Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Review Article
  • Published:

Microvascular endothelial dysfunction in rheumatoid arthritis

Abstract

The systemic autoimmune disease rheumatoid arthritis (RA) is characterized by increased cardiovascular mortality and morbidity and is an independent cardiovascular risk factor. Cardiovascular diseases (CVDs) result from accelerated atherogenesis, which is a consequence of endothelial dysfunction in the early stages of the disease. Endothelial dysfunction is a functional and reversible alteration of endothelial cells and leads to a shift in the properties of the endothelium towards reduced vasodilation, a pro-inflammatory state, and proliferative and prothrombotic properties. In RA, endothelial dysfunction can occur in the large vessels (such as the conduit arteries) and in the small vessels of the microvasculature, which supply oxygen and nutrients to the tissue and control inflammation, repair and fluid exchange with the surrounding tissues. Growing evidence suggests that microvascular endothelial dysfunction contributes to CVD development, as it precedes and predicts the development of conduit artery atherosclerosis and associated risk factors. As such, numerous studies have investigated microvascular endothelial dysfunction in RA, including its link with disease activity, disease duration and inflammation, the effect of treatments on endothelial function, and possible circulating biomarkers of microvascular endothelial dysfunction. Such findings could have important implications in the cardiovascular risk management of patients with RA.

Key points

  • Microvascular endothelial dysfunction is an early and/or seminal event in the development of cardiovascular diseases and associated organ damage and is also present in patients with rheumatoid arthritis (RA).

  • Microvascular endothelial dysfunction does not correlate with disease activity, disease duration, levels of C-reactive protein or the erythrocyte sedimentation rate.

  • Antirheumatic drugs and other therapies can be used to treat microvascular endothelial dysfunction, but the effects of these therapies differ.

  • Achieving remission in RA does not guarantee the normalization of microvascular endothelial function.

  • Semiautomated methods for the measurement of microvascular endothelial dysfunction exist; therefore, the concept of endothelial-guided therapies in RA deserves attention.

  • The predictive value of microvascular endothelial dysfunction for cardiovascular events needs to be demonstrated in future studies.

This is a preview of subscription content, access via your institution

Access options

Rent or buy this article

Prices vary by article type

from$1.95

to$39.95

Prices may be subject to local taxes which are calculated during checkout

Fig. 1: Microvascular and macrovascular crosstalk and associated cardiovascular diseases in RA.

Similar content being viewed by others

References

  1. Giles, J. T. Cardiovascular disease in rheumatoid arthritis: current perspectives on assessing and mitigating risk in clinical practice. Best Pract. Res. Clin. Rheumatol. 29, 597–613 (2015).

    Article  PubMed  Google Scholar 

  2. López-Mejías, R. et al. Cardiovascular risk assessment in patients with rheumatoid arthritis: The relevance of clinical, genetic and serological markers. Autoimmun. Rev. 15, 1013–1030 (2016).

    Article  PubMed  Google Scholar 

  3. Avina-Zubieta, J. A., Thomas, J., Sadatsafavi, M., Lehman, A. J. & Lacaille, D. Risk of incident cardiovascular events in patients with rheumatoid arthritis: a meta-analysis of observational studies. Ann. Rheum. Dis. 71, 1524–1529 (2012).

    Article  PubMed  Google Scholar 

  4. van Halm, V. P. et al. Rheumatoid arthritis versus diabetes as a risk factor for cardiovascular disease: a cross-sectional study, the CARRE Investigation. Ann. Rheum. Dis. 68, 1395–1400 (2009).

    Article  PubMed  Google Scholar 

  5. del Rincón, I. D., Williams, K., Stern, M. P., Freeman, G. L. & Escalante, A. High incidence of cardiovascular events in a rheumatoid arthritis cohort not explained by traditional cardiac risk factors. Arthritis Rheum. 44, 2737–2745 (2001).

    Article  PubMed  Google Scholar 

  6. Holmqvist, M. E. et al. Rapid increase in myocardial infarction risk following diagnosis of rheumatoid arthritis amongst patients diagnosed between 1995 and 2006. J. Intern. Med. 268, 578–585 (2010).

    Article  PubMed  CAS  Google Scholar 

  7. Kaplan, M. J. Cardiovascular complications of rheumatoid arthritis: assessment, prevention, and treatment. Rheum. Dis. Clin. North Am. 36, 405–426 (2010).

    Article  PubMed  PubMed Central  Google Scholar 

  8. van den Hoek, J. et al. Mortality in patients with rheumatoid arthritis: a 15-year prospective cohort study. Rheumatol. Int. 37, 487–493 (2017).

    Article  PubMed  Google Scholar 

  9. Prati, C., Demougeot, C., Guillot, X., Godfrin-Valnet, M. & Wendling, D. Endothelial dysfunction in joint disease. Joint Bone Spine 81, 386–391 (2014).

