|Ahead of print publication
Correlation of Inflammatory Markers and Disease Severity with Cardiovascular Autonomic Dysfunction in Indian Patients with Rheumatoid Arthritis
Mohan Babu Saminathan1, Renuka Sharma1, Arun Gogna2, Anita Rani3, Raj Kapoor1
1 Department of Physiology, Vardhman Mahavir Medical College and Safdarjung Hospital, New Delhi, India
2 Department of Medicine, Vardhman Mahavir Medical College and Safdarjung Hospital, New Delhi, India
3 Department of Biochemistry, Vardhman Mahavir Medical College and Safdarjung Hospital, New Delhi, India
Mohan Babu Saminathan,
Room No. 14, RDA Hostel, Vardhman Mahavir Medical College and Safdarjung Hospital, New Delhi
Source of Support: None, Conflict of Interest: None
Background: RA is an autoimmune disease characterized by chronic systemic inflammation, affecting approximately 1% of the population. Cardiovascular disease accounts for more than 40% of mortality in RA with cardiovascular autonomic nervous system dysfunction being commonly observed. Since few studies are available regarding the status of cardiac autonomic function in RA, we planned to study the same in RA patients and correlate it with their level of inflammatory markers and disease severity.
Objectives: 1. To study the heart rate variability, inflammatory markers in RA and controls. 2. To assess the correlation of inflammatory markers and disease severity with HRV.
Materials and Methods: The study was conducted on 35 diagnosed cases of RA and 35 controls. Short term heart rate variability was taken as an index of autonomic function. TNF-α and IL-10 were assessed in 3 ml overnight fasting serum. Severity of RA was assessed by DAS28 score.
Result: Disease severity of RA was low. LF, NN50 and RANGE were significantly decreased in RA patients. TNF-α was significantly elevated in RA patients. Correlation of TNF-α with LF/HF ratio and DAS28 with RMSSD, NN50 and HF were found to be significantly positive.
Conclusion: Our findings suggest that CAD is significantly correlated with inflammatory activity and disease severity in RA. Hence, we propose that HRV may serve as an accurate tool to screen RA patients for early signs of autonomic disturbance, which can greatly help to reduce future morbidity and mortality.
Keywords: Disease severity, heart rate variability, inflammatory markers, rheumatoid arthritis
|How to cite this URL:|
Saminathan MB, Sharma R, Gogna A, Rani A, Kapoor R. Correlation of Inflammatory Markers and Disease Severity with Cardiovascular Autonomic Dysfunction in Indian Patients with Rheumatoid Arthritis. Indian J Rheumatol [Epub ahead of print] [cited 2019 May 25]. Available from: http://www.indianjrheumatol.com/preprintarticle.asp?id=256371
| Introduction|| |
Rheumatoid arthritis (RA) is an autoimmune disease characterized by chronic systemic inflammation, affecting approximately 1% of the general population globally. Although pain, stiffness, and swelling of joints are the typical clinical features, extra-articular aspects such as cardiovascular disease account for >40% of mortality. Cardiovascular autonomic nervous system dysfunction is commonly observed in RA.
Heart rate variability (HRV) is a measurement (quantification) of central autonomic drive (activity) to the myocardium. It depends on a balance between sympathetic and parasympathetic drives to myocardium. A high HRV indicates a good cardiac adaptability, whereas a lower HRV often indicates an abnormal and insufficient adaptability of the autonomic nervous system and is associated with a high risk of adverse cardiovascular events.
Elevated levels of pro-inflammatory cytokines such as tumor necrosis factor (TNF)-α and interleukin (IL) IL-10 have been observed in RA. It had been established that they were responsible for the higher sympathetic dominance which leads to reduced HRV and a higher arrhythmogenic risk.
There is a paucity of literature on the correlation of HRV with inflammatory markers (TNF-α and IL-10) in Indian patients of RA. Despite the availability of data from Western populations, ethnically and geographically different populations are known to be different with respect to disease and its clinical presentation. Hence, this study was designed to explore the interplay of inflammatory markers on cardiovascular autonomic dysfunction in Indian patients.
| Materials and Methods|| |
The present study was designed as a case–control study in the Department of Physiology, in collaboration with the Department of Medicine and Department of Biochemistry, Vardhman Mahavir Medical College and Safdarjung Hospital, New Delhi, on 70 patients, of which 35 diagnosed cases of RA, who gave voluntary consent, were recruited consecutively between 2017 and 2018, at the outpatient clinics of the medicine and the other 35 were age- and sex-matched healthy controls. RA diagnosis was based on the revised 1987 American College of Rheumatology classification criteria. Disease Activity Score at 28 joints (DAS28) and Clinical Disease Activity Index criteria were used to assess their current disease activity. The institutional ethics committee approved our study protocol (IEC/VMMC/SJH/OCTOBER/2016/14, date 20.10.2016).
