Rheumatoid arthritis (RA) is the commonest inflammatory arthritis occurring throughout the world1. It is more prevalent in Indians and less prevalent in black Africans and Chinese. Both genetic and environmental factors are involved in the pathogenesis of RA. Cigarette smoking is a strong risk factor for RA2. Irrespective of the initiating stimulus, RA is characterized by infiltration of lymphocytes, plasma cells and macrophages into the synovium3. In RA, in the affected joints, activated lymphocytes secrete immunoglobulins including rheumatoid factor (RF) and macrophages release proinflammatory cytokines such as tumour necrosis factor- α (TNF-α). These chemicals act on synovial fibroblast, bone cells and chondrocytes to promote destruction of synovial membrane, bone, cartilage and soft tissues4.
From the studies carried out among western population, it has been observed that sympathetic nervous system activity is significantly elevated in RA patients5. Spectral analysis of heart rate variability (HRV) in RA patients have revealed a decrease in high frequency (HF) power representing vagal inhibition in addition to an increase in low frequency (LF) power indicating sympathetic activation6. It was suggested that the increased incidence of sudden cardiac death in these patients could have been due to the decreased vagal drive to the heart6. The magnitude of cardiovascular autonomic imbalance was linked to cardiovascular risks in patients suffering from RA7,8. Reduction in HRV, prolongation in QTc interval and higher sympathetic and decreased vagal drive were proposed as significant risk predictors for onset of sudden cardiac death in RA9,10. The cardiovascular autonomic dysfunction was suggested to stem from the underlying proinflammatory cytokines in RA11. It was also observed that in chronic arthritis such as RA, decreased responsiveness of hypothalamic-pituitary-adrenal axis causes inadequate production of cortisol in relation to inflammation that consequently leads to increased sympathetic activity, increased circulating cytokines, decreased local synovial sympathetic innervation, altered metabolism of estrogen in the synovium and high expression of estrogen receptors in synovial cells; all leading to exacerbation of neuroendocrine abnormalities in RA12.
In this issue, Yadav and colleagues13 report on HRV analysis in RA patients in Indian population. Authors have studied in details the HRV indices and correlated with immunological and biochemical parameters. They observed a decrease in total power (TP) of HRV in RA patients, which indicates poor cardiovascular health of these patients, as TP in general reflects cardiovascular status of the subject14. There was significant decrease in all time domain indices (TDI) in patients compared to controls indicating considerable decrease in vagal drive of cardiac modulation. In addition, there was increased sympathetic activity in these patients that corroborated with their significantly high systolic blood pressure (SBP) compared to the SBP of age and gender matched controls. The most important finding was the significant correlation of rheumatoid factor (RF) with changes in LF and HF powers of HRV indicating the alteration in sympathovagal activity with the severity of the disease. Though already there are reports of similar kind on autonomic imbalance in western population, a report from Indian subcontinent is worth publishing as there is wide ethnic variations in HRV indices and autonomic functions15. This study highlights the cardiovascular risks of RA patients, as mortality in patients suffering from RA is primarily due to cardiovascular events rather than the disease per se. However, the major limitations of the study are the less sample size and absence of plasma biochemical assessment of sympathetic activity.
The morbidity and mortality in RA is attributed mainly to the cardiovascular complications of the disease16,17. Cardiovascular events in RA are mainly due to the severity of inflammation and immunological reactions18–20. In recent years, RA has been considered as an independent risk factor for coronary artery disease20. Various studies have aimed to clarify important aspects of risk stratification and treatment options in patients with rheumatoid arthritis, and specific therapies are being evaluated that promise to reduce long-term cardiovascular risk in these patients. Chemicals released from the inflammatory cells in RA patients initiate and facilitate the cardiovascular damage. Hence, it is imperative to detect the mediators of inflammation linked to sympathovagal imbalance that impose cardiovascular risks in RA. As the mainstay of treatment in RA is anti-inflammatory drugs4, this will also explore the possibility of use of specific drugs from the very beginning of the disease process to check the rise in inflammatory chemicals that could be harmful for cardiovascular functions. Spectral HRV analysis is a non-invasive and sensitive tool to assess autonomic fluctuations in health and disease14. Hence, future studies should aim to assess the individual contribution of various inflammatory markers to the genesis of sympathovagal imbalance assessed by HRV analysis in RA in larger samples.
