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.

  • Article
  • Published:

Cerebrovascular reactivity impairment in resistant hypertension

Journal of Human Hypertension volume 39, pages 626–633 (2025)Cite this article

Subjects

Abstract

Resistant hypertension (RH) is defined as office systolic blood pressure (BP) that remains uncontrolled despite the concurrent use of three or more antihypertensive drug classes and may be associated with altered vasomotor responses to physiological stimuli. However, the effect of RH on cerebrovascular reactivity (CVR) remains poorly understood. Furthermore, the potential contribution of autonomic nervous system dysfunction to these alterations has not yet been fully clarified. Understanding these mechanisms may offer insights into the pathophysiology of resistant hypertension and could have important prognostic implications. This study aims to analyze CVR in a cohort of patients with RH, compared with patients with non-resistant hypertension (NRH), taking into account the differences in sympathovagal balance between the two groups. Forty consecutive hypertension patients, 20 with NRH and 20 with RH, underwent heart rate variability analysis and transcranial color-coded Doppler at rest and during a breath-holding maneuver to evaluate CVR. Hypertensive individuals presented a significant reduction of the Breath Holding Index (BHI) and time-domain parameters (SDNN and SDANN) in comparison to the control group (BHI control 1.32 ± 0.41 vs hypertensive 0.92 ± 0.65; p = 0.018; SDANN control 125.76 ± 24.96 vs hypertensive 87.65 ± 20.63; p < 0.0001). RH patients presented a significant reduction in BHI (NRH BHI 1.15 ± 0.65 vs RH BHI 0.70 ± 0.58; p = 0.027) and HRV parameters (SDANN in NRH 95.09 ± 22.12 vs RH 80.21 ± 16.36; p = 0.021). Our results show that RH is associated with impaired HRV and CRV. Autonomic dysfunction could be a concurrent cause of cerebral vasomotor reactivity impairment.

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

Access options

Buy this article

  • Purchase on SpringerLink
  • Instant access to the full article PDF.

USD 39.95

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

Fig. 1: Breath Holding Index comparison between resistant (RH), non-resistant hypertensives (NRH), and controls.
Fig. 2: Heart rate variability parameter SDANN comparison between non-resistant hypertensive patients (NRH), resistant hypertensive patients (RH), and controls.

Similar content being viewed by others

Data availability

The data and images used in the current study are available from the corresponding author upon reasonable request.

References

  1. Bertel O, Marx BE, Conen D. Effects of antihypertensive treatment on cerebral perfusion. Am J Med. 1987;82:29–36. https://doi.org/10.1016/0002-9343(87)90208-7

    Article  PubMed  CAS  Google Scholar 

  2. Calhoun DA, Jones D, Textor S, Goff DC, Murphy TP, Toto RD, et al. American Heart Association Professional Education Committee. Resistant hypertension: diagnosis, evaluation, and treatment: a scientific statement from the American Heart Association Professional Education Committee of the Council for High Blood Pressure Research. Circulation. 2008;117:e510–26. https://doi.org/10.1161/CIRCULATIONAHA.108.189141

    Article  PubMed  Google Scholar 

  3. Grassi G. Role of the sympathetic nervous system in human hypertension. J Hypertens. 1998;16:1979–87. https://doi.org/10.1097/00004872-199816121-00019

    Article  PubMed  CAS  Google Scholar 

  4. Bill A, Linder J. Sympathetic control of cerebral blood flow in acute arterial hypertension. Acta Physiol Scand. 1976;96:114–21. https://doi.org/10.1111/j.1748-1716.1976.tb10176.x

    Article  PubMed  CAS  Google Scholar 

  5. Kleiser B, Widder B. Course of carotid artery occlusions with impaired cerebrovascular reactivity. Stroke. 1992;23:171–4. https://doi.org/10.1161/01.str.23.2.171

    Article  PubMed  CAS  Google Scholar 

  6. Li Y, Shen Q, Huang S, Li W, Muir ER, Long JA, et al. Cerebral angiography, blood flow and vascular reactivity in progressive hypertension. Neuroimage. 2015;111:329–37. https://doi.org/10.1016/j.neuroimage.2015.02.053

    Article  PubMed  Google Scholar 

  7. Maeda H, Matsumoto M, Handa N, Hougaku H, Ogawa S, Itoh T, et al. Reactivity of cerebral blood flow to carbon dioxide in hypertensive patients: evaluation by the transcranial Doppler method. J Hypertens. 1994;12:191–197.8.

