The conductor of the autonomic orchestra

Abstract

Bad bedfellows - autonomic dysfunction, inflammation, and diabetes! Are they related? How? Evidence suggests the activation of inflammatory cytokines like IL-6 and TNFα in newly diagnosed type 2 diabetes and that the inflammatory change correlates with abnormalities in sympathovagal balance. Dysfunction of the autonomic system predicts cardiovascular risk and sudden death in patients with type 2 diabetes. It occurs in prediabetes, providing opportunities for early intervention. The importance of recognizing autonomic dysfunction as a predictor of morbidity and mortality with intensification of treatment suggests that all patients with type 2 diabetes at onset, and those with type 1 diabetes after 5 years should be screened for autonomic imbalance. These tests can be performed at the bedside with real time output of information - within the scope of the practicing physician - facilitates diagnosis and allows the application of sound strategies for management. The window of opportunity for aggressive control of all the traditional risk factors for cardiovascular events or sudden death with intensification of therapy is with short duration diabetes, the absence of cardiovascular disease, and a history of severe hypoglycemic events. To this list we can now add autonomic dysfunction and neuropathy, which have become the most powerful predictors of risk for mortality. It seems prudent that practitioners should be encouraged to become familiar with this information and apply risk stratification in clinical practice. After all, how difficult is it to ask patients "do you have numb feet?" and to determine their heart rate variability - it could be lifesaving. Ultimately methods to reset the hypothalamus and the inflammatory cascade are needed if we are to impact the care of patients with this compendium of conditions.

Keywords: autonomic; cardiovascular risk; hypothalamic; inflammation.

Figure 1

A diagrammatic illustration of the role of the two arms of the autonomic nervous system. Note that in general the actions of the sympathetic nervous system are illustrated as being in the opposite direction to that of the parasympathetic nervous system. Not shown here but discussed below is the CNS regulation of the immune system via the vagal cholinergic anti-inflammatory pathway adding yet another dimension to the role of the autonomic nervous system in survival of the organism. Note that Kurt Vonnegut recognized the importance of the CNS in stress but failed to recognize its role as the conductor of the endocrine and autonomic orchestra. But then he was not a biologist!

Figure 2

Afferent sensory signals are transmitted by the vagus to the nucleus of the solitary tract (NTS) and polysynaptic receptors relay to the sympathetic via the rostral ventromedullary nucleus (RVLS) and the parasympathetic nucleus ambiguous (NA and the dorsal vagal nucleus. There is both sympathetic and parasympathetic output to the celiac ganglion and the splenic nerve activates the inflammatory cascade in macrophages which may be in the spleen but occur diffusely throughout the body. Stimulation of the vagus inhibits this activation by acetylcholine binding to the α7nACHR receptor which curtails the response. Also shown is the coactivation of the hypothalamic pituitary axis with release of glucocorticoids which also modulate the inflammatory response. It is however unclear how this set point is determined in the body but what is clear is that autonomic modulation of inflammation can be achieved by altering sympathetic/parasympathetic balance.

Figure 3

The relationship between binding of ligands to the pattern recognition AGE receptor (RAGE) and inflammation, gene expression, oxidative and nitrosative stress, and damage to the macro- and microvasculature. Elevated levels of glucose bind to proteins and form AGEs, which bind to RAGEs. RAGE signaling activates NADPH oxidase and production of reactive oxygen species (ROS). Increased ROS increases advanced oxidation protein products (AOPPs), more AGEs, and AGE-modification of oxidized LDLs (oxLDLs). Furthermore, increased ROS may deplete glutathione, thereby suppressing glyoxalase I activity, a mechanism favoring further AGE accumulation. AGEs, AOPPs, macrophage glycoprotein (MAC-1), and AGE-oxLDL ligands of RAGE sustain stimulation of RAGE, and these processes, together with increased ROS, activate key transcription factors such as nuclear factor-κB (NF-κB) and Egr-1, which increase gene transcription factors and activate inflammatory mechanisms. Consequences include increased migration and activation of RAGE-expressing neutrophils, monocytes/macrophages, T-cells, and dendritic cells. This results in the release of the pro-inflammatory RAGE ligands S100/calgranulins and high-mobility group protein box-1 (HMGB1). In this inflammatory environment, further AGEs may be formed as well. Via interaction with RAGE, these ligands magnify activation of NF-κB, Agr-1, and other factors, thereby amplifying cellular stress and tissue damage leading to neurovascular dysfunction. Soluble RAGE (sRAGE) is formed from the cleavage of RAGE by disintegrins such as ADAM 10, a metalloproteinase, and β- and γ-secretases. sRAGE or a spliced variant (esRAGE) compete for binding of ligands to RAGE, and a deficiency could theoretically initiate the sequence of events activating an inflammatory cascade with an increase in the expression of pro-inflammatory cytokines [E-selectin, endothelin-1 tissue factor, vascular endothelial growth factor, and other pro-inflammatory cytokines (interleukin-6 and tumor necrosis factor-α)] and damage to neurons, kidney, eye, the vasculature, and even bone. Increasing sRAGE or its administration could competitively reduce activation of the AGE/RAGE pathway and it consequences. In addition endogenous and exogenous ligands bind to Toll-like receptors (TLR) also targeting NF-KB as well as inducing the secretion of pro-inflammatory cytokines which activate afferent sensory neurons reaching the brainstem via axons in the vagus. This in turn activates the cholinergic anti-inflammatory efferent arc which inhibits response in cytokine producing immune cells and signal through the nicotinic acetylcholine receptor subunit α7 (α7nACHR). This in turn inhibits NF-κB activation. Thus the pathways of AGE/RAGE activation of the inflammatory cascade and the inflammatory ligands target activation of an inflammatory cascade that can be abrogated by either competing with the binding of ligands to RAGE or by vagal activation of the anti-inflammatory reflex. Thus central to curtailing unbridled activation of the inflammatory cascade is the integrity of parasympathetic autonomic function or balance between the two arms of the autonomic nervous system.

Figure 4

Spectral analysis of heart rate variability.

Figure 5

The natural history of autonomic balance.

Figure 6

The effects of walking with and without a pet dog, on parasympathetic function (mean high frequency power). (A) 80-min walking programme including two 30-min walks without and with the dog (n = 13). (B) 80-min walking programme over three consecutive days (n = 3). (C) Interaction with the dog at home during 6 h of continuous monitoring (n = 4).

Figure 7

Restoration of autonomic balance.