    Article  PubMed  CAS  Google Scholar 

  10. Daiber, A. et al. Targeting vascular (endothelial) dysfunction. Br. J. Pharmacol. 174, 1591–1619 (2016).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  11. Gutterman, D. D. et al. The human microcirculation: regulation of flow and beyond. Circ. Res. 118, 157–172 (2016).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  12. Moroni, L., Selmi, C., Angelini, C. & Meroni, P. L. Evaluation of endothelial function by flow-mediated dilation: a comprehensive review in rheumatic disease. Arch. Immunol. Ther. Exp. 65, 463–475 (2017).

    Article  Google Scholar 

  13. Kotani, K., Miyamoto, M. & Ando, H. The effect of treatments for rheumatoid arthritis on endothelial dysfunction evaluated by flow-mediated vasodilation in patients with rheumatoid arthritis. Curr. Vasc. Pharmacol. 15, 10–18 (2017).

    Article  PubMed  CAS  Google Scholar 

  14. Gonzalez-Gay, M. A., Gonzalez-Juanatey, C., Vazquez-Rodriguez, T. R., Martin, J. & Llorca, J. Endothelial dysfunction, carotid intima-media thickness, and accelerated atherosclerosis in rheumatoid arthritis. Semin. Arthritis Rheum. 38, 67–70 (2008).

    Article  PubMed  Google Scholar 

  15. Haller, H. Endothelial function. General considerations. Drugs 53 (Suppl. 1), 1–10 (1997).

    Article  PubMed  CAS  Google Scholar 

  16. Kimura, K. et al. Diversity and variability of smooth muscle phenotypes of renal arterioles as revealed by myosin isoform expression. Kidney Int. 48, 372–382 (1995).

    Article  PubMed  CAS  Google Scholar 

  17. Napoli, C. et al. Efficacy and age-related effects of nitric oxide-releasing aspirin on experimental restenosis. Proc. Natl Acad. Sci. USA 99, 1689–1694 (2002).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  18. Takahashi, M., Ishida, T., Traub, O., Corson, M. A. & Berk, B. C. Mechanotransduction in endothelial cells: temporal signaling events in response to shear stress. J. Vasc. Res. 34, 212–219 (1997).

    Article  PubMed  CAS  Google Scholar 

  19. Triggle, C. R. & Ding, H. The endothelium in compliance and resistance vessels. Front. Biosci. Sch. Ed. 3, 730–744 (2011).

    Article  Google Scholar 

  20. Matsuzawa, Y. & Lerman, A. Endothelial dysfunction and coronary artery disease: assessment, prognosis, and treatment. Coron. Artery Dis. 25, 713–724 (2014).

    Article  PubMed  PubMed Central  Google Scholar 

  21. Liao, J. K. Linking endothelial dysfunction with endothelial cell activation. J. Clin. Invest. 123, 540–541 (2013).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  22. Linder, L., Kiowski, W., Bühler, F. R. & Lüscher, T. F. Indirect evidence for release of endothelium-derived relaxing factor in human forearm circulation in vivo. Blunted response in essential hypertension. Circulation 81, 1762–1767 (1990).

    Article  PubMed  CAS  Google Scholar 

  23. Panza, J. A., Quyyumi, A. A., Brush, J. E. & Epstein, S. E. Abnormal endothelium-dependent vascular relaxation in patients with essential hypertension. N. Engl. J. Med. 323, 22–27 (1990).

    Article  PubMed  CAS  Google Scholar 

  24. Treasure, C. B. et al. Epicardial coronary artery responses to acetylcholine are impaired in hypertensive patients. Circ. Res. 71, 776–781 (1992).

    Article  PubMed  CAS  Google Scholar 

  25. Calver, A., Collier, J. & Vallance, P. Inhibition and stimulation of nitric oxide synthesis in the human forearm arterial bed of patients with insulin-ependent diabetes. J. Clin. Invest. 90, 2548–2554 (1992).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  26. Cosentino, F. et al. High glucose causes upregulation of cyclooxygenase-2 and alters prostanoid profile in human endothelial cells: role of protein kinase C and reactive oxygen species. Circulation 107, 1017–1023 (2003).

    Article  PubMed  CAS  Google Scholar 

  27. Mäkimattila, S. et al. Chronic hyperglycemia impairs endothelial function and insulin sensitivity via different mechanisms in insulin-dependent diabetes mellitus. Circulation 94, 1276–1282 (1996).

    Article  PubMed  Google Scholar 

  28. Steinberg, H. O. et al. Obesity/insulin resistance is associated with endothelial dysfunction. Implications for the syndrome of insulin resistance. J. Clin. Invest. 97, 2601–2610 (1996).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  29. Casino, P. R., Kilcoyne, C. M., Quyyumi, A. A., Hoeg, J. M. & Panza, J. A. The role of nitric oxide in endothelium-dependent vasodilation of hypercholesterolemic patients. Circulation 88, 2541–2547 (1993).

