Too sympathetic to exercise: abnormal autonomic and metaboreflex activation in exercising rheumatoid arthritis patients

Rheumatoid arthritis (RA) is a systemic autoimmune rheumatic disease characterized by chronic inflammation and eventual degradation of synovium in the extremities, causing deterioration to the surrounding cartilage and bone (Avina-Zubieta et al. 2012). RA tends to be diagnosed and presented predominantly in post-menopausal women and has been linked with increased incidence of cardiovascular disease (CVD). A combination of RA pathophysiology and classical CVD risk factors such as hypertension, dyslipidaemia and obesity contribute to a ∼50% increase in CVD-related mortality in RA patients (Avina-Zubieta et al. 2012). Interestingly, RA patients show an augmented CV response to exercise, which may be linked to systemic inflammation-induced autonomic nervous system (ANS) dysfunction though the mechanism(s) behind this response are unknown. In a recent article in The Journal of Physiology, Peçanha et al. (2020) investigated the link between augmented ANS and CV responses to exercise and activation of the muscle metaboreflex in post-menopausal women with RA. In this cross-sectional study, 33 post-menopausal women with variable RA disease severity and 10 matched, non-RA controls were recruited. Participants underwent two preliminary visits for a clinical evaluation, a 12 h fasting blood sample to assess inflammatory and other biomarkers, and a maximal graded exercise test to assess baseline cardiorespiratory fitness. To assess autonomic and haemodynamic responses, participants underwent 15 min of basal measurements, including heart rate (HR), mean arterial pressure (MAP), cardiac baroreflex sensitivity, and HR variability (HRV), followed by isometric knee extensions (3 min, 30% of maximal voluntary contraction) and post-exercise ischaemia (PEI) to isolate the muscle metaboreflex. Importantly, multi-unit recordings of muscle sympathetic nerve activity (MSNA) were obtained from the non-exercising leg to determine sympathetic activity at baseline and during exercise and PEI. The authors found basal inflammatory biomarkers and pain-VAS scores were higher in the RA group. Moreover, despite no differences in resting haemodynamics and HRV between groups, RA subjects exhibited higher basal MSNA burst frequency and incidence and impaired cardiac baroreflex function. During both exercise and PEI, increases in MSNA and MAPs from baseline were greater in RA subjects. These findings provide novel mechanistic insight into the augmented ANS and CV responses to exercise in RA patients, which could be used to identify possible therapeutic applications for prevention of CVD in this cohort. This is the first study to demonstrate a potential role of an overactive metaboreflex in the increased sympathetic and pressor responses to exercise in RA. These findings are important, as an increased adrenergic response during exercise is a precursor to many CVDs. Moreover, the authors showed an association between increased pro- and anti-inflammatory cytokines and pain with increased sympathetic output at rest and increased haemodynamic responses during exercise, providing support for a bidirectional relationship between inflammation and ANS dysfunction. The authors should be commended for their focus on female participants given the underrepresentation of women in clinical studies. As the most prevalent subgroup among RA patients, the focus on post-menopausal women is an important first step to understand the interplay between ANS dysfunction and increased CV risk in RA. Nonetheless, the relationship between RA, CVD and menopause is complex and women are not the sole sufferers. Indeed, sex differences in the prevalence of RA are related to age, with the sex ratio approaching one with increasing age of disease onset (Talsania & Scofield, 2017). Therefore, future studies examining the mechanisms accounting for sex differences in disease onset and their convergence with ageing are warranted. Peçanha et al. (2020) used isometric (static) knee extension exercise in conjunction with microneurography. While this method is the gold standard for measuring changes in sympathetic vasomotor outflow, it cannot be used to record from actively contracting muscles, which limits its ability to assess MSNA during dynamic exercise. This is a challenge for researchers, given that dynamic aerobic/resistance exercise is commonly prescribed for RA treatment/management. While this limits the ability to fully assess ANS responses to exercise, other measurements utilized in this study are similarly valuable. The authors used maximal oxygen consumption (VO2max) to assess participants’ basal fitness levels. Though VO2 was not measured during the exercise protocol, it would have nicely complemented assessments of MAP, MSNA and HRV to provide a more holistic view of the autonomic and haemodynamic responses to exercise in this cohort. Indeed, these measures would have implications for tracking the success of exercise and/or pharmacological interventions in patients with RA or other autoimmune conditions and, as the authors note, the ability of these individuals to complete fundamental activities of daily living. Autonomic dysfunction is associated with not only increased sympathetic activation but also reduced parasympathetic nerve activity (PNA). Interestingly, the authors found no differences at rest in PNA between groups, conflicting with previous work showing reduced PNA in post-menopausal