Increased sympathetic nerve activity and reduced cardiac baroreflex sensitivity in rheumatoid arthritis

Abstract

Key points: Rheumatoid arthritis (RA) is a chronic inflammatory condition associated with an increased risk of cardiovascular mortality. Increased sympathetic nerve activity and reduced cardiac baroreflex sensitivity heighten cardiovascular risk, althogh whether such autonomic dysfunction is present in RA is not known. In the present study, we observed an increased sympathetic nerve activity and reduced cardiac baroreflex sensitivity in patients with RA compared to matched controls. Pain was positively correlated with sympathetic nerve activity and negatively correlated with cardiac baroreflex sensitivity. The pattern of autonomic dysfunction that we describe may help to explain the increased cardiovascular risk in RA, and raises the possibility that optimizing pain management may resolve autonomic dysfunction in RA.

Abstract: Rheumatoid arthritis (RA) is a chronic inflammatory condition associated with increased cardiovascular morbidity/mortality and an incompletely understood pathophysiology. In animal studies, central and blood borne inflammatory cytokines that can be elevated in RA evoke pathogenic increases in sympathetic activity and reductions in baroreflex sensitivity (BRS). We hypothesized that muscle sympathetic nerve activity (MSNA) was increased and BRS decreased in RA. MSNA, blood pressure and heart rate (HR) were recorded in age- and sex-matched RA-normotensive (n = 13), RA-hypertensive patients (RA-HTN; n = 17), normotensive (NC; n = 17) and hypertensive controls (HTN; n = 16). BRS was determined using the modified Oxford technique. Inflammation and pain were determined using serum high sensitivity C-reactive protein (hs-CRP) and a visual analogue scale (VAS), respectively. MSNA was elevated similarly in RA, RA-HTN and HTN patients (32 ± 9, 35 ± 14, 37 ± 8 bursts min^-1 ) compared to NC (22 ± 9 bursts min^-1 ; P = 0.004). Sympathetic BRS was similar between groups (P = 0.927), whereas cardiac BRS (cBRS) was reduced in RA, RA-HTN and HTN patients [5(3-8), 4 (2-7), 6 (4-9) ms mmHg^-1 ] compared to NC [11 (8-15) ms mmHg^-1 ; P = 0.002]. HR was independently associated with hs-CRP. Increased MSNA and reduced cBRS were associated with hs-CRP although confounded in multivariable analysis. VAS was independently associated with MSNA burst frequency, cBRS and HR. We provide the first evidence for heightened sympathetic outflow and reduced cBRS in RA that can be independent of hypertension. In RA patients, reported pain was positively correlated with MSNA and negatively correlated with cBRS. Future studies should assess whether therapies to ameliorate pain and inflammation in RA restores autonomic balance and reduces cardiovascular events.

Keywords: autonomic nervous system; cytokine; inflammation; pain.

Figure 1. BP and HR

Box and whisker plots showing mean blood pressure (A, geometric mean and 95% confidence intervals) and heart rate (B, mean ± SEM) in the RA, RA‐HTN, NC and HTN groups. Group (black squares) and individual (white circles) data are shown. Overall effect: P < 0.05. Post hoc: ^* P < 0.05 vs. NC, ^† P < 0.05 vs. HTN, ^‡ P < 0.05 vs. RA‐HTN. A and B, RA, n = 13; RA‐HTN, n = 17; NC, n = 17; HTN, n = 16.

Figure 2. MSNA

Box and whisker plots showing group mean ± SEM data for MSNA burst frequency (A) and MSNA burst incidence (B), as well as original sympathetic neurograms showing MSNA (C) in representative individuals from the RA, RA‐HTN, NC and HTN groups. Group (black squares) and individual (white circles) data are shown. Overall effect: P < 0.05. Post hoc: ^* P < 0.05 vs. NC. A and B, RA, n = 7; RA‐HTN, n = 7, NC, n = 13; HTN, n = 11.

Figure 3. Cardiovagal and arterial sympathetic baroreflex senstivity

Scatter plots from an original record of an RA patient demonstrating the relationship between RR‐interval and systolic BP (A), as well as between MSNA burst incidence and diastolic BP (B). Box and whisker plots showing cardiovagal baroreflex sensitivity (C), geometric mean and 95% confidence intervals) and baroreflex control of MSNA (D) (mean ± SEM) in the RA, RA‐HTN, NC and HTN groups. Group (black squares) and individual (white circles) data are shown. Overall effect: P < 0.05. Post hoc: ^* P < 0.05 vs. NC. A, RA, n = 13; RA‐HTN, n = 17; NC, n = 17; HTN, n = 16. B, RA, n = 6; RA‐HTN, n = 5; NC, n = 9; HTN, n = 7.

Figure 4. Inflammatory biomarkers

Box and whisker plots showing concentrations (geometric mean and 95% confidence intervals) of hs‐CRP (A), IL‐6 (B), TNF‐α (C) and IL‐10 (D) in the RA, RA‐HTN, NC and HTN groups. Group data are shown. Overall effect: P < 0.05. Post hoc: ^* P < 0.05 vs. NC, ^† P < 0.05 vs. HTN, ^‡ P < 0.05 vs. RA‐HTN. RA, n = 13; RA‐HTN, n = 17; NC, n = 17; HTN, n = 16.