    Article  PubMed  CAS  Google Scholar 

  30. Spieker, L. E. et al. High-density lipoprotein restores endothelial function in hypercholesterolemic men. Circulation 105, 1399–1402 (2002).

    Article  PubMed  CAS  Google Scholar 

  31. Hamburg, N. M. et al. Relation of brachial and digital measures of vascular function in the community: the Framingham heart study. Hypertension 57, 390–396 (2011).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  32. Sitia, S. et al. From endothelial dysfunction to atherosclerosis. Autoimmun. Rev. 9, 830–834 (2010).

    Article  PubMed  CAS  Google Scholar 

  33. Kieda, C. Heterogeneity of endothelial cells — role in vessel specialization and cooperation in vasculogenic mimicry. Postepy Biochem. 59, 372–378 (2013).

    PubMed  CAS  Google Scholar 

  34. Geiger, M., Stone, A., Mason, S. N., Oldham, K. T. & Guice, K. S. Differential nitric oxide production by microvascular and macrovascular endothelial cells. Am. J. Physiol. 273, L275–L281 (1997).

    PubMed  CAS  Google Scholar 

  35. Gerritsen, M. E., Niedbala, M. J., Szczepanski, A. & Carley, W. W. Cytokine activation of human macro- and microvessel-derived endothelial cells. Blood Cells 19, 325–339 (1993).

    PubMed  CAS  Google Scholar 

  36. Sumagin, R. & Sarelius, I. H. Emerging understanding of roles for arterioles in inflammation. Microcirculation 20, 679–692 (2013).

    PubMed  PubMed Central  CAS  Google Scholar 

  37. Aird, W. C. Phenotypic heterogeneity of the endothelium. I. Structure, function, and mechanisms. Circ. Res. 100, 158–173 (2007).

    Article  PubMed  CAS  Google Scholar 

  38. Stokes, K. Y. & Granger, D. N. The microcirculation: a motor for the systemic inflammatory response and large vessel disease induced by hypercholesterolaemia? J. Physiol. 562, 647–653 (2005).

    Article  PubMed  CAS  Google Scholar 

  39. Anderson, T. J. et al. Microvascular function predicts cardiovascular events in primary prevention: long-term results from the Firefighters and Their Endothelium (FATE) study. Circulation 123, 163–169 (2011).

    Article  PubMed  Google Scholar 

  40. Lind, L., Berglund, L., Larsson, A. & Sundström, J. Endothelial function in resistance and conduit arteries and 5-year risk of cardiovascular disease. Circulation 123, 1545–1551 (2011).

    Article  PubMed  Google Scholar 

  41. Reis, S. E. et al. Coronary microvascular dysfunction is highly prevalent in women with chest pain in the absence of coronary artery disease: results from the NHLBI WISE study. Am. Heart J. 141, 735–741 (2001).

    Article  PubMed  CAS  Google Scholar 

  42. von Mering, G. O. et al. Abnormal coronary vasomotion as a prognostic indicator of cardiovascular events in women: results from the National Heart, Lung, and Blood Institute-Sponsored Women’s Ischemia Syndrome Evaluation (WISE). Circulation 109, 722–725 (2004).

    Article  Google Scholar 

  43. Flammer, A. J. et al. The assessment of endothelial function: from research into clinical practice. Circulation 126, 753–767 (2012).

    Article  PubMed  PubMed Central  Google Scholar 

  44. Vizzardi, E. et al. Noninvasive assessment of endothelial function: the classic methods and the new peripheral arterial tonometry. J. Investig. Med. 62, 856–864 (2014).

    Article  PubMed  CAS  Google Scholar 

  45. Lockhart, C. J., Hamilton, P. K., Quinn, C. E. & McVeigh, G. E. End-organ dysfunction and cardiovascular outcomes: the role of the microcirculation. Clin. Sci. 116, 175–190 (2009).

    Article  PubMed  Google Scholar 

  46. Chantler, P. D. & Frisbee, J. C. Arterial function in cardio-metabolic diseases: from the microcirculation to the large conduits. Prog. Cardiovasc. Dis. 57, 489–496 (2015).

    Article  PubMed  Google Scholar 

  47. Anderson, T. J. & Phillips, S. A. Assessment and prognosis of peripheral artery measures of vascular function. Prog. Cardiovasc. Dis. 57, 497–509 (2015).

    Article  PubMed  Google Scholar 

  48. Lekakis, J. et al. Methods for evaluating endothelial function: a position statement from the European Society of Cardiology Working Group on Peripheral Circulation. Eur. J. Cardiovasc. Prev. Rehabil. 18, 775–789 (2011).