References
- 1.Bax M, van Heemst J, Huizinga TW, Toes RE. Genetics of rheumatoid arthritis: what have we learned? Immunogenetics. 2011;23:459–66. doi: 10.1007/s00251-011-0528-6. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 2.Mikuls TR, Hughes LB, Westfall AO, Holers VM, Parrish L, van der Heijde D, et al. Cigarette smoking, disease severity, and autoantibody expression in African Americans with recent-onset rheumatoid arthritis. Ann Rheum Dis. 2008;67:1529–34. doi: 10.1136/ard.2007.082669. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 3.Kinne RW, Stuhlmüller B, Burmester GR. Cells of the synovium in rheumatoid arthritis: Macrophages. Arthritis Res Ther. 2007;9:224. doi: 10.1186/ar2333. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 4.Doherty M, Ralston SH. Inflammatory joint disease: Rheumatoid arthritis. In: Colledge NR, Walker BR, Ralstron SH, editors. Davidson's principle and practice of medicine. 21st ed. London: Churchil Livingstone; 2010. p. 1088. [Google Scholar]
- 5.Dekkers JC, Geenen R, Godaert GL, Bijlsma JW, van Doornen LJ. Elevated sympathetic nervous system activity in patients with recently diagnosed rheumatoid arthritis with active disease. Clin Exp Rheumatol. 2004;22:63–70. [PubMed] [Google Scholar]
- 6.Kamal A. Assessment of autonomic function in patients with rheumatoid arthritis using spectral analysis and approximate entropy method. Neurosciences (Riyadh) 2007;12:136–9. [PubMed] [Google Scholar]
- 7.Stojanovich L, Milovanovich B, de Luka SR, Popovich-Kuzmanovich D, Bisenich V, Djukanovich B, et al. Cardiovascular autonomic dysfunction in systemic lupus, rheumatoid arthritis, primary Sjögren syndrome and other autoimmune diseases. Lupus. 2007;16:181–5. doi: 10.1177/0961203306076223. [DOI] [PubMed] [Google Scholar]
- 8.Vlcek M, Rovensky J, Blazicek P, Radikova Z, Penesova A, Kerlik J, et al. Sympathetic nervous system response to orthostatic stress in female patients with rheumatoid arthritis. Ann N Y Acad Sci. 2008;1148:556–61. doi: 10.1196/annals.1410.026. [DOI] [PubMed] [Google Scholar]
- 9.Milovanović B, Stojanović L, Milićevik N, Vasić K, Bjelaković B, Krotin M. Cardiac autonomic dysfunction in patients with systemic lupus, rheumatoid arthritis and sudden death risk. Srp Arh Celok Lek. 2010;138:26–32. doi: 10.2298/sarh1002026m. [DOI] [PubMed] [Google Scholar]
- 10.Vlcek M, Rovensky J, Eisenhofer G, Radikova Z, Penesova A, Kerlik J, et al. Autonomic nervous system function in rheumatoid arthritis. Cell Mol Neurobiol. 2012;32:897–910. doi: 10.1007/s10571-012-9805-7. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 11.Shahabi S, Hassan ZM, Jazani NH, Ebtekar M. Sympathetic nervous system plays an important role in the relationship between immune mediated diseases. Med Hypotheses. 2006;67:900–3. doi: 10.1016/j.mehy.2006.03.039. [DOI] [PubMed] [Google Scholar]
- 12.Capellino S, Straub RH. Neuroendocrine immune pathways in chronic arthritis. Best Pract Res Clin Rheumatol. 2008;22:285–97. doi: 10.1016/j.berh.2008.01.010. [DOI] [PubMed] [Google Scholar]
- 13.Yadav RK, Gupta R, Deepak KK. A pilot study on short term heart rate variability & its correlation with disease activity in Indian patients with rheumatoid arthritis. Indian J Med Res. 2012;136:593–8. [PMC free article] [PubMed] [Google Scholar]
- 14.Malliani A. Heart rate variability: from bench to bedside. Eur J Int Med. 2005;16:12–60. doi: 10.1016/j.ejim.2004.06.016. [DOI] [PubMed] [Google Scholar]
- 15.Li Z, Snieder H, Su S, Ding X, Thayer JF, Treiber FA, et al. A longitudinal study in youth of heart rate variability at rest and in response to stress. Int J Psychophysiol. 2009;73:212–7. doi: 10.1016/j.ijpsycho.2009.03.002. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 16.Prior P, Symmons DP, Scott DL, Brown R, Hawkins CF. Cause of death in rheumatoid arthritis. Br J Rheumatol. 1984;23:92–9. doi: 10.1093/rheumatology/23.2.92. [DOI] [PubMed] [Google Scholar]
- 17.del Rincon ID, Williams K, Stern MP, Freeman GL, Escalante A. High incidence of cardiovascular events in a rheumatoid arthritis cohort not explained by traditional cardiac risk factors. Arthritis Rheum. 2001;44:2737–45. doi: 10.1002/1529-0131(200112)44:12<2737::AID-ART460>3.0.CO;2-%23. [DOI] [PubMed] [Google Scholar]
- 18.Hjeltnes G, Hollan I, Førre O, Wiik A, Lyberg T, Mikkelsen K, et al. Relations of serum COMP to cardiovascular risk factors and endothelial function in patients with rheumatoid arthritis treated with methotrexate and TNF-α inhibitors. J Rheumatol. 2012;39:1341–7. doi: 10.3899/jrheum.111401. [DOI] [PubMed] [Google Scholar]
- 19.Goshayeshi L, Saber H, Sahebari M, Rezaieyazdi Z, Rafatpanah H, Esmaily H, et al. Association between metabolic syndrome, BMI, and serum vitamin D concentrations in rheumatoid arthritis. Clin Rheumatol. 2012;31:1197–203. doi: 10.1007/s10067-012-1995-3. [DOI] [PubMed] [Google Scholar]
- 20.de Matos Soeiro A, Haddad M, Feres de Almeida MC, Ruppert A D, Serrano C V., Jr Rheumatoid arthritis and cardiovascular disease: What is known about this relationship and what can currently be done for affected patients? Rev Port Cardiol. 2012;31:225–32. doi: 10.1016/j.repc.2012.01.005. [DOI] [PubMed] [Google Scholar]