RA patients that may be linked to differences in disease severity among their RA cohorts. PNA is inversely linked to inflammatory cytokines and independently associated with increased pain, with the current study providing support for these associations. Indeed, stimulation of the vagus nerve attenuates inflammatory cytokine release, with evidence of a bidirectional link between inflammation and ANS via the inflammatory reflex that may contribute to RA disease severity. However, HRV and its derived indices only provide an indirect estimate of cardiac parasympathetic regulation and may not accurately reflect changes in PNA and vagal nerve firing. Indeed, the ability of HRV to capture both sympatho-vagal balance and the interplay between the arms of the ANS has been debated, which limits its ability to fully capture the association between disease severity/progression with ANS dysfunction. Nonetheless, these measurements are informative, and further exploration of the relationship between HRV indices at rest and during recovery from exercise will be beneficial to assess ANS dysfunction and RA progression/severity. Given the use of transient blood flow occlusion to isolate the muscle metaboreflex, we wonder whether the authors considered simultaneously investigating endothelial function via flow-mediated dilatation (FMD). In clinical practice, FMD is an early predictor of the severity of atherosclerosis, endothelial dysfunction, and the development of CVD. Alterations in endothelial function contribute to haemodynamic responses during acute exercise, with endothelial dysfunction linked to exaggerated exercise blood pressure responses (Stewart et al. 2004). As endothelial function has been shown to be inversely associated with RA disease severity (Bordy et al. 2018), endothelial dysfunction may be a contributing factor to the haemodynamic responses during exercise in RA, independent of the ANS. The authors found that in addition to increased sympathetic activation, RA subjects have decreased cardiac baroreflex sensitivity and a hypersensitive metaboreflex response during exercise. While the potential cause of the hypersensitive metaboreflex and deficient baroreflex response is discussed, understanding their contribution to CVD in RA warrants further study. Specifically, the authors highlight a potential role of increased transient receptor potential cation channels of the vanilloid type 1 (TRPV1) channel in mediating enhanced metaboreflex sensitivity in RA. Indeed, inhibiting these channels with a capsaicin-based analgesic balm has been shown to attenuate the muscle metaboreflex (Vianna et al., 2018), which could be incorporated into future studies to further isolate metaboreflex involvement and offer a potential therapeutic target in RA. Additionally, the high prevalence of dyslipidaemia and obesity in the RA group may contribute to the blunted baroreflex sensitivity observed, independently or in concert with systemic inflammation. Triglyceride levels are positively correlated with both inflammation and increased arterial stiffness, the latter of which is elevated in RA (Bordy et al. 2018) and inversely correlated with baroreflex sensitivity. Interestingly, this may contribute to previous findings from this group as impaired baroreflex function may contribute to chronotropic incompetence and slower post-exercise HR recovery. Lastly, the authors have provided a foundation for further studies examining the link between haemodynamic and autonomic indexes as well as pain and inflammatory markers in RA. While a Spearman's rank correlation test was used in the current study, a multivariate analysis would be more informative, especially given the interrelations between autonomic indexes, inflammatory markers, and pain. Given the reliance on subsamples of the total RA and control groups due to issues with attaining high-quality microneurography measurements at all time points, we suspect that the study is underpowered to undertake such a complex analysis. Thus, a much larger cohort of RA subjects and matched controls would be required, especially to account for the influence of age, disease severity, comorbidities, and anti-rheumatic drug therapy on autonomic and haemodynamic responses at rest and to exercise. Nonetheless, this is outside the scope of the current study, and the association between multiple pro- and anti-inflammatory cytokines and pain with the augmented pressor and sympathetic responses to exercise is an important finding that we hope the authors pursue further. In conclusion, Peçanha et al. (2020) have provided novel mechanistic insight into the role of augmented sympathetic and pressor responses to exercise, which is linked to increased muscle metaboreflex sensitivity, attenuated baroreflex function, and systemic inflammation and elevated pain in RA patients. These findings have tremendous clinical significance given the established link between RA, inflammation, autonomic dysfunction and CV disease, and will be invaluable for assessing RA disease progression and the impact of therapeutic or pharmacological interventions on disease management. None declared. All authors have read and approved the final draft of the manuscript and agree to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. All persons designated as authors qualify for authorship, and all those who qualify for authorship are listed. None. We apologize for not referencing all relevant works due to reference limits.

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