    Article  PubMed  Google Scholar 

  49. Bourdarias, J. P. Coronary reserve: concept and physiological variations. Eur. Heart J. 16 (Suppl. 1), 2–6 (1995).

    Article  PubMed  Google Scholar 

  50. Al Mheid, I. et al. Vitamin D status is associated with arterial stiffness and vascular dysfunction in healthy humans. J. Am. Coll. Cardiol. 58, 186–192 (2011).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  51. Rammos, C. et al. Macrophage migration inhibitory factor is associated with vascular dysfunction in patients with end-stage renal disease. Int. J. Cardiol. 168, 5249–5256 (2013).

    Article  PubMed  Google Scholar 

  52. Secrest, A. M., Prince, C. T., Costacou, T., Miller, R. G. & Orchard, T. J. Predictors of and survival after incident stroke in type 1 diabetes. Diab. Vasc. Dis. Res. 10, 3–10 (2013).

    Article  PubMed  Google Scholar 

  53. Gonzalez-Juanatey, C. et al. HLA-DRB1 status affects endothelial function in treated patients with rheumatoid arthritis. Am. J. Med. 114, 647–652 (2003).

    Article  PubMed  CAS  Google Scholar 

  54. Bergholm, R. et al. Impaired responsiveness to NO in newly diagnosed patients with rheumatoid arthritis. Arterioscler. Thromb. Vasc. Biol. 22, 1637–1641 (2002).

    Article  PubMed  CAS  Google Scholar 

  55. Palomino-Morales, R. et al. A1298C polymorphism in the MTHFR gene predisposes to cardiovascular risk in rheumatoid arthritis. Arthritis Res. Ther. 12, R71 (2010).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  56. Palomino-Morales, R. et al. Interleukin-6 gene -174 promoter polymorphism is associated with endothelial dysfunction but not with disease susceptibility in patients with rheumatoid arthritis. Clin. Exp. Rheumatol. 27, 964–970 (2009).

    PubMed  CAS  Google Scholar 

  57. Liang, K. P. et al. Autoantibodies and the risk of cardiovascular events. J. Rheumatol. 36, 2462–2469 (2009).

    Article  PubMed  PubMed Central  Google Scholar 

  58. Marder, W. et al. Interleukin 17 as a novel predictor of vascular function in rheumatoid arthritis. Ann. Rheum. Dis. 70, 1550–1555 (2011).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  59. Amaya-Amaya, J. et al. Novel risk factors for cardiovascular disease in rheumatoid arthritis. Immunol. Res. 56, 267–286 (2013).

    Article  PubMed  Google Scholar 

  60. Fenton, S. A. M. et al. Sitting time is negatively related to microvascular endothelium-dependent function in rheumatoid arthritis. Microvasc. Res. 117, 57–60 (2018).

    Article  PubMed  CAS  Google Scholar 

  61. Roubille, C. et al. The effects of tumour necrosis factor inhibitors, methotrexate, non-steroidal anti-inflammatory drugs and corticosteroids on cardiovascular events in rheumatoid arthritis, psoriasis and psoriatic arthritis: a systematic review and meta-analysis. Ann. Rheum. Dis. 74, 480–489 (2015).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  62. Arosio, E. et al. Forearm haemodynamics, arterial stiffness and microcirculatory reactivity in rheumatoid arthritis. J. Hypertens. 25, 1273–1278 (2007).

    Article  PubMed  CAS  Google Scholar 

  63. Sandoo, A. et al. Lack of association between asymmetric dimethylarginine and in vivo microvascular and macrovascular endothelial function in patients with rheumatoid arthritis. Clin. Exp. Rheumatol. 30, 388–396 (2012).

    PubMed  CAS  Google Scholar 

  64. Sandoo, A., Kitas, G. D., Carroll, D. & Veldhuijzen van Zanten, J. J. C. S. The role of inflammation and cardiovascular disease risk on microvascular and macrovascular endothelial function in patients with rheumatoid arthritis: a cross-sectional and longitudinal study. Arthritis Res. Ther. 14, R117 (2012).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  65. Sandoo, A. et al. Classical cardiovascular disease risk factors associate with vascular function and morphology in rheumatoid arthritis: a six-year prospective study. Arthritis Res. Ther. 15, R203 (2013).

    Article  PubMed  PubMed Central  Google Scholar 

  66. Sandoo, A., Carroll, D., Metsios, G. S., Kitas, G. D. & Veldhuijzen van Zanten, J. J. The association between microvascular and macrovascular endothelial function in patients with rheumatoid arthritis: a cross-sectional study. Arthritis Res. Ther. 13, R99 (2011).

    Article  PubMed  PubMed Central  Google Scholar 

  67. Faccini, A., Kaski, J. C. & Camici, P. G. Coronary microvascular dysfunction in chronic inflammatory rheumatoid diseases. Eur. Heart J. 37, 1799–1806 (2016).

