The Relationship between a New Biomarker of Vagal Neuroimmunomodulation and Survival in Two Fatal Cancers.

BACKGROUND: The vagus nerve may slow tumor progression because it inhibits inflammation. This study examined the relationship between a new vagal neuroimmunomodulation (NIM) index and survival in fatal cancers. METHOD: We retroactively derived markers of vagal nerve activity indexed by heart rate variability (HRV), specifically the root mean square of successive differences (RMSSD), from patients' electrocardiograms near diagnosis. The NIM index was the ratio of RMSSD to C-reactive protein levels (RMSSD/CRP). Sample 1 included 202 Belgian patients with advanced pancreatic cancer (PC), while sample 2 included 71 Belgian patients with non-small cell lung cancer (NSCLC). In both samples, we examined the overall survival, while in sample 2, we additionally examined the survival time in deceased patients. RESULTS: In PC patients, in a multivariate Cox regression controlling for confounders, the NIM index had a protective relative risk (RR) of 0.68 and 95% confidence interval (95% CI) of 0.51-0.92. In NSCLC patients, the NIM index also had a protective RR of 0.53 and 95% CI of 0.32-0.88. Finally, in NSCLC, patients with a higher NIM index survived more days (475.2) than those with lower NIM (285.1) (p < 0.05). CONCLUSIONS: The NIM index, reflecting vagal modulation of inflammation, may be a new independent prognostic biomarker in fatal cancers.

Effects of short and prolonged transcutaneous vagus nerve stimulation on heart rate variability in healthy subjects.

The vagus nerve is strategically located in the body, and has multiple homeostatic and health-promoting effects. Low vagal activity predicts onset and progression of diseases. These are the reasons to activate this nerve. This study examined the effects of transcutaneous vagus nerve stimulation (t-VNS) on a main index of vagal activity, namely heart rate variability (HRV). In Study 1, we compared short (10min) left versus right ear t-VNS versus sham (no stimulation) in a within-subjects experimental design. Results revealed significant increases in only one HRV parameter (standard deviation of the RR intervals (SDNN)) following right-ear t-VNS. Study 2 examined the prolonged effects of t-VNS (1h) in the right ear. Compared to baseline, right-t-VNS significantly increased the LF and LF/HF components of HRV, and SDNN in women, but not in men. These results show limited effects of t-VNS on HRV, and are discussed in light of neuroanatomical and statistical considerations and future directions are proposed.

If you have an active vagus nerve, cancer stage may no longer be important.

The parasympathetic system, and primarily the vagus nerve, informs the brain about multiple signals and returns the body to homeostasis. Recent studies have shown that vagal nerve activity independently predicts prognosis in cancer. Here, we take this one step further and show that when vagal nerve activity is high, cancer stage no longer predicts tumor burden. We examined whether vagal nerve activity, indexed by Heart Rate Variability (HRV), moderated the effects of initial tumor stage on tumor burden at followup. Patients' HRVs were derived from ECGs near diagnosis in colorectal cancer (CRC) and in prostate cancer (PC) patients. Outcomes included the tumor markers carcinoembryonic antigen (CEA) at 12 months for CRC and prostate-specific antigen (PSA) at 6 months for PC. As would be expected, initially advanced tumor stages of CRC or PC predicted higher tumor marker levels at follow-up than did early stages. However, this occurred only in patients with low, not high, vagal activity (HRV). Furthermore, in patients with advanced tumor stage at diagnosis, high HRV predicted lower tumor marker levels than did low HRV, in both cancers. Estimating a cancer patient's prognosis by determining his tumor stage needs to also consider the vagal nerve activity. This activity is easily measurable, and it determines in which subjects the tumor stage is prognostic. Importantly, higher vagal activity may even protect against the adverse effects of advanced cancer stage. These findings, observed in two distinct cancers, support the hypothesized neuroimmunomodulatory effects of vagal nerve activity on tumors.

Norms of vagal nerve activity, indexed by Heart Rate Variability, in cancer patients.

Recent research has begun to show the role of the activity of the vagus nerve in cancer prognosis. However, it remains unknown whether cancer severity can impair vagal nerve activity. This study combined data (N=657) of five different cancers (colorectal, pancreas, prostate, lung and ovarian) concerning patients' Heart Rate Variability (HRV), a vagal nerve activity index. These data were compared to HRV levels of a healthy sample in another study. In addition, we examined the moderating effects of age, gender and cancer stage on HRV. The mean HRV of the cancer patients sample was significantly lower (HRV=22 ms) compared to the healthy sample (HRV=50 ms) (p<0.000001). While age and gender did not significantly affect HRV, cancer patients with advanced stages had significantly lower HRV than those with early stages (p=0.011). A possible bi-directional relation between cancer and vagal nerve activity is discussed. These findings are of importance for prognostication since they provide researchers and clinicians with expected values of vagal nerve activity in cancer patients.