    Article  PubMed  CAS  Google Scholar 

  8. Grassi G, Seravalle G, Brambilla G, Pini C, Alimento M, Facchetti R, et al. Marked sympathetic activation and baroreflex dysfunction in true resistant hypertension. Int J Cardiol. 2014;177:1020–5. https://doi.org/10.1016/j.ijcard.2014.09.138

    Article  PubMed  Google Scholar 

  9. Koep JL, Taylor CE, Coombes JS, Bond B, Ainslie PN, Bailey TG. Autonomic control of cerebral blood flow: fundamental comparisons between peripheral and cerebrovascular circulations in humans. J Physiol. 2022;600:15–39. https://doi.org/10.1113/JP281058

    Article  PubMed  CAS  Google Scholar 

  10. Task Force of the European Society of Cardiology and the North American Society of Pacing and Electrophysiology. Heart rate variability. Standards of measurement, physiological interpretation, and clinical use. Eur Heart J. 1996;17:354–81.

    Article  Google Scholar 

  11. La Rovere MT, Bigger JT Jr, Marcus FI, Mortara A, Schwartz PJ. Baroreflex sensitivity and heart-rate variability in prediction of total cardiac mortality after myocardial infarction. ATRAMI (Autonomic Tone and Reflexes After Myocardial Infarction) Investigators. Lancet. 1998;351:478–84. https://doi.org/10.1016/s0140-6736(97)11144-8

    Article  PubMed  Google Scholar 

  12. Mussalo H, Vanninen E, Ikäheimo R, Laitinen T, Laakso M, Länsimies E, et al. Heart rate variability and its determinants in patients with severe or mild essential hypertension. Clinical Physiology. 2001;21:594–604. https://doi.org/10.1046/j.1365-2281.2001.00359.x

    Article  PubMed  CAS  Google Scholar 

  13. Yugar LBT, Yugar-Toledo JC, Dinamarco N, Sedenho-Prado LG, Moreno BVD, Rubio TA, et al. The role of heart rate variability (HRV) in different hypertensive syndromes. Diagnostics (Basel). 2023;13:785 https://doi.org/10.3390/diagnostics13040785

    Article  PubMed  CAS  Google Scholar 

  14. Morisky DE, Green LW, Levine DM. Concurrent and predictive validity of a self-reported measure of medication adherence. Med Care. 1986;24:67–74.

    Article  PubMed  CAS  Google Scholar 

  15. Williams B, Mancia G, Spiering W, Agabiti Rosei E, Azizi M, Burnier M, et al. 2018 ESC/ESH Guidelines for the management of arterial hypertension. The Task Force for the management of arterial hypertension of the European Society of Cardiology (ESC) and the European Society of Hypertension (ESH). Eur Heart J. 2018;39:3021–104.

    Article  PubMed  Google Scholar 

  16. Cosentino F, Grant PJ, Aboyans V, Bailey CJ, Ceriello A, Delgado V, et al. 2019 ESC Guidelines on diabetes, pre-diabetes, and cardiovascular diseases developed in collaboration with the EASD. Eur Heart J. 2020;41:255–323.

    Article  PubMed  Google Scholar 

  17. Kleiger RE, Bigger JT, Bosner MS, Chung MK, Cook JR, Rolnitzky LM, et al. Stability over time of variables measuring heart rate variability in normal subjects. Am J Cardiol. 1991;68:626–30.

    Article  PubMed  CAS  Google Scholar 

  18. Markus HS, Harrison MJ. Estimation of cerebrovascular reactivity using transcranial Doppler, including the use of breath-holding as the vasodilatory stimulus. Stroke. 1992;23:668–73.

    Article  PubMed  CAS  Google Scholar 

  19. Silvestrini M, Vernieri F, Pasqualetti P, Matteis M, Passarelli F, Troisi E, et al. Impaired cerebral vasoreactivity and risk of stroke in patients with asymptomatic carotid artery stenosis. JAMA. 2000;283:2122–7. https://doi.org/10.1001/jama.283.16.2122

    Article  PubMed  CAS  Google Scholar 

  20. Leiba A, Yekutiel N, Chodick G, Wortsman J, Angel-Korman A, Weinreb B. Resistant hypertension is associated with an increased cardiovascular risk compared to patients controlled on a similar multi-drug regimen. J Hum Hypertens. 2023;37:542–7. https://doi.org/10.1038/s41371-022-00749-y

    Article  PubMed  Google Scholar 

  21. Tsujimoto T, Kajio H. Intensive blood pressure treatment for resistant hypertension. Hypertension. 2019;73:415–23. https://doi.org/10.1161/HYPERTENSIONAHA.118.12156

    Article  PubMed  CAS  Google Scholar 

  22. Di Raimondo D, Miceli G, Casuccio A, Tuttolomondo A, Buttà C, Zappulla V, et al. Does sympathetic overactivation feature all hypertensives? Differences of sympathovagal balance according to night/day blood pressure ratio in patients with essential hypertension. Hypertens Res. 2016;39:440–8. https://doi.org/10.1038/hr.2016.6

    Article  PubMed  CAS  Google Scholar 

  23. Monteiro A, Castro P, Pereira G, Ferreira C, Polonia J, Lobo M, et al. Cerebral blood flow regulation and cognitive performance in hypertension. J Cereb Blood Flow Metab. 2024;0. https://doi.org/10.1177/0271678X241254680

  24. Muela HCS, Costa-Hong VA, Yassuda MS, Machado MF, Nogueira RC, Moraes NC, et al. Impact of hypertension severity on arterial stiffness, cerebral vasoreactivity, and cognitive performance. Dement Neuropsychol. 2017;11:389–97. https://doi.org/10.1590/1980-57642016dn11-040008

    Article  PubMed  PubMed Central  Google Scholar 

  25. Georgiadis D, Sievert M, Cencetti S, Uhlmann F, Krivokuca M, Zierz S, et al. Cerebrovascular reactivity is impaired in patients with cardiac failure. Eur Heart J. 2000;21:407–13. https://doi.org/10.1053/euhj.1999.1742

    Article  PubMed  CAS  Google Scholar 

  26. Ficzere A, Valikovics A, Fülesdi B, Juhász A, Czuriga I, Csiba L. Cerebrovascular reactivity in hypertensive patients: a transcranial Doppler study. J Clin Ultrasound. 1997;25:383–9. 1https://doi.org/10.1002/(sici)1097-0096(199709)25:7<383::aid-jcu6>3.0.co;2-6

    Article  PubMed  CAS  Google Scholar 

  27. O’Rourke MF, Safar ME. Relationship between aortic stiffening and microvascular disease in brain and kidney Cause and logic of therapy. Hypertension. 2005;46:200–4.

    Article  PubMed  Google Scholar 

  28. Iadecola C, Gottesman RF. Neurovascular and cognitive dysfunction in hypertension. Circ Res. 2019;124:1025–44. https://doi.org/10.1161/CIRCRESAHA.118.313260

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  29. Ungvari Z, Toth P, Tarantini S, Prodan CI, Sorond F, Merkely B, et al. Hypertension-induced cognitive impairment: from pathophysiology to public health. Nat Rev Nephrol. 2021;17:639–54. https://doi.org/10.1038/s41581-021-00430-6

    Article  PubMed  PubMed Central  Google Scholar 

  30. Rosengarten B, Budden C, Osthaus S, Kaps M. Effect of heart rate on regulative features of the cortical activity-flow coupling. Cerebrovasc Dis. 2003;16:47–52. https://doi.org/10.1159/000070115

    Article  PubMed  CAS  Google Scholar 

  31. Wallbach M, Lehnig LY, Schroer C, Helms H-J, Lüders S, Patschan D, et al. Effects of baroreflex activation therapy on arterial stiffness and central hemodynamics in patients with resistant hypertension. J Hypertens. 2015;33:181–6. https://doi.org/10.1097/HJH.0000000000000361

    Article  PubMed  CAS  Google Scholar 

  32. Hirata K, Yaginuma T, O’Rourke MF, Kawakami M. Age-related changes in carotid artery flow and pressure pulses possible implications for cerebral microvascular disease. Stroke. 2006;37:2552–6.

    Article  PubMed  Google Scholar 

  33. Terborg C, Gora F, Weiller C, Röther J. Reduced vasomotor reactivity in cerebral microangiopathy: a study with near-infrared spectroscopy and transcranial Doppler sonography. Stroke. 2000;31:924–9.

    Article  PubMed  CAS  Google Scholar 

  34. Hirooka Y, Kishi T, Sakai K, Takeshita A, Sunagawa K. Imbalance of central nitric oxide and reactive oxygen species in the regulation of sympathetic activity and neural mechanisms of hypertension. Am J Physiol Regul Integr Comp Physiol. 2011;300:R818–26. https://doi.org/10.1152/ajpregu.00426.2010

    Article  PubMed  CAS  Google Scholar 

  35. Castro PM, Santos R, Freitas J, Panerai RB, Azevedo E. Autonomic dysfunction affects dynamic cerebral autoregulation during Valsalva maneuver: comparison between healthy and autonomic dysfunction subjects. J Appl Physiol (1985). 2014;117:205–13. https://doi.org/10.1152/japplphysiol.00893.2013

    Article  PubMed  Google Scholar 

Download references

Acknowledgements

We thank the Italian Society of Neurosonology and Cerebral Hemodynamic (SINSEC) group for training, education, and general supervision of the research group.

Author information

Authors and Affiliations

  1. Department of Health Promotion, Mother and Child Care, Internal Medicine and Medical Specialities (ProMISE) Università degli Studi di Palermo, Piazza delle Cliniche 2, 90127, Palermo, Italy

    G. Miceli, M. Velardo, A. Casuccio, M. Daidone, M. G. Basso & A. Tuttolomondo

  2. Internal Medicine and Stroke Care Ward. University Hospital, Policlinico “P. Giaccone”, Palermo, Italy

    G. Miceli, M. Daidone & A. Tuttolomondo

Authors
  1. G. Miceli
    View author publications

    Search author on:PubMed Google Scholar

  2. M. Velardo
    View author publications

    Search author on:PubMed Google Scholar

  3. A. Casuccio
    View author publications

    Search author on:PubMed Google Scholar

  4. M. Daidone
    View author publications

    Search author on:PubMed Google Scholar

  5. M. G. Basso
    View author publications

    Search author on:PubMed Google Scholar

  6. A. Tuttolomondo
    View author publications

    Search author on:PubMed Google Scholar

Contributions

GM projected the study, coordinated the research group, and contributed to manuscript preparation and revisions; MV collaborated on manuscript and research coordination; MGB collaborated to collect and process data; AC was mainly responsible for statistical analysis; MD was responsible for Holter monitoring and interpretations; AT collaborated in supervision and manuscript revisions.

Corresponding author

Correspondence to G. Miceli.

Ethics declarations

Competing interests

The authors declare no competing interests.

Ethical approval and consent to participate

All patients gave their informed consent to the study. The study protocol received approval from the Ethics Committee of the “Paolo Giaccone” University Hospital, and in accordance with the Helsinki Declaration.

Consent to participate and publication

all patients expressed their informed consent to participate in the study and supplied their personal information for publication.

Additional information

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

Supplementary information

Rights and permissions

Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Miceli, G., Velardo, M., Casuccio, A. et al. Cerebrovascular reactivity impairment in resistant hypertension. J Hum Hypertens 39, 626–633 (2025). https://doi.org/10.1038/s41371-025-01058-w

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Version of record:

  • Issue date:

  • DOI: https://doi.org/10.1038/s41371-025-01058-w

Search

Advanced search

Quick links