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Sympathovagal imbalance in early ischemic stroke is linked to impaired cerebral autoregulation and increased infarct volumes

  • Pedro Castro
    Correspondence
    Corresponding author at: Centro Hospitalar Universitário São João, Alameda Professor Hernâni Monteiro, 4200-319 Porto, Portugal.
    Affiliations
    Cardiovascular Research and Development Center, Faculty of Medicine of University of Porto, Porto, Portugal

    Department of Neurology, Centro Hospitalar Universitário de São João, Porto, Portugal
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  • Jorge Serrador
    Affiliations
    The MARCS Institute for Brain, Behaviour and Development, Western Sydney University, Sydney, Australia

    Department of Pharmacology, Physiology and Neuroscience, New Jersey Medical School, Rutgers University, NJ, USA

    National University of Ireland Galway, Galway, Ireland
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  • Farzaneh Sorond
    Affiliations
    Department of Neurology, Division of Stroke and Neurocritical, Northwestern University Feinberg School of Medicine, Chicago, IL, USA
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  • Elsa Azevedo
    Affiliations
    Cardiovascular Research and Development Center, Faculty of Medicine of University of Porto, Porto, Portugal

    Department of Neurology, Centro Hospitalar Universitário de São João, Porto, Portugal
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  • Isabel Rocha
    Affiliations
    Cardiovascular Autonomic Function Lab, Institute of Physiology, Faculty of Medicine of University of Lisbon, Portugal
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      Highlights

      • We examined 26 patients with acute ischemic stroke within 6 hours from symptom-onset and assessed non-invasively heart rate variability, baroreflex sensitivity and dynamic cerebral autoregulation
      • Increased heart rate spectral power towards high frequencies (tonic parasympathetic) and baroreflex sensitivity (reflex parasympathetic) were correlated with higher gain, thus worse cerebral autoregulation
      • Predominant vagal activity was associated with the development of larger infarct volumes
      • The modulation of autonomic and vagal activity should be subject to study in acute ischemic stroke

      Abstract

      Background and purpose

      Autonomic dysfunction is associated with worse outcome of ischemic stroke patients by mechanisms that are not fully understood. There is evidence of autonomic influence in cerebrovascular control but this has not been studied in acute stroke. Therefore, we examined the relationship between heart rate variability (HRV) and baroreflex sensitivity (BRS) in dynamic cerebral autoregulation in the early hours post ischemia, and its impact in clinical and radiological outcome.

      Methods

      We prospectively enrolled 26 patients with acute ischemic stroke in middle cerebral artery. Arterial blood pressure (Finometer), cerebral blood flow velocity (transcranial Doppler), and electrocardiogram were recorded within 6 h. HRV was assessed by the standard side deviations of normal inter-beat intervals, spectral analysis and non-linear entropy indexes. Spontaneous BRS was assessed by spectral and sequence methods. Dynamic cerebral autoregulation was assessed by transfer function analysis (coherence, phase and gain). Infarct volume was calculated from computed tomography at 24 h. Clinical outcome was assessed by the modified Rankin scale.

      Results

      Increased BRS and HRV high frequencies power, both reflecting increased vagal modulation, were correlated with higher gain values of cerebral autoregulation (p < 0.05). The higher vagal modulation was also associated with later large infarct volumes (p < 0.05) but not with clinical outcome.

      Conclusions

      Increased vagal modulation in early hours of acute ischemic stroke, may interfere with cerebrovascular control and is associated with larger infarcts. Understanding the mechanisms that govern this complex interplay can be useful as novel therapeutic targets to improvement of outcome.