    Article  PubMed  Google Scholar 

  68. Klimek, E. et al. Alterations in skin microvascular function in patients with rheumatoid arthritis and ankylosing spondylitis. Clin. Hemorheol. Microcirc. 65, 77–91 (2017).

    Article  PubMed  CAS  Google Scholar 

  69. Turiel, M. et al. Non-invasive assessment of coronary flow reserve and ADMA levels: a case-control study of early rheumatoid arthritis patients. Rheumatology 48, 834–839 (2009).

    Article  PubMed  CAS  Google Scholar 

  70. Foster, W., Lip, G. Y. H., Raza, K., Carruthers, D. & Blann, A. D. An observational study of endothelial function in early arthritis. Eur. J. Clin. Invest. 42, 510–516 (2012).

    Article  PubMed  CAS  Google Scholar 

  71. van Eijk, I. C., Serné, E. H., Dijkmans, B. A. C., Smulders, Y. & Nurmohamed, M. Microvascular function is preserved in newly diagnosed rheumatoid arthritis and low systemic inflammatory activity. Clin. Rheumatol. 30, 1113–1118 (2011).

    Article  PubMed  PubMed Central  Google Scholar 

  72. Verhoeven, F. et al. Glucocorticoids improve endothelial function in rheumatoid arthritis: a study in rats with adjuvant-induced arthritis. Clin. Exp. Immunol. 188, 208–218 (2017).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  73. Verhoeven, F. et al. Diclofenac but not celecoxib improves endothelial function in rheumatoid arthritis: a study in adjuvant-induced arthritis. Atherosclerosis 266, 136–144 (2017).

    Article  PubMed  CAS  Google Scholar 

  74. Yki-Jarvinen, H., Bergholm, R. & Leirisalo-Repo, M. Increased inflammatory activity parallels increased basal nitric oxide production and blunted response to nitric oxide in vivo in rheumatoid arthritis. Ann. Rheum. Dis. 62, 630–634 (2003).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  75. Hänsel, S., Lässig, G., Pistrosch, F. & Passauer, J. Endothelial dysfunction in young patients with long-term rheumatoid arthritis and low disease activity. Atherosclerosis 170, 177–180 (2003).

    Article  PubMed  CAS  Google Scholar 

  76. Mäki-Petäjä, K. M. et al. Inducible nitric oxide synthase activity is increased in patients with rheumatoid arthritis and contributes to endothelial dysfunction. Int. J. Cardiol. 129, 399–405 (2008).

    Article  PubMed  Google Scholar 

  77. Alomari, M. A. et al. Vascular function and handgrip strength in rheumatoid arthritis patients. ScientificWorldJournal 2012, 580863 (2012).

    PubMed  PubMed Central  Google Scholar 

  78. Ciftci, O. et al. Impaired coronary microvascular function and increased intima-media thickness in rheumatoid arthritis. Atherosclerosis 198, 332–337 (2008).

    Article  PubMed  CAS  Google Scholar 

  79. Recio-Mayoral, A. et al. Chronic inflammation and coronary microvascular dysfunction in patients without risk factors for coronary artery disease. Eur. Heart J. 30, 1837–1843 (2009).

    Article  PubMed  CAS  Google Scholar 

  80. Kakuta, K. et al. Chronic inflammatory disease is an independent risk factor for coronary flow velocity reserve impairment unrelated to the processes of coronary artery calcium deposition. J. Am. Soc. Echocardiogr. 29, 173–180 (2016).

    Article  PubMed  Google Scholar 

  81. Ikonomidis, I. et al. Increased benefit of interleukin 1 inhibition on vascular function, myocardial deformation, and twisting in patients with coronary artery disease and coexisting rheumatoid arthritis. Circ. Cardiovasc. Imag. 7, 619–628 (2014).

    Article  Google Scholar 

  82. Anyfanti, P. et al. Subendocardial viability ratio in patients with rheumatoid arthritis: comparison with healthy controls and identification of prognostic factors. Clin. Rheumatol. 36, 1229–1236 (2017).

    Article  PubMed  Google Scholar 

  83. Foster, W., Carruthers, D., Lip, G. Y. H. & Blann, A. D. Inflammation and microvascular and macrovascular endothelial dysfunction in rheumatoid arthritis: effect of treatment. J. Rheumatol. 37, 711–716 (2010).

    Article  PubMed  CAS  Google Scholar 

  84. Provan, S. A. et al. Remission is the goal for cardiovascular risk management in patients with rheumatoid arthritis: a cross-sectional comparative study. Ann. Rheum. Dis. 70, 812–817 (2011).