All participants were inquired about the history of illness and underwent anthropometric and general physical examinations. For the HRV recording and analysis, ML 870B80 Exercise Physiology system (A.D. Instruments) was used. All recordings were obtained between 8.00 and 10.00 h; a 2-h fasting was ensured prior to testing including all beverages. Patients and healthy controls were relaxed and remained in recumbent position during the recordings. The blood pressure (BP) and heart rate (HR) were recorded for each participant after 10–15 min of rest. Following a recording of continuous electrocardiogram (ECG) for 5 min in standard test conditions, short-term HRV was assessed offline by the inbuilt HRV module. Both time and frequency domains were analyzed.
Time domain parameters
- SDNN (ms): Standard deviation of all NN intervals (also known as SDRR) usually over 24 h
- RMSSD (ms): The square root of the mean of the sum of the squares of differences between adjacent NN intervals
- SDNN index (ms): Mean of the standard deviations of all NN intervals for all 5-min segments of the entire (24 h) recording
- NN50 (count): Number of pairs of adjacent NN intervals differing by >50 ms in the entire recording; three variants are possible counting all such NN interval pairs, counting only pairs in which the first interval is longer, and counting only pairs in which the second interval is longer
- pNN50: It is the percentage of adjacent NN differing by >50 ms over an entire 24 h ECG recording.
Frequency domain parameters
Frequency domain parameters include total power, high frequency (HF) power, low frequency (LF) power, and very LF (VLF) power.
Contemporarily, 3-ml venous blood sample was collected for evaluating pro- and anti-inflammatory markers, TNF-α and IL-10, respectively. Serum was separated on the same day and frozen immediately at –20°C until analyzed. Concentrations of TNF-α and IL-10 were analyzed using typical two-step capture or sandwich-type enzyme-linked immunosorbent assay (Thermo Fischer Scientific, Austria).
Statistical analysis was performed using SPSS version 21 (SPSS, Inc., Chicago, IL, USA). Continuous variables were expressed as mean ± standard deviation or as median with interquartile range. Data were checked for normality using Shapiro–Wilk and Kolmogorov–Smirnov test before statistical analysis. Normally distributed parameters were compared using unpaired t-test, and Mann–Whitney test was used for those variables that were not normally distributed. Correlation analysis was done to determine the relation between HRV, disease activity scores, and inflammatory markers, using Pearson's and Spearman's correlation. For all statistical tests, P < 0.05 was considered statistically significant.
| Results|| |
The mean age of the patients with RA was 38 ± 12.02 years and that of healthy controls was 35.51 ± 5.8 years. The anthropometric parameters including height (153.11 ± 8.11 cm vs. 160.37 ± 5.41 cm, P < 0.001) and weight (55.43 ± 12.95 kg vs. 61.03 ± 8.75 kg, P = 0.038) were significantly lower in patients with RA as compared to that of healthy controls. Other anthropometric parameters such as waist and hip circumference, waist–hip ratio, body surface area, and body mass index were comparable in the two groups. Cardiovascular parameters such as systolic BP, diastolic BP, and HR were also comparable in the patients and controls [Table 1]. The mean duration of illness in RA patients was 5.83 ± 4.54 years. The mean DAS 28 in RA was 3.2 ± 1.0, indicating mild disease activity.
Regarding short-term HRV, it was observed in our study that the overall HRV was diminished in patients with RA compared to that of controls. We observed that LF of the frequency domain parameter (P = 0.007); NN50 (P < 0.001), and range (P = 0.028) of the time domain parameters were significantly lower in patients with RA as compared to that of healthy controls [Table 2].
|Table 2: Heart rate variability parameters in rheumatoid arthritis patients and controls|
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Serum concentration of TNF-α was found to be significantly higher in RA cases as compared to that of controls (0.40 vs. 0 pg/ml; P < 0.001). IL-10 was also found to be lower in controls than RA patients, though the difference was not statistically significant.