      Abbreviations:

      dCA (dynamic cerebral autoregulation), HRV (heart rate variability), BRS (baroreflex sensitivity), IS (ischemic stroke), MAP (mean arterial blood pressure), RR (heart period between R-peaks)

      Keywords

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      References

        • Azevedo E.
        • Castro P.
        • Santos R.
        • Freitas J.
        • Coelho T.
        • Rosengarten B.
        • Panerai R.
        Autonomic dysfunction affects cerebral neurovascular coupling.
        Clin. Auton. Res. 2011; 21: 395-403
        • Bassi A.
        • Colivicchi F.
        • Santini M.
        • Caltagirone C.
        Cardiac autonomic dysfunction and functional outcome after ischaemic stroke.
        Eur. J. Neurol. 2007; 14: 917-922
        • Bettoni M.
        • Zimmermann M.
        Autonomic tone variations before the onset of paroxysmal atrial fibrillation.
        Circulation. 2002; 105: 2753-2759
        • Campos L.A.
        • Pereira Jr., V.L.
        • Muralikrishna A.
        • Albarwani S.
        • Bras S.
        • Gouveia S.
        Mathematical biomarkers for the autonomic regulation of cardiovascular system.
        Front. Physiol. 2013; 4: 279
        • Castro P.
        • Azevedo E.
        • Serrador J.
        • Rocha I.
        • Sorond F.
        Hemorrhagic transformation and cerebral edema in acute ischemic stroke: link to cerebral autoregulation.
        J. Neurol. Sci. 2017; 372: 256-261
        • Castro P.
        • Azevedo E.
        • Sorond F.
        Cerebral autoregulation in stroke.
        Curr. Atheroscler. Rep. 2018; 20: 37
        • Castro P.
        • Santos R.
        • Freitas J.
        • Rosengarten B.
        • Panerai R.
        • Azevedo E.
        Adaptation of cerebral pressure-velocity hemodynamic changes of neurovascular coupling to orthostatic challenge.
        Perspect.Med. 2012; 2012 (Available online 1028 March)https://doi.org/10.1016/j.permed.2012.1002.1052
        • Castro P.
        • Serrador J.M.
        • Rocha I.
        • Sorond F.
        • Azevedo E.
        Efficacy of cerebral autoregulation in early ischemic stroke predicts smaller infarcts and better outcome.
        Front. Neurol. 2017; 8: 113
        • Castro P.M.
        • Santos R.
        • Freitas J.
        • Panerai R.B.
        • Azevedo E.
        Autonomic dysfunction affects dynamic cerebral autoregulation during Valsalva maneuver: comparison between healthy and autonomic dysfunction subjects.
        J. Appl. Physiol. 2014; 117: 205-213
        • Chen W.
        • Zhuang J.
        • Yu W.
        • Wang Z.
        Measuring complexity using FuzzyEn, ApEn, and SampEn.
        Med. Eng. Phys. 2009; 31: 61-68
        • Claassen J.A.
        • Meel-van den Abeelen A.S.
        • Simpson D.M.
        • Panerai R.B.
        Transfer function analysis of dynamic cerebral autoregulation: a white paper from the international cerebral autoregulation research network.
        J. Cereb. Blood Flow Metab. 2016; 36: 665-680
        • Colivicchi F.
        • Bassi A.
        • Santini M.
        • Caltagirone C.
        Prognostic implications of right-sided insular damage, cardiac autonomic derangement, and arrhythmias after acute ischemic stroke.
        Stroke. 2005; 36: 1710-1715
        • De Raedt S.
        • De Vos A.
        • De Keyser J.
        Autonomic dysfunction in acute ischemic stroke: an underexplored therapeutic area?.
        J. Neurol. Sci. 2015; 348: 24-34