    Article  PubMed  Google Scholar 

  85. Santos, M. J. et al. Early vascular alterations in SLE and RA patients — a step towards understanding the associated cardiovascular risk. PLoS ONE 7, e44668 (2012).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  86. Pieringer, H., Stuby, U., Pohanka, E. & Biesenbach, G. Augmentation index in patients with rheumatoid arthritis and ankylosing spondylitis treated with infliximab. Clin. Rheumatol. 29, 723–727 (2010).

    Article  PubMed  Google Scholar 

  87. Pieringer, H. et al. Heart rate, ejection duration and subendocardial viability ratio in patients with rheumatoid arthritis as compared to controls. Int. J. Rheum. Dis. 17, 39–43 (2014).

    Article  PubMed  Google Scholar 

  88. Heffernan, K. S., Karas, R. H., Patvardhan, E. A., Jafri, H. & Kuvin, J. T. Peripheral arterial tonometry for risk stratification in men with coronary artery disease. Clin. Cardiol. 33, 94–98 (2010).

    Article  PubMed  PubMed Central  Google Scholar 

  89. Dimitroulas, T., Sandoo, A., Hodson, J., Smith, J. P. & Kitas, G. D. In vivo microvascular and macrovascular endothelial function is not associated with circulating dimethylarginines in patients with rheumatoid arthritis: a prospective analysis of the DRACCO cohort. Scand. J. Clin. Lab. Invest. 76, 331–337 (2016).

    Article  PubMed  CAS  Google Scholar 

  90. Galarraga, B., Khan, F., Kumar, P., Pullar, T. & Belch, J. J. F. C-reactive protein: the underlying cause of microvascular dysfunction in rheumatoid arthritis. Rheumatology 47, 1780–1784 (2008).

    Article  PubMed  CAS  Google Scholar 

  91. Galarraga, B., Belch, J. J. F., Pullar, T., Ogston, S. & Khan, F. Clinical improvement in rheumatoid arthritis is associated with healthier microvascular function in patients who respond to antirheumatic therapy. J. Rheumatol. 37, 521–528 (2010).

    Article  PubMed  CAS  Google Scholar 

  92. Shrivastava, A. K., Singh, H. V., Raizada, A. & Singh, S. K. C-Reactive protein, inflammation and coronary heart disease. Egypt. Heart J. 67, 89–97 (2015).

    Article  Google Scholar 

  93. Datta, D., Ferrell, W. R., Sturrock, R. D., Jadhav, S. T. & Sattar, N. Inflammatory suppression rapidly attenuates microvascular dysfunction in rheumatoid arthritis. Atherosclerosis 192, 391–395 (2007).

    Article  PubMed  CAS  Google Scholar 

  94. Sandoo, A. et al. Anti-TNFα therapy may lead to blood pressure reductions through improved endothelium-dependent microvascular function in patients with rheumatoid arthritis. J. Hum. Hypertens. 25, 699–702 (2011).

    Article  PubMed  CAS  Google Scholar 

  95. Toutouzas, K. et al. Myocardial ischaemia without obstructive coronary artery disease in rheumatoid arthritis: hypothesis-generating insights from a cross-sectional study. Rheumatology 52, 76–80 (2013).

    Article  PubMed  Google Scholar 

  96. Dimitroulas, T., Hodson, J., Sandoo, A., Smith, J. & Kitas, G. D. Endothelial injury in rheumatoid arthritis: a crosstalk between dimethylarginines and systemic inflammation. Arthritis Res. Ther. 19, 32 (2017).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  97. Komai, N., Morita, Y., Sakuta, T., Kuwabara, A. & Kashihara, N. Anti-tumor necrosis factor therapy increases serum adiponectin levels with the improvement of endothelial dysfunction in patients with rheumatoid arthritis. Mod. Rheumatol. 17, 385–390 (2007).

    Article  PubMed  CAS  Google Scholar 

  98. Rongen, G. A. et al. Vasodilator function worsens after cessation of tumour necrosis factor inhibitor therapy in patients with rheumatoid arthritis only if a flare occurs. Clin. Rheumatol. 37, 909–916 (2018).

    Article  PubMed  Google Scholar 

  99. Hjeltnes, G. 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. 39, 1341–1347 (2012).

    Article  PubMed  CAS  Google Scholar 

  100. Hjeltnes, G. et al. Serum levels of lipoprotein(a) and E-selectin are reduced in rheumatoid arthritis patients treated with methotrexate or methotrexate in combination with TNF-α-inhibitor. Clin. Exp. Rheumatol. 31, 415–421 (2013).

    PubMed  Google Scholar 

  101. Sandoo, A. & Kitas, G. D. The impact of abatacept treatment on the vasculature in patients with rheumatoid arthritis. Clin. Exp. Rheumatol. 33, 589 (2015).

