Endotoxemia is Associated With Partial Uncoupling of Cardiac Pacemaker From Cholinergic Neural Control in Rats

Abstract

Cardiac cycle is regulated by a complex interplay between autonomic nervous system and cardiac pacemaker cells. Decreased heart rate variability (HRV) and increased cardiac rhythm regularity are associated with poor prognosis in patients with systemic inflammation (e.g., sepsis). However, the underlying mechanism of decreased HRV in systemic inflammation is not understood. It is known that greater regularity in a complex system could indicate uncoupling of the system's components. The present study aimed to test the hypothesis that impaired responsiveness of cardiac pacemaker to autonomic nervous system may lead to uncoupling of the cardiovascular regulatory mechanisms during systemic inflammation. Systemic inflammation was induced by intraperitoneal injection of endotoxin (lipopolysaccharide, 1 mg/kg) in rats. Cardiovascular signals were recorded in conscious animals using a telemetric system. Heart rate dynamics was analyzed using Poincaré plot, and cardiac cycle regularity was assessed by sample entropy analysis. Spontaneously beating atria were isolated, and chronotropic responsiveness to adrenergic and cholinergic stimulation was assessed using standard organ bath. Sample entropy decreased significantly 4 h after endotoxin injection in conscious rats. Vagal modulation of cardiac cycle (as assessed by Poincaré plot) also exhibited a significant reduction in endotoxemic rats. Acute endotoxin challenge was associated with a significant hyporesponsiveness of isolated spontaneously beating atria to cholinergic stimulation. The chronotropic responsiveness to adrenergic stimulation was identical in controls and endotoxin-treated rats. These data propose that systemic inflammation is linked to reduced cardiac responsiveness to cholinergic stimulation. This may lead to partial uncoupling of cardiac pacemaker cells from autonomic neural control and can explain decreased HRV during systemic inflammation.

Heart rate variability analysis is more sensitive at identifying neonatal sepsis than conventional vital signs

“…ELBW septic neonates demonstrated a greater SD2 than SD1 as compared to healthy neonates, and this correlated with the SDRR, in that sepsis has a greater influence on LF. These findings are similar to an animal study examining HRV after injection of endotoxin (37). CSI (SD2/SD1) and CVI (log (SD1×SD2)) are additional values calculated from the Poincare plot (38).…”

A Multiscale Entropy-Based Tool for Scoring Severity of Systemic Inflammation*

“…The extreme and fast loss of variability, also detected with linear indices and DFA, argues in favor of a direct neurological effect on control of the heart, most likely mediated via chemosensitive afferent fibers of the sympathetic and parasympathetic ANS that react to inflammatory substances such as reactive oxygen species, cytokines, and prostaglandins, as well as direct effects on cardiac ion channels (24)(25)(26)(27). The loss of variability was reflected in a very acute decline of S E over low scales, expanding to higher scales during the progression of TNF-or LPS-induced inflammatory shock, until in some cases the profile was approaching that of white noise.…”

On heart rate variability and autonomic activity in homeostasis and in systemic inflammation

“…Parasympathetic afferent sensory fibers are activated in response to inflammation, leading to not only the central release of hormones, but also efferent parasympathetic activity which exerts an anti-inflammatory effect through acetylcholine signaling. Based on the view that HF power reflects parasympathetic activity, some have deemed it paradoxical that HF power and other correlated HRV metrics are so significantly suppressed in endotoxemia (Fairchild et al, 2011; Gholami et al, 2012). Fairchild et al .…”