Adrenergic hyperactivity: a missing link between multiple sclerosis and cardiovascular comorbidities?

  • Mario HabekEmail author
  • Tomislav Mutak
  • Bojana Nevajdić
  • Dunja Pucić
  • Luka Crnošija
  • Magdalena Krbot Skorić
Original Article


The aim of the study is to investigate differences in non-standard adrenergic baroreflex sensitivity (BRS) indices in patients with different phenotypes of multiple sclerosis (pwMS) and healthy controls (HC). Retrospective analysis of types of systolic blood pressure (BP) curves during Valsalva maneuver (VM) [balanced (BAR), augmented (AAR) and suppressed (SAR) autonomic responses] and adrenergic baroreflex sensitivity (BRSa) measured with BRSa1, α-BRSa and β-BRSa in patients with clinically isolated syndrome (CIS), relapsing remitting multiple sclerosis (RRMS), progressive multiple sclerosis (PMS) and HC. We also investigated correlations between BRSa1, α-BRSa, β-BRSa and resting catecholamine levels. pwMS had higher α-BRSa compared to HC (p = 0.02). There was no difference in BRSa1, s and β-BRSa between patients with CIS, RRMS and PMS. There was no association between pwMS and HC, and the type of sBP curve [χ2 = 4.332, p = 0.114]. pwMS and BAR or AAR had higher supine systolic and diastolic BP compared to pwMS and SAR. There was a significant correlation between α-BRSa and upright systolic BP (rp =0.194, p = 0.017), α-BRSa and norepinephrine (rs =0.228, p = 0.021), and BRSa1 and epinephrine (rs = 0.226, p = 0.040). pwMS and HC exhibit different alpha-adrenergic response to Valsalva maneuver. These results may explain the connection between MS and increased cardiovascular risk.


Multiple sclerosis Valsalva maneuver Cardiovascular autonomic dysfunction Adrenergic baroreflex sensitivity 


Author contributions

Study concept and design: MH. Acquisition of data: TM, BN, DP, MKS, LC, MH. Analysis and interpretation of data: TM, BN, DP, MKS, LC, MH. Drafting of the manuscript: MH. Critical revision of the manuscript for important intellectual content: TM, BN, DP, MKS, LC, MH. Administrative, technical, and material support: TM, BN, DP, MKS, LC, MH.


This study was funded by the Installation Research project 2622 of the Croatian Science Foundation and University of Zagreb research support for the academic years 2015/2016 and 2016/2017.

Compliance with ethical standards

Conflict of interest

None of the authors have relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties. No writing assistance was utilized in the production of this manuscript.

Ethical approval

We retrospectively analyzed data of all patients with the diagnosis of clinically isolated syndrome (CIS), relapsing remitting multiple sclerosis (RRMS), progressive forms of multiple sclerosis (PMS) and healthy controls (HC), who were examined in the Referral Center for Autonomic Nervous System Disorders, University Hospital Center Zagreb. Ethical committees of the University Hospital Center Zagreb approved the study.

Informed consent

All patients signed informed consent at the examination.