    PubMed  Google Scholar 

  102. Ruiz-Limón, P. et al. Tocilizumab improves the proatherothrombotic profile of rheumatoid arthritis patients modulating endothelial dysfunction, NETosis, and inflammation. Transl Res. 183, 87–103 (2017).

    Article  PubMed  CAS  Google Scholar 

  103. Petersons, C. J. et al. Low dose prednisolone and insulin sensitivity differentially affect arterial stiffness and endothelial function: An open interventional and cross-sectional study. Atherosclerosis 258, 34–39 (2017).

    Article  PubMed  CAS  Google Scholar 

  104. Radhakutty, A. et al. Effect of acute and chronic glucocorticoid therapy on insulin sensitivity and postprandial vascular function. Clin. Endocrinol. 84, 501–508 (2016).

    Article  CAS  Google Scholar 

  105. Verhoeven, F., Prati, C., Maguin-Gaté, K., Wendling, D. & Demougeot, C. Glucocorticoids and endothelial function in inflammatory diseases: focus on rheumatoid arthritis. Arthritis Res. Ther. 18, 258 (2016).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  106. Marder, W. et al. The peroxisome proliferator activated receptor-γ pioglitazone improves vascular function and decreases disease activity in patients with rheumatoid arthritis. J. Am. Heart Assoc. 2, e000441 (2013).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  107. Ormseth, M. J. et al. Reversing vascular dysfunction in rheumatoid arthritis: improved augmentation index but not endothelial function with peroxisome proliferator–activated receptor γ agonist therapy. Arthritis Rheumatol. 66, 2331–2338 (2014).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  108. Tam, L.-S. et al. Effects of rosuvastatin on subclinical atherosclerosis and arterial stiffness in rheumatoid arthritis: a randomized controlled pilot trial. Scand. J. Rheumatol. 40, 411–421 (2011).

    Article  PubMed  CAS  Google Scholar 

  109. Arts, E. E. A. et al. Statins inhibit the antirheumatic effects of rituximab in rheumatoid arthritis: results from the Dutch Rheumatoid Arthritis Monitoring (DREAM) registry. Ann. Rheum. Dis. 70, 877–878 (2011).

    Article  PubMed  CAS  Google Scholar 

  110. Crowson, C. S. et al. Rheumatoid arthritis and cardiovascular disease. Am. Heart J. 166, 622–628.e1 (2013).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  111. Metsios, G. S. et al. Individualised exercise improves endothelial function in patients with rheumatoid arthritis. Ann. Rheum. Dis. 73, 748–751 (2014).

    Article  PubMed  Google Scholar 

  112. Sandoo, A., van Zanten, J. J., Toms, T. E., Carroll, D. & Kitas, G. D. Anti-TNFα therapy transiently improves high density lipoprotein cholesterol levels and microvascular endothelial function in patients with rheumatoid arthritis: a pilot study. BMC Musculoskelet. Disord. 13, 127 (2012).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  113. Gonzalez-Juanatey, C. et al. Active but transient improvement of endothelial function in rheumatoid arthritis patients undergoing long-term treatment with anti-tumor necrosis factor alpha antibody. Arthritis Rheum. 51, 447–450 (2004).

    Article  PubMed  CAS  Google Scholar 

  114. Bernelot Moens, S. J. et al. Unexpected arterial wall and cellular inflammation in patients with rheumatoid arthritis in remission using biological therapy: a cross-sectional study. Arthritis Res. Ther. 18, 115 (2016).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  115. Turiel, M. et al. Effects of long-term disease-modifying antirheumatic drugs on endothelial function in patients with early rheumatoid arthritis. Cardiovasc. Ther. 28, e53–64 (2010).

    Article  PubMed  CAS  Google Scholar 

  116. Ranganathan, P. et al. Vitamin D deficiency, interleukin 17, and vascular function in rheumatoid arthritis. J. Rheumatol. 40, 1529–1534 (2013).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  117. Nordestgaard, B. G. et al. Lipoprotein(a) as a cardiovascular risk factor: current status. Eur. Heart J. 31, 2844–2853 (2010).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  118. Fleck, C., Schweitzer, F., Karge, E., Busch, M. & Stein, G. Serum concentrations of asymmetric (ADMA) and symmetric (SDMA) dimethylarginine in patients with chronic kidney diseases. Clin. Chim. Acta 336, 1–12 (2003).

    Article  PubMed  CAS  Google Scholar 

  119. Zsuga, J. et al. Dimethylarginines at the crossroad of insulin resistance and atherosclerosis. Metabolism 56, 394–399 (2007).

    Article  PubMed  CAS  Google Scholar 

  120. Kiechl, S. et al. Asymmetric and symmetric dimethylarginines are of similar predictive value for cardiovascular risk in the general population. Atherosclerosis 205, 261–265 (2009).

