Discussion
In this study, we reproduce previous findings of an increased prevalence of CAN in patients with SLE. As a new finding, this study shows that the type of autonomic dysfunction in these patients depends on the severity of CAN. SLE patients without CAN presented with impaired parasympathetic activity, whereas SLE patients with definitive CAN also showed signs of mixed sympathetic/parasympathetic dysfunction. Moreover, SLE patients with impairment of parasympathetic as well as mixed sympathetic/parasympathetic activity reported lower HRQoL scores in the physical component of the SF-12 questionnaire.
The prevalence of definitive CAN in this study was 24.1% in the matched patients with SLE, 1.9% in the controls and 24.8% in the 109 patients with SLE. This and the prevalence of early CAN could be underestimated as not all subjects completed all three CARTs necessary for CAN staging. However, the number of subjects not completing all tests were equally distributed in the two groups.
In previous studies, the prevalence of CART-based CAN has ranged from 23.5% to 82.7%, proposedly caused by methodological inconsistency, unstandardised test conditions and varying age of the studied populations.2 Two authors, Stojanovich et al9 and Milovanovic et al,32 report on two SLE populations, resembling ours by age, and reported higher CAN prevalences (79.6% and 82.7%) than in the current study. Like in the current study, both authors considered CAN present when two or more of the CARTs were abnormal. However, our subjects performed fewer CARTs (three) than those of Stojanovic et al and Milovanovic et al (five and four, respectively). Furthermore, recommended age dependent cut-off values4 was applied only in this study. Hence, the method used by our colleagues may be more sensitive, however also less specific, as indicated by CAN prevalence estimates in control subjects ranging from 11.4% to 43.6% versus 1.9% in our study.
A recent review on SLE and HRV report that patients with SLE consistently present with lower HRV compared with controls,1 corresponding to our findings: patients with SLE presented with lower variability in all items except LF power, whereas the LF/HF ratio was increased. The LF band reflects both PNS and SNS activity,21 whereas higher values of LF/HF may reflect sympathetic predominance.22 Thus, in accordance with previous findings,1 our results indicate that the parasympathetic and to some extent the sympathetic activities are impaired in SLE, with a relative sympathetic predominance.
As the ANS is highly adaptive to its environment, it is recommended to minimise the influence of confounders to increase the reliability of ANS tests.4 26 However, adjusting for differences in baseline MAP, smoking status and ACE inhibitor in the SLE control comparison did not change our results. When adjusting for heart rate, the association between SLE and especially mixed SNS-PNS activity was less pronounced. However, the argument for these adjustments is debatable since resting heart rate was elevated in patients with SLE and associated with autonomic function in the patients only thereby inferring risk of over adjustment. Hence, it seems likely that patients with SLE presented with impaired autonomic activity associated with SLE disease properties, despite differences in potential confounders compared with controls.
To our knowledge, only two studies have investigated SLE patients with CARTs and HRV concurrently.32 33 However, no previous SLE studies have previously investigated HRV in patients without CAN. Doing this, results suggesting that even patients with no evident CARTs-determined CAN have impaired HRV compared with similar controls. As HRV is a more sensitive marker of ANS dysfunction than reflex test scores,34 35 our findings may imply that SLE patients with a seemingly well-functioning ANS may show signs of incipient autonomic dysfunction, possibly increasing the risk of developing CAN. However, based on our cross-sectional design, this remains to be confirmed in prospective SLE studies.
The potential incipient CAN was characterised by low PNS function (based on HF) with a sympathetic predominance (based on high LF/HF ratio), probably based on the impaired parasympathetic activity rather than increased sympathetic activity. Definitive CAN was, in addition to impaired PNS activity (based on RMSSD and HF power), further characterised by HRV impairments reflecting both SNS and PNS dysfunction (SDNN, LF power, TP). Hence, it seems that involvement of both the parasympathetic and, perhaps, especially the sympathetic nervous system characterises late CAN in SLE. Altogether, this may indicate that, in SLE, dysfunction of the PNS precedes the SNS and the presentation with definitive CAN. Similar progression was suggested in diabetes,36 while other suggest simultaneous PNS and SNS impairment.37 Clinically, another important finding was the association between ANS dysfunction and self-report of low physical HRQoL. Self-perceived physical health evaluated by the physical component score of SF12 comprises perception of general health, physical function, capacity to perform physical activities compared with the subjectively expected capacity and the influence of pain on daily work.29
The perception of low physical HRQoL was associated with measures reflecting PNS impairment (RMSSD and HF) and mixed ANS impairment (LF power, TP and definitive CAN). Hence, this finding suggests that both early and extensive/late CAN may contribute to self-perceived low physical health, function, capacity and elevated pain in patients with SLE. Whereas the relationship between autonomic function and physical HRQoL has not previously been investigated in SLE, similar results were found in healthy subjects12 and patients with end-stage renal disease,15 paroxysmal atrial fibrillation,13 chronic obstructive pulmonary disease,14 Parkinson’s disease38 and diabetes.39 Furthermore, this association in SLE is supported by the recent pilot study in which 12 days of PNS stimulation led to decreased experience of pain and fatigue.10
We speculate that altered autonomic function may affect physical HRQoL in SLE by: (1) altered perception due to reduced psychological resiliency,22 (2) symptoms of autonomic dysfunction, which in diabetes are considered late complications of CAN4 or (3) by interaction with SLE-related disease mechanisms such as inflammation, autoantibody production, neuropsychiatric and cardiovascular comorbidities.6–9
Whereas physical HRQoL was associated to impaired autonomic function in the current study, mental HRQoL was not. In non-SLE populations, impaired ANS function has been implicated in psychiatric diseases with impaired mental HRQoL.40 41 Patients with SLE experience a high level of neuropsychiatric disorders like depression and anxiety, of which both are strong independent predictors of low level of HRQoL.42 Therefore, we hypothesise that the subjective symptoms of impaired mental health is stronger associated to the SLE disease itself than ANS function. However, this was not investigated currently.
The present study has some limitations. First, due to the cross-sectional design, causality of the observed associations regarding the natural course of autonomic dysfunction in SLE and the association between autonomic dysfunction and HRQoL cannot be inferred. Furthermore, none of the currently included measures of ANS function were influenced solely by sympathetic modulation. The most specific measures of sympathetic function include blood pressure CARTs,43 and these could yield new sympathetic characteristics of the autonomic dysfunction present in SLE. However, these were not included in this study. Despite evident limitations, this study has been the first to explore early signs of autonomic dysfunction in SLE by associating CART-based CAN staging with HRV analyses. Furthermore, this is the first study to provide insight to how ANS dysfunction may influence physical signs of SLE from a patient perspective. The study findings may, if validated in prospective studies, prove clinically useful by providing an alternative understanding of poor HRQoL that is not readily explained by known disease characteristics of SLE.
In conclusion, we found that compared with controls, patients with SLE presented more frequently with CAN characterised by mixed parasympathetic/sympathetic impairment. Furthermore, even in patients without clinical signs of CAN, we demonstrated impaired parasympathetic function. These impairments were in patients with SLE associated with self-report of poor physical quality of life.