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    • Expression levels of the parasympathetic receptor

    2018-11-07

    Expression levels of the parasympathetic receptor α7nAChR on peripheral blood monocytes could be evaluated in a subset of AR subjects. Expression levels were significantly decreased in individuals with RHR ≥70bpm compared to those with RHR <70bpm. Alpha-7nAChR is expressed on many different immune po1 (Koopman et al., 2011); it is currently not known how expression levels are regulated. Binding of acetylcholine, produced by the vagus nerve (PNS) and immune cells, to α7nAChR has an immunosuppressive effect (Koopman et al., 2014). Decreased levels of α7nAChR are in line with reduced activity of the cholinergic anti-inflammatory reflex preceding the development of clinically manifest RA. Levels of the sympathomimetic hormone norepinephrine were significantly increased in AR subjects compared to HS, and there was a trend towards higher levels compared to RA patients. Norepinephrine levels in peripheral blood depend on release, turn over and clearance, and may with care be interpreted as an estimate of overall sympathetic activity (Adlan et al., 2014). Norepinephrine levels in established RA have been reported to be increased (Igari et al., 1977; Vlcek et al., 2008) or similar compared to HS (Palm et al., 1992; Vlcek et al., 2012). The role of increased norepinephrine levels in AR subjects is not clear. Catecholamine depletion before onset of arthritis in animal models of RA has an anti-inflammatory effect, suggesting that catecholamines may promote the immune response before onset of disease (Koopman et al., 2011). In our study norepinephrine levels are relatively low, which could result in activation of the alpha adrenergic receptor types (α-AR), mainly expressed on innate immune cells (Koopman et al., 2011). Activation of α-AR could result in a more pro-inflammatory status, but data are limited (Koopman et al., 2011). Epinephrine levels tend to be lower (Igari et al., 1977; Vlcek et al., 2008) in RA compared to healthy controls or show similar levels (Vlcek et al., 2012; Hirano et al., 2001). In our study we did not find differences in epinephrine levels between the groups. Several studies have evaluated the autonomic balance in established RA patients and demonstrated autonomic changes using various HRV parameters (Aydemir et al., 2010; Evrengul et al., 2004; Goldstein et al., 2007; Lazzerini et al., 2013). Most of these studies did not adjust for confounding factors of HRV parameters with multivariable analysis, despite known influence of confounders, such as age and sex identified in large cohorts (Valentini and Parati, 2009). In our study PNS activity was attenuated in RA patients compared to HS, as HR was significantly higher in both positions. As a result, other HRV parameters were lowered, but only statistically significant in active position. LF (nu) as a more distinct parameter of the SNS was higher in RA patients at rest, but the difference did not reach statistical significance. Overall, these findings are consistent with decreased parasympathetic activity in RA patients with little indication of an overactive sympathetic system, which is in line with the literature (Adlan et al., 2014). A limitation of this study is that continuous BP and HR measurements were only available in the study cohort. However, automated BP and HR measurements are also used in other studies and we were able to show excellent correlation between continuous and automated BP and HR measurements in the study cohort (Pearson\'s test r=0.78, p<0.001), indicating that single BP and HR measurements provide reliable data. Finally, we did not investigate the level of physical activity or chronic stress in the study subjects, which could have provided interesting information with regard to the cause of the decreased vagus nerve activity. Data presented here are consistent with a pathogenic role of the autonomic nervous system in the development of RA. Could these findings help to develop preventive strategies? It is tempting to speculate that decreasing RHR by for instance exercise or meditation (Janse van Rensburg et al., 2012; Nesvold et al., 2012; Routledge et al., 2010) could reduce the risk of transition of preclinical RA to clinically manifest RA. Alternatively, a bioelectronics approach aimed at stimulation of the vagus nerve might be explored as a preventive intervention in subjects at high risk of developing RA (Koopman et al., 2014). Clearly, the possible value of such interventions needs to be demonstrated in future studies.