        • Eames P.J.
        • Blake M.J.
        • Dawson S.L.
        • Panerai R.B.
        • Potter J.F.
        Dynamic cerebral autoregulation and beat to beat blood pressure control are impaired in acute ischaemic stroke.
        J. Neurol. Neurosurg. Psychiatry. 2002; 72: 467-472
        • Freitas J.
        • Santos R.
        • Azevedo E.
        • Carvalho M.
        • Boomsma F.
        • Meiracker A.
        • Falcao de Freitas A.
        • Abreu-Lima C.
        Hemodynamic, autonomic and neurohormonal behaviour of familial amyloidotic polyneuropathy and neurally mediated syncope patients during supine and orthostatic stress.
        Int. J. Cardiol. 2007; 116: 242-248
        • Graff B.
        • Gasecki D.
        • Rojek A.
        • Boutouyrie P.
        • Nyka W.
        • Laurent S.
        • Narkiewicz K.
        Heart rate variability and functional outcome in ischemic stroke: a multiparameter approach.
        J. Hypertens. 2013; 31: 1629-1636
        • Gunther A.
        • Salzmann I.
        • Nowack S.
        • Schwab M.
        • Surber R.
        • Hoyer H.
        • Witte O.W.
        • Hoyer D.
        Heart rate variability - a potential early marker of sub-acute post-stroke infections.
        Acta Neurol. Scand. 2012; 126: 189-196
        • Haubrich C.
        • Kruska W.
        • Diehl R.R.
        • Moller-Hartmann W.
        • Klotzsch C.
        Dynamic autoregulation testing in patients with middle cerebral artery stenosis.
        Stroke. 2003; 34: 1881-1885
        • Hu H.H.
        • Kuo T.B.
        • Wong W.J.
        • Luk Y.O.
        • Chern C.M.
        • Hsu L.C.
        • Sheng W.Y.
        Transfer function analysis of cerebral hemodynamics in patients with carotid stenosis.
        J. Cereb. Blood Flow Metab. 1999; 19: 460-465
        • Korpelainen J.T.
        • Sotaniemi K.A.
        • Makikallio A.
        • Huikuri H.V.
        • Myllyla V.V.
        Dynamic behavior of heart rate in ischemic stroke.
        Stroke. 1999; 30: 1008-1013
        • Magagnin V.
        • Bassani T.
        • Bari V.
        • Turiel M.
        • Maestri R.
        • Pinna G.D.
        • Porta A.
        Non-stationarities significantly distort short-term spectral, symbolic and entropy heart rate variability indices.
        Physiol. Meas. 2011; 32: 1775-1786
        • Makikallio A.M.
        • Makikallio T.H.
        • Korpelainen J.T.
        • Sotaniemi K.A.
        • Huikuri H.V.
        • Myllyla V.V.
        Heart rate dynamics predict poststroke mortality.
        Neurology. 2004; 62: 1822-1826
        • Marchi A.
        • Bari V.
        • De Maria B.
        • Esler M.
        • Lambert E.
        • Baumert M.
        • Porta A.
        Calibrated variability of muscle sympathetic nerve activity during graded head-up tilt in humans and its link with noradrenaline data and cardiovascular rhythms.
        Am. J. Physiol. Regul. Integr. Comp. Physiol. 2016; 310: R1134-R1143
        • Meel-van den Abeelen A.S.
        • van Beek A.H.
        • Slump C.H.
        • Panerai R.B.
        • Claassen J.A.
        Transfer function analysis for the assessment of cerebral autoregulation using spontaneous oscillations in blood pressure and cerebral blood flow.
        Med. Eng. Phys. 2014; 36: 563-575
      1. Nakagawaet al., n.d.K. Nakagawa J.M. Serrador S.L. LaRose F.A Sorond. Dynamic cerebral autoregulation after intracerebral hemorrhage: A case-control study. BMC Neurol 11, 108.