    Article  PubMed  CAS  Google Scholar 

  121. Mangiacapra, F. et al. Relationship of asymmetric dimethylarginine (ADMA) with extent and functional severity of coronary atherosclerosis. Int. J. Cardiol. 220, 629–633 (2016).

    Article  PubMed  Google Scholar 

  122. Vitiello, L. et al. Microvascular inflammation in atherosclerosis. IJC Metab. Endocr. 3, 1–7 (2014).

    Article  Google Scholar 

  123. Hjeltnes, G. et al. Anti-CCP and RF IgM: predictors of impaired endothelial function in rheumatoid arthritis patients. Scand. J. Rheumatol. 40, 422–427 (2011).

    Article  PubMed  CAS  Google Scholar 

  124. Totoson, P., Maguin-Gaté, K., Prati, C., Wendling, D. & Demougeot, C. Mechanisms of endothelial dysfunction in rheumatoid arthritis: lessons from animal studies. Arthritis Res. Ther. 16, 202 (2014).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  125. Dooley, L. M. et al. Endothelial dysfunction in an ovine model of collagen-induced arthritis. J. Vasc. Res. 51, 90–101 (2014).

    Article  PubMed  CAS  Google Scholar 

  126. Dooley, L. M. et al. Effect of mesenchymal precursor cells on the systemic inflammatory response and endothelial dysfunction in an ovine model of collagen-induced arthritis. PLoS ONE 10, e0124144 (2015).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  127. Totoson, P. et al. Microvascular abnormalities in adjuvant-induced arthritis: relationship to macrovascular endothelial function and markers of endothelial activation. Arthritis Rheumatol. 67, 1203–1213 (2015).

    Article  PubMed  CAS  Google Scholar 

  128. Agca, R. et al. EULAR recommendations for cardiovascular disease risk management in patients with rheumatoid arthritis and other forms of inflammatory joint disorders: 2015/2016 update. Ann. Rheum. Dis. 76, 17–28 (2017).

    Article  PubMed  CAS  Google Scholar 

  129. Gómez-Vaquero, C. et al. SCORE and REGICOR function charts underestimate the cardiovascular risk in Spanish patients with rheumatoid arthritis. Arthritis Res. Ther. 15, R91 (2013).

    Article  PubMed  PubMed Central  Google Scholar 

  130. Arts, E. E. A. et al. Prediction of cardiovascular risk in rheumatoid arthritis: performance of original and adapted SCORE algorithms. Ann. Rheum. Dis. 75, 674–680 (2016).

    Article  PubMed  CAS  Google Scholar 

  131. Kalaria, R. N. Cerebrovascular disease and mechanisms of cognitive impairment: evidence from clinicopathological studies in humans. Stroke 43, 2526–2534 (2012).

    Article  PubMed  Google Scholar 

  132. Oláh, C. et al. Assessment of intracranial vessels in association with carotid atherosclerosis and brain vascular lesions in rheumatoid arthritis. Arthritis Res. Ther. 19, 213 (2017).

    Article  PubMed  PubMed Central  Google Scholar 

  133. Rodriguez-Rodriguez, L. et al. Rheumatoid arthritis: genetic variants as biomarkers of cardiovascular disease. Curr. Pharm. Des. 21, 182–201 (2015).

    Article  PubMed  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

Authors

Contributions

C.D. and R.B. researched data for the article and wrote the article. C.D. provided substantial contribution to the discussion of its content. All authors reviewed and/or edited the article before submission.

Corresponding author

Correspondence to Céline Demougeot.

Ethics declarations

Competing interests

The authors declare no competing interests.

Additional information

Publisher’s note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Supplementary information

Glossary

Dyslipidaemia

A disorder of lipoprotein metabolism characterized by a spectrum of quantitative and qualitative changes in lipids and lipoproteins.

Framingham risk score

An algorithm used to estimate the 10-year risk of developing coronary heart disease on the basis of age, sex, cholesterol levels, blood pressure (and whether the individual is being treated for hypertension), diabetes and smoking status.

Pulsatile pressure

The difference between the systolic and diastolic blood pressure (also called pulse pressure), which is governed by the relationship between ventricular ejection and the viscoelastic properties of the large arteries (arterial stiffness).

Reactive hyperaemia

A transient increase in blood flow that occurs following a brief period of ischaemia (for example, arterial occlusion).

Myocardial ischaemia

A restriction in blood supply to the myocardium resulting from reduced blood flow in the coronary arteries. This restriction leads to an imbalance between myocardial oxygen supply and demand, causing cardiac dysfunction, myocardial infarction, arrhythmias and sudden death.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Bordy, R., Totoson, P., Prati, C. et al. Microvascular endothelial dysfunction in rheumatoid arthritis. Nat Rev Rheumatol 14, 404–420 (2018). https://doi.org/10.1038/s41584-018-0022-8

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/s41584-018-0022-8

This article is cited by

Search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing