Acta Neurologica Belgica

, Volume 119, Issue 4, pp 567–575 | Cite as

Impaired cerebrovascular reactivity in chronic obstructive pulmonary disease

  • Marina HlavatiEmail author
  • Krunoslav Buljan
  • Svetlana Tomić
  • Mirjana Horvat
  • Silva Butković-Soldo
Original article


Impaired cerebrovascular reactivity (CVR) is associated with stroke. Cerebrovascular diseases are common comorbidity in chronic obstructive pulmonary disease (COPD) patients. The aim of our study was to quantify CVR in the anterior and posterior cerebral circulation during voluntary breath-holding in COPD patients according to airflow limitation severity. In this cross-sectional study, we compared 90 COPD patients without previous cerebrovascular disease and 30 age- and sex-matched healthy volunteers (mean age 67 ± 7.9, 87 males). Using transcranial Doppler ultrasound and breath-holding index (BHI), we analysed baseline mean flow velocities (MFV) and CVR of middle cerebral artery (MCA) and basilar artery (BA). Our results demonstrated that COPD patients had lower baseline MFV of both MCA and BA than controls. COPD patients had significantly lower BHImMCA and BHImBA than controls (0.8 and 0.7 versus 1.24 and 1.07, respectively; p < 0.001). With the severity of airflow obstruction, there were significant declines of BHImMCA and BHImBA in mild (0.94 and 0.83), moderate (0.8 and 0.7) and severe to very severe COPD (0.7 and 0.6), respectively (p < 0.001). For all participants, we found a significant and positive correlation between forced expiratory volume in one second (FEV1) and BHImMCA (Rho = 0.761, p < 0.001) and between FEV1 and BHImBA (Rho = 0.409, p < 0.001). COPD patients have impaired CVR in anterior and posterior cerebral circulation. Impairment of CVR increase with the airflow limitation severity. CVR is an appropriate marker to identify vulnerable COPD subjects at high risk to develop cerebrovascular disease. Prospective studies are needed for further evaluation.


Cerebrovascular reactivity Chronic obstructive pulmonary disease Transcranial Doppler ultrasound Breath-holding index 



We gratefully acknowledge the time and effort of our research participants.

Author contributions

M. Hlavati designed the study, performed the assessments and participant examinations. KB and ST performed the data collection. M. Hlavati, KB, ST and M. Horvat performed the data analysis and interpretation. SBS supervised the measurements. All authors contributed to data interpretation and to the writing of the manuscript. All authors have read and approved the final version of the manuscript.


The study was not funded.

Compliance with ethical standards

Conflict of interest

The authors declare that they have no conflict of interest.

Ethics approval and consent to participate

The study was approved by the ethics committee of General Hospital Našice (No. 01-497/3-2017) and by ethics committee Faculty of Medicine Osijek, University Josip Juraj Strossmayer Osijek, Croatia (No. 2158-61-07-17-209). All data were anonymized and the study was conducted in accordance with the amended Declaration of Helsinki. Informed consent was obtained from all individual participants included in the study. All participants signed an informed consent form before entering the study.

Availability of data and materials

The datasets generated and analysed during the current study are available from the corresponding author on reasonable request.


  1. 1.
    Willie CK, Colino FL, Bailey DM et al (2011) Utility of transcranial Doppler ultrasound for the integrative assessment of cerebrovascular function. J Neurosci Methods 196:221–237. CrossRefPubMedGoogle Scholar
  2. 2.
    Aaslid R (2006) Cerebral autoregulation and vasomotor reactivity. Front Neurol Neurosci 21:216–228. CrossRefPubMedGoogle Scholar
  3. 3.
    Zavoreo I, Demarin V (2004) Breath holding index in the evaluation of cerebral vasoreactivity. Acta Clin Croat 43:15–19Google Scholar
  4. 4.
    Lavi S, Gaitini D, Milloul V, Jacob G (2006) Impaired cerebral CO2 vasoreactivity: association with endothelial dysfunction. Am J Physiol Circ Physiol 291:H1856–H1861. CrossRefGoogle Scholar
  5. 5.
    Staszewski J, Skrobowska E, Piusińska-Macoch R et al (2018) Cerebral and extracerebral vasoreactivity in patients with different clinical manifestations of cerebral small-vessel disease: data from the significance of hemodynamic and hemostatic factors in the course of different manifestations of cerebral small-ves. J Ultrasound Med 00:1–13. CrossRefGoogle Scholar
  6. 6.
    Portegies MLP, De Bruijn RFAG, Hofman A et al (2014) Cerebral vasomotor reactivity and risk of mortality: the Rotterdam study. Stroke 45:42–47. CrossRefPubMedGoogle Scholar
  7. 7.
    Aries MJH, Elting JW, De Keyser J et al (2010) Cerebral autoregulation in stroke: a review of transcranial doppler studies. Stroke 41:2697–2704. CrossRefPubMedGoogle Scholar
  8. 8.
    Moreton FC, Cullen B, Delles C et al (2018) Vasoreactivity in CADASIL: comparison to structural MRI and neuropsychology. J Cereb Blood Flow Metab 38:1085–1095. CrossRefPubMedGoogle Scholar
  9. 9.
    Pantoni L (2010) Cerebral small vessel disease: from pathogenesis and clinical characteristics to therapeutic challenges. Lancet Neurol 9:689–701. CrossRefPubMedGoogle Scholar
  10. 10.
    Greenberg SM, Vernooij MW, Cordonnier C et al (2009) Cerebral microbleeds: a guide to detection and interpretation. Lancet Neurol 8:165–174. CrossRefPubMedPubMedCentralGoogle Scholar
  11. 11.
    Wardlaw JM, Smith C, Dichgans M (2013) Mechanisms of sporadic cerebral small vessel disease: insights from neuroimaging. Lancet Neurol 12:483–497. CrossRefPubMedGoogle Scholar
  12. 12.
    Dodd JW, Chung AW, Van Den Broek MD et al (2012) Brain structure and function in chronic obstructive pulmonary disease: a multimodal cranial magnetic resonance imaging study. Am J Respir Crit Care Med 186:240–245. CrossRefPubMedPubMedCentralGoogle Scholar
  13. 13.
    Lahousse L, Vernooij MW, Darweesh SKL et al (2013) Chronic obstructive pulmonary disease and cerebral microbleeds the Rotterdam study. Am J Respir Crit Care Med 188:783–788. CrossRefPubMedGoogle Scholar
  14. 14.
    Feary JR, Rodrigues LC, Smith CJ et al (2010) Prevalence of major comorbidities in subjects with COPD and incidence of myocardial infarction and stroke: a comprehensive analysis using data from primary care. Thorax 65:956–962. CrossRefPubMedGoogle Scholar
  15. 15.
    Smith MC, Wrobel JP (2014) Epidemiology and clinical impact of major comorbidities in patients with COPD. Int J COPD 9:871–888. CrossRefGoogle Scholar
  16. 16.
    Negewo NA, McDonald VM, Gibson PG (2015) Comorbidity in chronic obstructive pulmonary disease. Respir Investig 53:249–258. CrossRefPubMedGoogle Scholar
  17. 17.
    Rabe KF, Hurst JR, Suissa S (2018) Cardiovascular disease and COPD: dangerous liaisons? Eur Respir Rev 27:180057. CrossRefPubMedGoogle Scholar
  18. 18.
    Söderholm M, Inghammar M, Hedblad B et al (2016) Incidence of stroke and stroke subtypes in chronic obstructive pulmonary disease. Eur J Epidemiol 31:159–168. CrossRefPubMedGoogle Scholar
  19. 19.
    Feigin VL, Norrving B, Mensah GA (2017) Global burden of stroke. Circ Res 120:439–448. CrossRefPubMedGoogle Scholar
  20. 20.
    Lõpez-Campos JL, Tan W, Soriano JB (2016) Global burden of COPD. Respirology 21:14–23. CrossRefPubMedGoogle Scholar
  21. 21.
    Bernardi L, Casucci G, Haider T et al (2008) Autonomic and cerebrovascular abnormalities in mild COPD are worsened by chronic smoking. Eur Respir J 32:1458–1465. CrossRefPubMedGoogle Scholar
  22. 22.
    Clivati A, Ciofetti M, Cavestri R, Longhini E (1992) Cerebral vascular responsiveness in chronic hypercapnia. Chest 102:135–138. CrossRefPubMedGoogle Scholar
  23. 23.
    Hartmann SE, Pialoux V, Leigh R, Poulin MJ (2012) Decreased cerebrovascular response to CO2 in post-menopausal females with COPD: role of oxidative stress. Eur Respir J 40:1354–1361. CrossRefPubMedGoogle Scholar