        • Nogueira R.C.
        • Aries M.
        • Minhas J.S.
        • N H.P.
        • Xiong L.
        • Kainerstorfer J.M.
        • Castro P.
        Review of studies on dynamic cerebral autoregulation in the acute phase of stroke and the relationship with clinical outcome.
        J. Cereb. Blood Flow Metab. 2021; 42 (271678X211045222, 34515547): 430-453
        • Otite F.
        • Mink S.
        • Tan C.O.
        • Puri A.
        • Zamani A.A.
        • Mehregan A.
        • Chou S.
        • Orzell S.
        • Purkayastha S.
        • Du R.
        • Sorond F.A.
        Impaired cerebral autoregulation is associated with vasospasm and delayed cerebral ischemia in subarachnoid hemorrhage.
        Stroke. 2014; 45: 677-682
        • Panerai R.B.
        Assessment of cerebral pressure autoregulation in humans–a review of measurement methods.
        Physiol. Meas. 1998; 19: 305-338
        • Parati G.
        • Di Rienzo M.
        • Mancia G.
        How to measure baroreflex sensitivity: from the cardiovascular laboratory to daily life.
        J. Hypertens. 2000; 18: 7-19
        • Porta A.
        • Bari V.
        • Bassani T.
        • Marchi A.
        • Pistuddi V.
        • Ranucci M.
        Model-based causal closed-loop approach to the estimate of baroreflex sensitivity during propofol anesthesia in patients undergoing coronary artery bypass graft.
        J. Appl. Physiol. 2013; 115: 1032-1042
        • Porta A.
        • D'Addio G.
        • Guzzetti S.
        • Lucini D.
        • Pagani M.
        Testing the presence of non stationarities in short heart rate variability.
        Comput.Cardiol. 2004; : 31
        • Reinhard M.
        • Hetzel A.
        • Lauk M.
        • Lucking C.H.
        Dynamic cerebral autoregulation testing as a diagnostic tool in patients with carotid artery stenosis.
        Neurol. Res. 2001; 23: 55-63
        • Reinhard M.
        • Neunhoeffer F.
        • Gerds T.A.
        • Niesen W.D.
        • Buttler K.J.
        • Timmer J.
        • Schmidt B.
        • Czosnyka M.
        • Weiller C.
        • Hetzel A.
        Secondary decline of cerebral autoregulation is associated with worse outcome after intracerebral hemorrhage.
        Intensive Care Med. 2010; 36: 264-271
        • Reinhard M.
        • Roth M.
        • Guschlbauer B.
        • Harloff A.
        • Timmer J.
        • Czosnyka M.
        • Hetzel A.
        Dynamic cerebral autoregulation in acute ischemic stroke assessed from spontaneous blood pressure fluctuations.
        Stroke. 2005; 36: 1684-1689
        • Richman J.S.
        • Moorman J.R.
        Physiological time-series analysis using approximate entropy and sample entropy.
        Am. J. Physiol. Heart Circ. Physiol. 2000; 278: H2039-H2049
        • Serrador J.M.
        • Sorond F.A.
        • Vyas M.
        • Gagnon M.
        • Iloputaife I.D.
        • Lipsitz L.A.
        Cerebral pressure-flow relations in hypertensive elderly humans: transfer gain in different frequency domains.
        J. Appl. Physiol. 2005; 98: 151-159
        • Sims J.R.
        • Gharai L.R.
        • Schaefer P.W.
        • Vangel M.
        • Rosenthal E.S.
        • Lev M.H.
        • Schwamm L.H.
        ABC/2 for rapid clinical estimate of infarct, perfusion, and mismatch volumes.
        Neurology. 2009; 72: 2104-2110
        • Sykora M.
        • Steiner T.
        • Rocco A.
        • Turcani P.
        • Hacke W.
        • Diedler J.
        Baroreflex sensitivity to predict malignant middle cerebral artery infarction.
        Stroke. 2012; 43: 714-719
        • Tzeng Y.C.
        • Lucas S.J.
        • Atkinson G.
        • Willie C.K.
        • Ainslie P.N.
        Fundamental relationships between arterial baroreflex sensitivity and dynamic cerebral autoregulation in humans.
        J. Appl. Physiol. 2010; 108: 1162-1168
        • Zhang R.
        • Crandall C.G.
        • Levine B.D.
        Cerebral hemodynamics during the Valsalva maneuver: insights from ganglionic blockade.
        Stroke. 2004; 35: 843-847
        • Zhang R.
        • Zuckerman J.H.
        • Giller C.A.
        • Levine B.D.
        Transfer function analysis of dynamic cerebral autoregulation in humans.
        Am. J. Phys. 1998; 274: H233-H241