from the initial bradycardia, depressed heart rate variability developed in some mice and was correlated with elevated plasma cytokine levels and mortality. Our findings of decreased HRV and transient heart rate decelerations in infected mice are similar to heart rate changes described by our group in preterm neonates with sepsis. Pathogen sensing and signaling via the vagus nerve, and the desensitization of this response, may account for periods of both increased and decreased heart rate variability in sepsis.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Atropine / pharmacology
  • Autonomic Pathways / physiology
  • Bradycardia / etiology
  • Bradycardia / physiopathology
  • Brain Stem / physiology
  • Candida albicans
  • Candidiasis / blood
  • Candidiasis / complications
  • Candidiasis / physiopathology
  • Cholinergic Fibers / drug effects
  • Cholinergic Fibers / physiology*
  • Cytokines / blood
  • Efferent Pathways / drug effects
  • Efferent Pathways / physiology
  • Electrocardiography
  • Ganglia, Sensory / physiology
  • Heart / drug effects
  • Heart / physiopathology
  • Heart Rate / physiology*
  • Infections / blood
  • Infections / complications
  • Infections / physiopathology*
  • Klebsiella Infections / blood
  • Klebsiella Infections / complications
  • Klebsiella Infections / physiopathology
  • Klebsiella pneumoniae
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Proto-Oncogene Proteins c-fos / metabolism
  • Sepsis / mortality
  • Sepsis / physiopathology
  • Staphylococcal Infections / blood
  • Staphylococcal Infections / complications
  • Staphylococcal Infections / physiopathology
  • Staphylococcus aureus
  • Telemetry
  • Vagus Nerve / drug effects
  • Vagus Nerve / physiology*


  • Cytokines
  • Proto-Oncogene Proteins c-fos
  • Atropine