As readers here know, inflammation is a fundamental factor in chronic disease and accelerated aging (neurodegeneration). A functional approach to treatment requires an objective understanding of how this system is working for each patient. Here are several of the many studies that illustrate how nervous system function and inflammation can be evaluated with heart rate variability (HRV) analysis and cytokine (‘messenger molecules’ of inflammation) levels.

The practical focus is on restoring parasympathetic nervous system (PNS) activity which inhibits inflammation. (PNS resources decline with disease, stress and age resulting in a state of ‘sympathetic nervous system dominance’.) This paper just published in the journal  Shock shows how autonomic nervous system activity (sympathetic and parasympathetic) as measured by HRV corresponds to inflammatory cytokine activity, in this case when stimulated by endotoxins (poisons produced by bacterial infections):

“Autonomic inputs from the sympathetic and parasympathetic nervous systems, as measured by heart rate variability (HRV), have been reported to correlate to the… responses to infectious challenge… In addition, parasympathetic/vagal activity has been shown experimentally to exert anti-inflammatory effects via attenuation of splanchnic tissue TNF-α [cytokine] production. We sought… to determine if baseline HRV parameters correlated with endotoxin-mediated circulating cytokine responses.”

They documented a strong correspondence regardless of gender, body mass index and resting heart rate:

“…we found a significant correlation of several baseline HRV parameters…on TNF-α release after endotoxin exposure.”

This is not a new observation. An interesting study published a few years ago in the journal Psychosomatic Medicine documents the HRV expression of autonomic activity in response to an inflammatory challenge and its correspondence to cytokine production. They begin by noting that:

“…the autonomic nervous system plays a key role in regulating the magnitude of immune responses to inflammatory stimuli. Signaling by the parasympathetic system inhibits the production of proinflammatory cytokines by activated monocytes/macrophages and thus decreases local and systemic inflammation.”

They examined the relationship of HRV to lipopolysaccharide-induced production of the inflammatory cytokines interleukin (IL)-1ß, IL-6, tumor necrosis factor (TNF)-{alpha}, and IL-10. What did the data show?

“Consistent with animal findings, higher derived estimates of vagal activity measured during paced respiration* were associated with lower production of the proinflammatory cytokines TNF-{alpha} and IL-6…These associations persisted after controlling for demographic and health characteristics, including age, gender, race, years of education, smoking, hypertension, and white blood cell count.”

Their conclusion has profound implications for the biological mechanism by which stress causes inflammation:

“These data provide initial human evidence that vagal activity is inversely related to inflammatory competence, raising the possibility that vagal regulation of immune reactivity may represent a pathway linking psychosocial factors to risk for inflammatory disease.”

How might this show up in heart disease? This paper published not long ago in the journal Brain, Behavior, and Immunity investigates the links between HRV, inflammatory cytokines, coronary heart disease and depression:

“Studies show negative correlations between heart rate variability (HRV) and inflammatory markers [less variability = more inflammation]…We investigated links between short-term HRV and inflammatory markers in relation to depression in acute coronary syndrome (ACS) patients.”

They measured C-reactive protein (CRP), interleukin-6 (IL-6, a cytokine), depression symptoms and heart rate variability determinants of autonomic function. What did their data show?

“…all HRV measures were negatively and significantly associated with both inflammatory markers…HRV independently accounted for at least 4% of the variance in CRP in the depressed, more than any factor except BMI.”

Interestingly, they also noted that:

“Relationships between measures of inflammation and autonomic function are stronger among depressed than non-depressed cardiac patients. Interventions targeting regulation of both autonomic control and inflammation may be of particular importance.”

The research of another group published in the Journal of Critical Care used sepsis as their model.

“The aim of the study was to investigate possible associations between different heart rate variability (HRV) indices and various biomarkers of inflammation in 45 septic patients.”

They examined the correlation between HRV, C-reactive protein, and the cytokines  interleukin 6 and interleukin 10:

“Our data suggest that low HRV and sympathovagal balance during septic shock are associated with both an increased hyperinflammatory and antiinflammatory response.”

The antiinflammatory response corresponds to high HRV and interleukin-10, the cytokine that is also increased by vitamin D.

How can we reduce inflammation by increasing HRV and reducing inflammatory cytokines? There are numerous methods; one is to increase cholinergic activity in the nervous system (parasympathetic activity mediated by the neurotransmitter acetylcholine). We can increase this with natural precursor support for acetylcholine. This study published recently in the Journal of Internal Medicine shows the connection between vagal parasympathetic function (as shown by HRV), inflammatory cytokines, cholinergic activity and rheumatoid arthritis:

“The central nervous system regulates innate immunity in part via the cholinergic anti-inflammatory pathway, a neural circuit that transmits signals in the vagus nerve that suppress pro-inflammatory cytokine production…Vagus nerve activity is significantly suppressed in patients with autoimmune diseases, including rheumatoid arthritis (RA). It has been suggested that stimulating the cholinergic anti-inflammatory pathway may be beneficial to patients…”

They found that increasing cholinergic signaling in stimulated whole blood cultures suppressed cytokine production in rheumatoid arthritis patients whose vagal activity was deficient:

“These findings suggest that it is possible to pharmacologically target the α7nAChR dependent control of cytokine release in RA patients with suppressed vagus nerve activity.”

In a functional medicine practice, of course, we use natural acetylcholine precursors.

This is a drop in the bucket, but here’s one more fascinating paper published recently in the journal Brain, Behavior, and Immunity that shows how acetylcholine activity in the brain (the upper level of autonomic regulation) controls systemic cytokine levels through vagal function:

“The excessive release of cytokines by the immune system contributes importantly to the pathogenesis of inflammatory diseases. Recent advances in understanding the biology of cytokine toxicity led to the discovery of the “cholinergic anti-inflammatory pathway,” defined as neural signals transmitted via the vagus nerve that inhibit cytokine release…Vagus nerve regulation of peripheral functions is controlled by brain nuclei and neural networks…Here we report that brain acetylcholinesterase activity controls systemic and organ specific TNF [cytokine] production during endotoxemia.”

They demonstrated that inhibiting the breakdown of acetylcholine† markedly reduced proinflammatory serum TNF levels through the resulting increasing vagus nerve signaling which prevented inflammatory damage. What do they conclude from their research?

“These findings show that inhibition of brain acetylcholinesterase [that breaks down acetylcholine] suppresses systemic inflammation through a central…mediated and vagal…dependent mechanism. Our data also indicate that a clinically used centrally-acting acetylcholinesterase inhibitor† can be utilized to suppress abnormal inflammation to therapeutic advantage.”

* There are numerous therapies to reduce inflammation by increasing parasympathetic function. Breathing is a powerful stimulus to the autonomic nervous system. We train breathing with biofeedback while simultaneously monitoring for CO2 (capnography) and coherence in HRV to hit the physiological “sweet spot”.

† Agents that inhibit the breakdown of neurotransmitters including reuptake inhibitors do not restore the body’s ability to make its own. Precursor therapy provides the natural ingredients that have been depleted or are insufficient to meet genetic needs so neurotransmitters can be increased naturally.