  1. 1.
    Adamec I, Habek M (2013) Autonomic dysfunction in multiple sclerosis. Clin Neurol Neurosurg 115(Suppl 1):S73–S78CrossRefGoogle Scholar
  2. 2.
    Marrie RA, Reider N, Cohen J, Stuve O, Trojano M, Cutter G, Reingold S, Sorensen PS (2015) A systematic review of the incidence and prevalence of cardiac, cerebrovascular, and peripheral vascular disease in multiple sclerosis. Mult Scler 21:318–331CrossRefGoogle Scholar
  3. 3.
    Christiansen CF, Christensen S, Farkas DK, Miret M, Sørensen HT, Pedersen L (2010) Risk of arterial cardiovascular diseases in patients with multiple sclerosis: a population-based cohort study. Neuroepidemiology 35:267–274CrossRefGoogle Scholar
  4. 4.
    Habek M, Crnošija L, Lovrić M, Junaković A, Krbot Skorić M, Adamec I (2016) Sympathetic cardiovascular and sudomotor functions are frequently affected in early multiple sclerosis. Clin Auton Res 26:385–393CrossRefGoogle Scholar
  5. 5.
    Novak P. Quantitative autonomic testing. J Vis Exp 2011;(53)Google Scholar
  6. 6.
    Freeman R (2006) Assessment of cardiovascular autonomic function. Clin Neurophysiol 117:716–730CrossRefGoogle Scholar
  7. 7.
    Low PA (1993) Composite autonomic scoring scale for laboratory quantification of generalized autonomic failure. Mayo Clin Proc 68:748–752CrossRefGoogle Scholar
  8. 8.
    Schrezenmaier C, Singer W, Swift NM, Sletten D, Tanabe J, Low PA (2007) Adrenergic and vagal baroreflex sensitivity in autonomic failure. Arch Neurol 64:381–386CrossRefGoogle Scholar
  9. 9.
    Palamarchuk I, Baker J, Kimpinski K (2016) Non-invasive measurement of adrenergic baroreflex during Valsalva maneuver reveals three distinct patterns in healthy subjects. Clin Neurophysiol 127:858–863CrossRefGoogle Scholar
  10. 10.
    Palamarchuk IS, Baker J, Kimpinski K (2016) Non-invasive measurement of baroreflex during Valsalva maneuver: Evaluation of alpha and beta-adrenergic components. Clin Neurophysiol 127:1645–1651CrossRefGoogle Scholar
  11. 11.
    Keller DM, Fadel PJ, Harnsberger MA, Remington GM, Frohman EM, Davis SL (2014) Reduced spontaneous sympathetic nerve activity in multiple sclerosis patients. J Neurol Sci 344:210–214CrossRefGoogle Scholar
  12. 12.
    Brownlee WJ, Miller DH (2014) Clinically isolated syndromes and the relationship to multiple sclerosis. J Clin Neurosci 21:2065–2071CrossRefGoogle Scholar
  13. 13.
    Polman CH, Reingold SC, Banwell B, Clanet M, Cohen JA, Filippi M, Fujihara K, Havrdova E, Hutchinson M, Kappos L, Lublin FD, Montalban X, O’Connor P, Sandberg-Wollheim M, Thompson AJ, Waubant E, Weinshenker B, Wolinsky JS (2011) Diagnostic criteria for multiple sclerosis: 2010 revisions to the McDonald criteria. Ann Neurol 69:292–302CrossRefGoogle Scholar
  14. 14.
    Grassi G, Seravalle G, Brambilla G, Pini C, Alimento M, Facchetti R, Spaziani D, Cuspidi C, Mancia G (2014) Marked sympathetic activation and baroreflex dysfunction in true resistant hypertension. Int J Cardiol 177:1020–1025CrossRefGoogle Scholar
  15. 15.
    Conway DS, Thompson NR, Cohen JA (2017) Influence of hypertension, diabetes, hyperlipidemia, and obstructive lung disease on multiple sclerosis disease course. Mult Scler 23:277–285CrossRefGoogle Scholar
  16. 16.
    Truijen J, Davis SC, Stok WJ, Kim YS, van Westerloo DJ, Levi M, van der Poll T, Westerhof BE, Karemaker JM, van Lieshout JJ (2011) Baroreflex sensitivity is higher during acute psychological stress in healthy subjects under β-adrenergic blockade. Clin Sci (Lond) 120:161–167CrossRefGoogle Scholar
  17. 17.
    Sternberg Z (2017) Impaired neurovisceral integration of cardiovascular modulation contributes to multiple sclerosis morbidities. Mol Neurobiol 54:362–374CrossRefGoogle Scholar
  18. 18.
    Habek M, Krbot Skorić M, Crnošija L, Gabelić T, Barun B, Adamec I (2017) Postural orthostatic tachycardia predicts early conversion to multiple sclerosis after clinically isolated syndrome. Eur Neurol 77:253–257CrossRefGoogle Scholar
  19. 19.
    Flachenecker P, Reiners K, Krauser M, Wolf A, Toyka KV (2001) Autonomic dysfunction in multiple sclerosis is related to disease activity and progression of disability. Mult Scler 7:327–334CrossRefGoogle Scholar
  20. 20.
    Yufu K, Okada N, Ebata Y, Murozono Y, Shinohara T, Nakagawa M, Takahashi N (2014) Plasma norepinephrine is an independent predictor of adverse cerebral and cardiovascular events in type 2 diabetic patients without structural heart disease. J Cardiol 64:225–230CrossRefGoogle Scholar

Copyright information

© Belgian Neurological Society 2018

Authors and Affiliations

  1. 1.School of MedicineUniversity of ZagrebZagrebCroatia
  2. 2.Department of Neurology, Referral Center for Autonomic Nervous System DisordersUniversity Hospital Center ZagrebZagrebCroatia

Personalised recommendations