It was observed that DAS28 showed a significantly positive correlation with RMSSD, NN50, and HF of HRV parameters. Pro-inflammatory markers such as TNF-α also showed a significantly positive correlation with LF/HF ratio though IL-10 did not display any correlation with HRV [Table 3].
|Table 3: Pearson's correlation of disease activity score, and inflammatory markers with heart rate variability parameters in rheumatoid arthritis patients and controls|
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| Discussion|| |
Cardiovascular autonomic dysfunction is the most common complication of RA and is associated with high mortality due to associated arrhythmia and myocardial infarction., Analysis of HRV is the most commonly used measure of cardiovascular autonomic system, for both sympathetic and parasympathetic functions. Normal HR variation depends on the balance between sympathetic and parasympathetic systems.
Analyzing the time domain parameters in our study, we found that NN50 and range were significantly decreased in RA patients. Regarding the frequency domain parameters in our study, only LF was found to be significantly reduced in cases as compared to controls, whereas other parameters were also reduced though not significantly so. It was observed in our study that the overall HRV was diminished in patients with RA compared to that of controls. A reduced HRV is suggestive of a relative increase in sympathetic and reduced vagal modulation of sinus node. Our findings are in tune with several studies which analyzed short-term HRV and observed similar results.,
The activation of pituitary-dependent adrenal responses after endotoxin administration provided early evidence that inflammatory stimuli can activate anti-inflammatory signals from the central nervous system. Subsequently, Besedovsky et al. directly showed that inflammation in peripheral tissues alters neuronal signaling in the hypothalamus. It has been intriguing to consider whether pro-inflammatory and anti-inflammatory pathways could be modified due to altered neuronal signaling.
We chose to measure the levels of TNF-α and IL-10 as an indicator of pro-inflammatory and anti-inflammatory status, respectively, because they have been well established as markers for both the conditions.
RA patients have been observed to show significantly reduced IL-10 levels in serum in comparison to healthy donors, suggesting that IL-10 synthesis is depressed in RA. TNF-α is a potent cytokine involved in normal inflammatory and immune responses. Individuals with RA have been observed to have high levels of TNF-α in the synovial fluid, suggesting a currently active nature of the disease and also reflecting the presence of inflammation in these patients. Chronic exposure of the pro-inflammatory cytokines (TNF-α and IL-1) modulates the IL-10 signaling and bioactivity in synovial macrophages during chronic inflammation. In addition, patients with advanced RA have been shown to have the lowest values of IL-10 in serum.
The other cardiovascular parameters such as BP and HR remained comparable between cases and controls.
We then performed the Pearson's correlation analysis to assess the strength of association of inflammatory markers and disease severity score with HRV. We observed a positive correlation between disease severity score DAS28 and HF, RMSSD, and NN50 parameters of HRV despite their low disease activity. LF/HF ratio was found to be positively correlated with inflammatory mediator (TNF-α), suggesting that the inflammatory burden affects the autonomic nervous system and causes the decrease in HRV.
Our study findings suggest the existence of a direct relationship between the degree of systemic inflammation and sympathetic outflow in patients with chronic arthritis. A possible explanation for these results, particularly HRV abnormalities, is that chronic systemic inflammation could produce relevant changes in the cardiac autonomic system, via the persistent activation of the inflammatory reflex, in turn increasing the central sympathetic system output. However, the central sympathetic system, when activated, affects not only the immune system, but also all the body parts under its control, including the heart, thus possibly favoring directly and indirectly (by prolonging QTc interval) the onset of arrhythmias. In accordance with these considerations, patients with RA commonly show signs of cardiac sympathetic overactivity, as reflected by a significant HRV reduction and an increased QT interval dispersion, both established predictors of arrhythmic risk and sudden death in the general population.
Previous studies' data support our finding that pro-inflammatory cytokines (particularly TNF-alpha) exert a direct prolonging effect on cardiomyocyte action potential duration, depicting the possibility of direct contribution of inflammation in affecting the autonomic system of heart.
| Conclusion|| |
On the basis of our study findings, we were able to establish a link between raised inflammatory markers and sympathetic overdrive, which leads to lower HRV.
We hope our results encourage clinicians to monitor and influence adverse autonomic profile and levels of inflammatory markers as effective tools to enhance treatment response for inflammatory arthritis.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
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[Table 1], [Table 2], [Table 3]