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Review
. 2025 Feb 4;14(3):e036752.
doi: 10.1161/JAHA.124.036752. Epub 2025 Feb 3.

Cerebral Blood Flow in Orthostatic Intolerance

Muhammad Shahzeb Khan  1 , Amanda J Miller  2 , Arooba Ejaz  3 , Jeroen Molinger  1   4 , Parag Goyal  5 , David B MacLeod  4 , Ashley Swavely  1 , Elyse Wilson  1 , Meghan Pergola  1 , Harikrishna Tandri  6 , Camille Frazier Mills  1 , Satish R Raj  7 , Marat Fudim  1   8
Affiliations
Review

Cerebral Blood Flow in Orthostatic Intolerance

Muhammad Shahzeb Khan et al. J Am Heart Assoc. .

Abstract

Cerebral blood flow (CBF) is vital for delivering oxygen and nutrients to the brain. Many forms of orthostatic intolerance (OI) involve impaired regulation of CBF in the upright posture, which results in disabling symptoms that decrease quality of life. Because CBF is not easy to measure, rises in heart rate or drops in blood pressure are used as proxies for abnormal CBF. These result in diagnoses such as postural orthostatic tachycardia syndrome and orthostatic hypotension. However, in many other OI syndromes such as myalgic encephalomyelitis/chronic fatigue syndrome and long COVID, heart rate and blood pressure are frequently normal despite significant drops in CBF. This often leads to the incorrect conclusion that there is nothing hemodynamically abnormal in these patients and thus no explanation or treatment is needed. There is a need to measure CBF, as orthostatic hypoperfusion is the shared pathophysiology for all forms of OI. In this review, we examine the literature studying CBF dysfunction in various syndromes with OI and evaluate methods of measuring CBF including transcranial Doppler ultrasound, extracranial cerebral blood flow ultrasound, near infrared spectroscopy, and wearable devices.

Keywords: ME/CFS; POTS; cerebral blood flow; long COVID; orthostatic intolerance.

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Conflict of interest statement

Dr Miller is a consultant to Lumia Health. Dr Fudim was supported by the National Institutes of Health, Reprieve, Sardocor, and Doris Duke. He is a consultant/has ownership interest in Abbott, Ajax, Alio Health, Alleviant, Artha, Audicor, AxonTherapies, Bayer, Bodyguide, Bodyport, Boston Scientific, Broadview, Cadence, Cardioflow, CVRx, Daxor, Edwards LifeSciences, Echosens, EKO, Feldschuh Foundation, Fire1, FutureCardia, Galvani, Gradient, Hatteras, HemodynamiQ, Impulse Dynamics, Intershunt, Medtronic, Merck, NovoNordisk, NucleusRx, NXT Biomedical, Orchestra, Pharmacosmos, Presidio, Procyreon, Proton Intelligence, ReCor, SCPharma, Shifamed, Splendo, Lumia Health, Summacor, SyMap, Verily, Vironix, Viscardia, and Zoll. Dr Tandri is a consultant to Lumia Health and Abbott. Dr Frazier Mills is a consultant to Medtronic, Johnson & Johnson, and Boston Scientific. Dr Raj is a consultant to Theravance Biopharma, Amneal Pharma, Servier Affaires Medicales, Regeneron, argenx BV, Antag Pharma, and Lumia Health. Jeroen Molinger has received honoraria or travel expenses for lectures from Abbott, Baxter, Danone‐Nutricia, Nestlé, Corsano Health, CalibreBio, VO2Master, Rockley Photonics, Vital Impact, Train‐Red, Vyaire Medical, MuscleSound. Dr Goyal received consulting fees from Agepha Pharma, Akros Pharma, Axon Therapies, Bayer HealthCare Pharmaceuticals, and Sensorum Health.

Figures

Figure 1
Figure 1. Physiological mechanisms involved in regulating blood flow with orthostasis (left) and order of activation of physiological changes that occur with standing (right).
Figure 2
Figure 2. BP and CBF patterns in mixed syncope.
The figure depicts CBF drops being consistent with syncope, whereas BP drops only correlate in some cases (eg, orthostatic hypotension). Charts reproduced from Novak under the terms and conditions of the Creative Commons Attribution Non‐Commercial‐NoDerivatives license (https://creativecommons.org/licenses/by‐nc‐nd/4.0/). BP indicates blood pressure; and CBF, cerebral blood flow.
Figure 3
Figure 3. HR, BP, and CBF velocity patterns in example participants with orthostatic hypotension, orthostatic cerebral hypoperfusion syndrome, and POTS during supine (gray) and head‐up tilt (white) compared with a healthy control on the left.
Despite different changes or no change in BP and HR during head‐up tilt, participants with orthostatic intolerance experience a similar and excessive decline in cerebral blood velocity. Charts reproduced from Novak under the terms and conditions of the Creative Commons Attribution Non‐Commercial‐NoDerivatives license (https://creativecommons.org/licenses/by‐nc‐nd/4.0/). BP indicates blood pressure; CBF, cerebral blood flow; HR, heart rate; and POTS, postural orthostatic tachycardia syndrome.
Figure 4
Figure 4. Methods for CBF measurement.
Ultrasound is used to assess blood flow velocity to the head either at the middle cerebral artery using TCD ultrasound or at the external carotid artery via extracranial ultrasound. NIRS supplies an index of oxygen saturation of the frontal lobe with oximetry by shining near‐infrared light at the forehead. In‐ear pulse‐wave analysis is an emerging technique to remotely measure blood flow to the head using infrared light to the posterior auricular branch of the external carotid artery. CBF indicates cerebral blood flow; NIRS, near‐infrared spectroscopy; and TCD, transcranial Doppler.
See this image and copyright information in PMC

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