Heart rate variability predicts levels of inflammatory markers: Evidence for the vagal anti-inflammatory pathway
Introduction
The vagus nerve plays an important role in regulating inflammation and preventing tissue damage from excessive inflammatory responses. Vagal activity decreases production of pro-inflammatory cytokines such as TNF (Bernik et al., 2002) and inhibits the migration of leukocytes to sites of inflammation (Saeed et al., 2005), in part by its action on the reticuloendothelial system of the liver and spleen where cytokines are produced, and may function to dampen systemic inflammatory processes (Tracey et al., 2007). Data from numerous animal studies support this anti-inflammatory pathway. For example, administration of endotoxin in mice following vagotomy or in mice possessing knockout of the α7 subunit of the nicotinic acetylcholine receptor (α7nAChR) expressed in macrophages causes an unrestrained cytokine response (Borovikova et al., 2000, Wang et al., 2003). On the other hand, stimulation of the vagus nerve or administration of α7nAChR agonists has been found to decrease cytokine release (Wang et al., 2004).
Because heart rate variability (HRV) is a well-established and reliable index of cardiac vagal regulation, it should be inversely related to levels of inflammatory markers. Many studies show this predicted inverse relationship. For example, decreased low frequency HRV (LF-HRV) was found to be associated with increased levels of C-reactive protein (CRP) in a study of 1601 healthy young people (Haarala et al., 2011). A prospective cohort study of 188 middle-aged and older adults found an inverse relationship between high frequency HRV (HF-HRV) and CRP (p < 0.01) (Singh et al., 2009). A study of 264 middle-aged male twins found that ultra low frequency HRV and very low frequency HRV were inversely related to CRP and IL-6 after controlling for a host of factors (p < 0.01) (Lampert et al., 2008). IL-6 levels were shown to have an inverse relationship with HF-HRV and LF-HRV in a study of 682 patients after cardiac catheterization for acute myocardial infarction (MI) or unstable angina with elevated Troponin-T levels (Frasure-Smith et al., 2009). Inverse relationships between IL-6 and HRV have also been observed in patients with sepsis, type 1 diabetes and type 2 diabetes (Tateishi et al., 2007, Gonzalez-Clemente et al., 2007, Stuckey and Petrella, 2013).
Inflammatory processes are also influenced by the sympathetic nervous system (SNS), but its role is less well understood. The SNS possesses both pro- and anti-inflammatory properties and has been implicated in the production of cytokines (Koopman et al., 2011). Adrenergic signaling may activate or suppress macrophages depending on the subtype of adrenergic receptor they express (Bellinger et al., 2008). SNS activity can reduce Th1 response in favor of Th2 (Elenkov et al., 2000). Sympathetic activity has also been found to enhance leukocyte attraction (Viswanathan et al., 2005) and alter expression of cell adhesion markers (Redwine et al., 2003).
A thorough examination of the inflammatory role of the autonomic nervous system thus requires consideration of both vagally-mediated and sympathetically-mediated effects. With only a single exception, studies linking HRV and inflammation fail to control for levels of SNS activity. In that study, Thayer and Fischer found that even after controlling for SNS effects, measured by urinary epinephrine, the inverse relationships between HRV and CRP and between HRV and WBC count remained significant (Thayer and Fischer, 2009). In addition, they observed interesting sex differences in these relationships. For example, an increase of 1 SD in HRV measured as root mean square of successive interval differences was associated with a 48% decrease in CRP in men (p = 0.05), whereas in women, an increase of 1 SD in HRV was associated with a 104% decrease in CRP (p = 0.008). Larger differences in WBC count, another marker of inflammation, were also seen in women. This study suggests that there may be important sex differences in the relationship between parasympathetic activity and inflammatory markers. However, the study was limited by a small number of women (n = 66) relative to men (n = 545) and a relatively homogeneous sample of factory workers.
In the current study, we sought to replicate these findings on the relationship between HF-HRV and inflammatory markers using a larger, more diverse, and more representative sample. We tested the hypothesis that HF-HRV, as an index of cardiac vagal regulation, would be inversely related to inflammatory markers even after control for sympathetic effects. Because many studies also examine the relationship between LF-HRV and inflammatory markers, we also tested this relationship.
Section snippets
Participants
The data were collected from 1255 participants in Midlife Development in the U.S. (MIDUS), a study of the behavioral, psychological and social factors accounting for age-related variation in health and well-being in a national sample of middle-aged and older Americans (Brim et al., 2004). Data for the current study are from MIDUS II, a 9-year follow-up of the MIDUS I cohort, conducted between 2004 and 2006. MIDUS II consisted of five projects, including a self-administered survey of a wide
Demographic data
Analysis was carried out on participants with data for HF-HRV and LF-HRV as well as at least one inflammatory marker (n = 1153). 91.3% of study participants were white. Demographic data are shown in Table 1a, Table 1b. Men and women did not significantly differ in age, BMI, smoking status, history of hypertension, history of diabetes, LDL levels, ratio of total cholesterol to HDL, 12-h urinary norepinephrine, or urinary norepinephrine adjusted for creatinine. Men had significantly higher levels
Discussion
This study provides further support for the anti-inflammatory role of the vagus nerve, even after controlling for SNS activity. Using a large, diverse and nationally representative sample, we found that HF-HRV and LF-HRV were significantly and inversely related to several inflammatory markers after controlling for relevant covariates. These results confirm and extend those of Thayer and Fischer (2009), which demonstrated an inverse relationship between an index of HF-HRV and both CRP and WBC
Acknowledgments
The MIDUS I study (Midlife in the U.S.) was supported by the John D. and Catherine T. MacArthur Foundation Research Network on Successful Midlife Development. The MIDUS II research was supported by a grant from the (P01-AG020166) to conduct a longitudinal follow-up of the MIDUS I investigation.
The research was further supported by the following grants M01-RR023942 (Georgetown), M01-RR00865 (UCLA) from the General Clinical Research Centers Program and UL1TR000427 (UW) from the National Center
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