  24. 24.
    Mirza S, Clay RD, Koslow MA, Scanlon PD (2018) COPD guidelines: a review of the 2018 GOLD report. Mayo Clin Proc 93:1488–1502. CrossRefPubMedGoogle Scholar
  25. 25.
    Miller MR, Hankinson J, Brusasco V et al (2005) Standardisation of spirometry. Eur Respir J 26:319–338. CrossRefPubMedGoogle Scholar
  26. 26.
    Skow RJ, MacKay CM, Tymko MM et al (2013) Differential cerebrovascular CO2 reactivity in anterior and posterior cerebral circulations. Respir Physiol Neurobiol 189:76–86. CrossRefPubMedGoogle Scholar
  27. 27.
    Bruce CD, Steinback CD, Chauhan UV et al (2016) Quantifying cerebrovascular reactivity in anterior and posterior cerebral circulations during voluntary breath holding. Exp Physiol 101:1517–1527. CrossRefPubMedGoogle Scholar
  28. 28.
    Lin YP, Fu MH, Tan TY (2015) Factors associated with no or insufficient temporal bone window using transcranial color-coded sonography. J Med Ultrasound 23:129–132. CrossRefGoogle Scholar
  29. 29.
    De Lucas-Ramos P, Izquierdo- JL, Rodriguez- JM, Frances JF (2012) Chronic obstructive pulmonary disease as a cardiovascular risk factor. Results of a case—control study (CONSISTE study). Int J Chron Obstr Pulm Dis 7:679–686. CrossRefGoogle Scholar
  30. 30.
    Peng SL, Chen X, Li Y et al (2018) Age-related changes in cerebrovascular reactivity and their relationship to cognition: a 4-year longitudinal study. Neuroimage 174:257–262. CrossRefPubMedPubMedCentralGoogle Scholar
  31. 31.
    Debette S, Markus HS (2010) The clinical importance of white matter hyperintensities on brain magnetic resonance imaging: systematic review and meta-analysis. BMJ 341:1–9. CrossRefGoogle Scholar
  32. 32.
    Zakharchuk NV, Chertok VM, Nevzorova VA, Gonchar EY (2017) Effects of chronic tobacco smoking on the distribution of tachykinin receptors in rat pial arteries. Bull Exp Biol Med 163:313–316. CrossRefPubMedGoogle Scholar
  33. 33.
    Markus HS, Harrison MJG (1992) Estimation of cerebrovascular reactivity using transcranial doppler, including the use of breath-holding as the vasodilatory stimulus. Stroke 23:668–673. CrossRefPubMedGoogle Scholar
  34. 34.
    Chung JW, Park SH, Kim N et al (2014) Trial of ORG 10172 in acute stroke treatment (TOAST) classification and vascular territory of ischemic stroke lesions diagnosed by diffusion-weighted imaging. J Am Heart Assoc 3:1–8. CrossRefGoogle Scholar
  35. 35.
    Amin-Hanjani S, Pandey DK, Rose-Finnell L et al (2016) Effect of hemodynamics on stroke risk in symptomatic atherosclerotic vertebrobasilar occlusive disease. JAMA Neurol 73:178–185. CrossRefPubMedPubMedCentralGoogle Scholar
  36. 36.
    Ainslie PN, Duffin J (2009) Integration of cerebrovascular CO2 reactivity and chemoreflex control of breathing: mechanisms of regulation, measurement, and interpretation. AJP Regul Integr Comp Physiol 296:R1473–R1495. CrossRefGoogle Scholar
  37. 37.
    Phillips DB, Steinback CD, Collins S et al (2018) The carotid chemoreceptor contributes to the elevated arterial stiffness and vasoconstrictor outflow in chronic obstructive pulmonary disease. J Physiol 596:3233–3244. CrossRefPubMedPubMedCentralGoogle Scholar
  38. 38.
    Hoiland RL, Ainslie PN, Wildfong KW et al (2015) Indomethacin-induced impairment of regional cerebrovascular reactivity: implications for respiratory control. J Physiol 593:1291–1306. CrossRefPubMedPubMedCentralGoogle Scholar
  39. 39.
    Fisher JA (2016) The CO2 stimulus for cerebrovascular reactivity: fixing inspired concentrations vs. targeting end-tidal partial pressures. J Cereb Blood Flow Metab 36:1004–2016. CrossRefPubMedPubMedCentralGoogle Scholar
  40. 40.
    Al-Khazraji BK, Shoemaker LN, Gati JS et al (2018) Reactivity of larger intracranial arteries using 7 T MRI in young adults. J Cereb Blood Flow Metab 1:11. CrossRefGoogle Scholar

Copyright information

© Belgian Neurological Society 2019

Authors and Affiliations

  1. 1.Department for Diagnostic and Therapeutical Procedures, Neurology UnitGeneral Hospital NašiceNašiceCroatia
  2. 2.Faculty of Medicine OsijekUniversity Josip Juraj Strossmayer OsijekOsijekCroatia
  3. 3.Neurology ClinicClinic Hospital Centre OsijekOsijekCroatia
  4. 4.Department of Internal Medicine, Pulmonology UnitGeneral Hospital NašiceNašiceCroatia

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