Abstract
BackgroundDecreased heart rate variability (HRV) is associated with adverse outcomes in cardiovascular diseases and has been observed in patients with systemic lupus erythematosus (SLE). We examined the relationship of HRV with SLE disease activity and selected cytokine pathways.MethodsFifty-three patients from the Oklahoma Lupus Cohort were evaluated at two visits each. Clinical assessments included the Systemic Lupus Erythematosus Disease Activity Index (SLEDAI), British Isles Lupus Assessment Group (BILAG) index, physician global assessment (PGA), and Safety of Estrogens in Lupus Erythematosus National Assessment-SLEDAI Flare Index. HRV was assessed with a 5-minute electrocardiogram, and the following HRV parameters were calculated: square root of the mean of the squares of differences between adjacent NN intervals (RMSSD), percentage of pairs of adjacent NN intervals differing by more than 50 milliseconds (pNN50), high-frequency power (HF power), and low frequency to high frequency (LF/HF) ratio, which reflects sympathetic/vagal balance. Plasma cytokine levels were measured with a multiplex, bead-based immunoassay. Serum B lymphocyte stimulator (BLyS) and a proliferation-inducing ligand (APRIL) were measured with an enzyme-linked immunosorbent assay. Linear regression analysis was applied.ResultsBaseline HRV (pNN50, HF power, LF/HF ratio) was inversely related to disease activity (BILAG, PGA) and flare. Changes in RMSSD between visits were inversely related to changes in SLEDAI (p = 0.007). Age, caffeine, tobacco and medication use had no impact on HRV. Plasma soluble tumor necrosis factor receptor II (sTNFRII) and monokine induced by interferon gamma (MIG) were inversely related with all baseline measures of HRV (p = 0.039 to <0.001). Plasma stem cell factor (SCF), interleukin (IL)-1 receptor antagonist (IL-1RA), and IL-15 showed similar inverse relationships with baseline HRV, and weaker trends were observed for interferon (IFN)-α, interferon gamma-induced protein (IP)-10, and serum BLyS. Changes in the LF/HF ratio between visits were also associated with changes in sTNFRII (p = 0.021), MIG (p = 0.003), IFN-α (p = 0.012), SCF (p = 0.001), IL-1RA (p = 0.023), and IL-15 (p = 0.010). On the basis of multivariate linear regression, MIG was an independent predictor of baseline HRV after adjusting for plasma IL-1RA, SCF, IFN-α, IP-10, and serum BLyS. In a similar model, the sTNFRII impact remained significant after adjusting for the same variables.ConclusionsImpaired HRV, particularly the LF/HF ratio, is associated with lupus disease activity and several cytokines related to IFN type II and TNF pathways. The strongest association was with MIG and sTNFRII, expanding previous immune connections of vagal signaling.Electronic supplementary materialThe online version of this article (doi:10.1186/s13075-016-1087-x) contains supplementary material, which is available to authorized users.
Highlights
Decreased heart rate variability (HRV) is associated with adverse outcomes in cardiovascular diseases and has been observed in patients with systemic lupus erythematosus (SLE)
The following plasma cytokines were included in the panel: interferon (IFN)-γ, IL-12p70, IL-2, IL-1α, IL-1β, interleukin (IL)-1 receptor antagonist (IL-1RA), IL-15, IL-17A, IL-21, tumor necrosis factor (TNF)-α, soluble tumor necrosis factor receptors I and II, soluble CD40L, B lymphocyte stimulator (BLyS), a proliferation-inducing ligand (APRIL), transforming growth factor (TGF)-β, IL-10, IFN-α, interferon gamma-induced protein 10 (IP-10), macrophage inflammatory protein 1 alpha (MIP-1α), monokine induced by interferon gamma (MIG), IL-8, plasminogen activator inhibitor 1 (PAI-1), stem cell factor (SCF), and resistin
Total British Isles Lupus Assessment BLyS B lymphocyte stimulator (Group) (BILAG) disease activity scores were inversely related to HRV parameters [pNN50 (p = 0.019), HF power (p = 0.020), low frequency to high frequency (LF/HF) (p = 0.024)], and similar associations were observed when we focused on the most commonly involved organ, the musculoskeletal system [pNN50 (p = 0.043), HF power (p = 0.010)]
Summary
Decreased heart rate variability (HRV) is associated with adverse outcomes in cardiovascular diseases and has been observed in patients with systemic lupus erythematosus (SLE). Autonomic dysfunction is well documented in SLE, with increased sympathetic and decreased parasympathetic activity reported by different studies [2,3,4,5,6,7,8,9] Such autonomic aberrations can be the result of inflammatory cytokines acting on the central nervous system and may reciprocally modulate inflammatory responses in the periphery, exerting a pathogenic role in chronic inflammation [10]. Both sympathetic and parasympathetic pathways are relevant in acute and chronic inflammation, based on in vitro studies and animal models. Recent understanding of this pathway suggests a non-neural link between the vagus nerve and the spleen, possibly through vagus-induced mobilization of peripheral lymphocyte pools that subsequently accumulate in the spleen [12]
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