Autonomic Dysfunction Precedes Development of Rheumatoid Arthritis: A Prospective Cohort Study F.A. Koopman, M.W. Tang, J. Vermeij, M.J. de Hair, I.Y. Choi, M.J. Vervoordeldonk, D.M. Gerlag, J.M. Karemaker, P.P. Tak PII: DOI: Reference:
S2352-3964(16)30068-8 doi: 10.1016/j.ebiom.2016.02.029 EBIOM 490
To appear in:
EBioMedicine
Received date: Revised date: Accepted date:
16 December 2015 2 February 2016 16 February 2016
Please cite this article as: Koopman, F.A., Tang, M.W., Vermeij, J., de Hair, M.J., Choi, I.Y., Vervoordeldonk, M.J., Gerlag, D.M., Karemaker, J.M., Tak, P.P., Autonomic Dysfunction Precedes Development of Rheumatoid Arthritis: A Prospective Cohort Study, EBioMedicine (2016), doi: 10.1016/j.ebiom.2016.02.029
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ACCEPTED MANUSCRIPT Autonomic dysfunction precedes development of rheumatoid arthritis: a prospective cohort study F.A.Koopman1, M.W.Tang1, J.Vermeij1, M.J. de Hair1,2, I.Y. Choi1, M.J.Vervoordeldonk1, D.M.Gerlag1*,
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J.M.Karemaker3, P.P.Tak1† 1
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Amsterdam Rheumatology and immunology Center | Department of Clinical Immunology & Rheumatology,
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Academic Medical Center, University of Amsterdam, Amsterdam, the Netherlands 2
Department of Rheumatology & Clinical Immunology, University Medical Center Utrecht
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Department of Physiology, Academic Medical Center, University of Amsterdam, Amsterdam, the Netherlands Current affiliation: GlaxoSmithKline, Cambridge, United Kingdom
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Current affiliations also: University of Cambridge, Cambridge, United Kingdom; University of Ghent, Ghent,
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NU
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Belgium; and GlaxoSmithKline, Stevenage, United Kingdom
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Corresponding author:
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Professor Paul P. Tak, MD, PhD
Room F4-105
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Amsterdam Rheumatology and immunology Center | Department of Clinical Immunology & Rheumatology,
Academic Medical Center University of Amsterdam
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PO Box 22700, 1100 DE Amsterdam, the Netherlands Phone: +31 20 566 7765; Fax: +31 20 691 9658; Email:
[email protected]. Running head: autonomic dysfunction in subjects at risk of arthritis Keywords: ‘heart rate variability’ ‘RA’ ‘autonomic nervous system’ ‘norepinephrine’ ‘heart rate’ ‘preclinical’ Abstract Background Heart rate variability (HRV) is a validated method to establish autonomic nervous system (ANS) activity. Rheumatoid arthritis (RA) is accompanied by ANS imbalance. We hypothesized that ANS dysfunction may precede the development of RA, which would suggest that it plays a role in its etiopathogenesis. Methods First, we assessed HRV parameters in supine (resting) and upright (active) position in healthy subjects (HS, n=20), individuals at risk of developing arthritis (AR subjects, n=50) and RA patients (RA, n=20).
ACCEPTED MANUSCRIPT Next, we measured resting heart rate (RHR), a parasympathetic HRV parameter, in an independent prospective cohort of AR subjects (n=45). We also evaluated expression levels of the parasympathetic nicotinic acetylcholine receptor type 7 (α7nAChR) on circulating monocytes. Findings Both AR subjects (68 beats per minute (bpm), interquartile range (IQR) 68-73) and RA patients (68
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bpm, IQR 62-76) had a significantly higher RHR compared to HS (60 bpm, IQR 56-63). RHR was significantly
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higher at baseline in individuals who subsequently developed arthritis. Expression levels of α7nAChR were
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lower in AR subjects with RHR ≥ 70 bpm compared to those with RHR
