Cardiac Output–Cerebral Blood Flow Relationship Is Abnormal in Most ME/CFS Patients with a Normal Heart Rate & Blood Pressure ..., 2024, van Campen

[John Mac]

Published
Link here: Cardiac Output–Cerebral Blood Flow Relationship Is Abnormal in Most ME/CFS Patients with a Normal Heart Rate & Blood Pressure ..., 2024, van Campen

Preprint
Full title:
The cardiac output - cerebral blood flow relation is abnormal in most ME/CFS patients with a normal heart rate and blood pressure response during a tilt test


Abstract
Introduction: Orthostatic intolerance is highly prevalent in patients with myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) and is caused by an abnormal reduction in cerebral blood flow (CBF). In healthy controls (HC) regulation of CBF is complex and involves multiple mechanisms including cardiac output (CO), cerebral perfusion pressure, PO2 and PCO2, flow-metabolism coupling, and innervation of cerebral vessels. In ME/CFS multiple other mechanisms have also been identified.

Aim of the study: We previously found that both CBF and CO were reduced in ME/CFS patients during tilt testing, and we hypothesized that the relation between CBF and CO is abnormal and different from HC. In this retrospective study we analyzed this relation in a large group of patients. To compare the patient data with those of HC, we focused on patients with a normal heart rate (HR) and blood pressure (BP) response to upright tilt. Also, the influence of clinical data was analyzed.

Methods: A total of 534 ME/CFS patients and 49 HC underwent tilt testing with measurements of HR, BP, CBF, and CO. In 46 (9%) patients CO and CBF changes were in the normal range of HC, and in 488 (91%) an abnormal CO and CBF reduction was found.

Results: patients with a CO and CBF reduction in the range of HC had less severe disease and were more likely to be male. In patients with an abnormal CO and CBF reduction the slope of the regression line of CO versus CBF reduction was almost 1. A multiple regression analysis of the latter group, including patients with PetCO2 measurements (440/488: 90%) showed that the CO reduction for the major part predicted the CBF reduction, with a limited role for the PetCO2 reduction and the tilt duration. Other data did not add to the model.

Conclusions: Two different patient groups with a normal HR and BP response during the tilt were identified: those with a CO and CBF in the normal range of HC and those with an abnormal CO and CBF reduction during the tilt (91% of patients). The former group had milder disease and included more men. In the largest group of patients there was an almost 1:1 relation between the CO and CBF reduction, suggesting absence of compensatory vasodilation in the cerebral vasculature. This may be an appropriate target for clinical and therapeutic interventions.

https://www.medrxiv.org/content/10.1101/2024.08.02.24311436v1

 

[Fizzlou]

Diagnosis and management of OI in MECFS. (2022)

Video description: Cardiologists Professor Frans Visser and Dr Linda van Campen explain all about Orthostatic Intolerance in ME/CFS. This webinar was organised by the Irish ME/CFS Association and the Irish ME Trust.



Been a while since I watched this but as authors of the above paper I’m adding here.

 

[poetinsf]

So, low CBF was caused by low cardiac output. Which means low CBF or perfusion is more likely a symptom or intermediary rather than the immediate cause. It's well timed with the paper from Younger's lab that found low blood perfusion in GWI patients. The low perfusion that they found could be mediated by low cardiac output w/o the tilt, perhaps due to hypotension.

 

[Hutan]

For comparison with HC, we only analyzed in the present study patients with a normal HR-BP response where blood pressures were within normal limits.

1135 ME/CFS patients attended the clinic in ten years (met Fukuda and Carruthers(is that CCC) criteria) and who had a tilt test due to suspicion of orthostatic intolerance. 664 patients had a normal HR and BP response. Patients younger than 18 years or with a very high BMI were excluded, leaving 612 patients. Patients with poor quality or missing data and patients taking drugs that might confound results were excluded, leaving 534 patients.

Three groups:
46 patients with normal change in CBF upon tilt
488 patients with abnormal change in CBF upon tilt
49 healthy controls

Abnormal group had higher heart rate at rest and at the end of tilt, higher percentage of females, higher percentage of moderately and severely affected.

Figure 1 shows the relation between the %CO reduction and %CBF reduction in the three groups. In patients with an abnormal %CBF reduction the relation was highly significant: %CBF reduction = 0.971*%CO reduction – 1.027; R2 = 0.762; p<0.001. In patients with a normal %CBF reduction the slope was not significantly different from zero: %CBF reduction = 0.076*%CO reduction – 4.420; R2 = 0.014; p=0.438. In HC the slope was marginally significant: %CBF reduction = 0.171*%CO reduction – 4.708; R2 = 0.114; p=0.018.

That does sound quite significant - a slope of close to 1 in the abnormal group, while the slope is close to 0 for the healthy controls.

 

[Ken Turnbull]

With 91% of patients in the study showing reduced cerebral blood flow, it seems that it would be worthwhile for everyone with ME/CFS to carefully try some low-risk orthostatic intolerance treatments, given that cerebral blood flow testing is not that easy to access.

 

[Ken Turnbull]

And I suppose the question to answer is:

Is there not enough blood getting to the head, due to low blood volume, blood pooling in the lower body, exaggerated postprandial effects (found in some POTS patients), poor activation of veins that should be squeezing it all upwards.

Or is the blood getting to the head but can’t get in, due to abnormal vasoconstriction or lack of vasodilation.

Or both.

The authors hint at the second one, saying the findings suggest an “absence of compensatory vasodilation in the cerebral vasculature”.

Dr Novak has postulated that some of his OCHOS patients have the first problem and some have the second problem. He seems to think they are distinct groups, treats them differently, and seems to have some success with improving their symptoms.

Edit: OCHOS is orthostatic cerebral hypoperfusion syndrome. Low blood flow to the brain during tilt table testing with no abnormalities in blood pressure or heart rate. Entity named by Dr Novak but also found by other research groups that either use different names, or just describe it as Visser et al do.

 

[obeat]

@Caroline Struthers are there any drugs affecting cerebral blood flow that could be tested in your trailblazer trial?

Pyridostigmine does not cross the blood brain barrier but rivastigmine does. There was discussion on the Rob Wust paper thread about the possibility of acetylcholinesterase receptors being involved.

Triptans for migraine cause cerebral vasoconstriction but the gepant group doesn't. Would patients with both ME and migraine get better function on g epants, not just pain relief?

 

[Hutan]

The %CBF reduction was related to gender, age, disease duration and severity, length, weight, the heart rate increase, the %CO reduction, PetCO2 reduction, patients with a PetCO2 < 30 mmHg, the %MAP increase, and tilt duration. Table 3 shows the results of the univariate analysis: increasing disease severity was associated with a larger %CBF reduction, a larger %CO reduction, a larger PetCO2 reduction, and an end-tilt PetCO2 < 30 mmHg resulted in significantly larger %CBF reductions. Other variables showed no significant relations. For the multivariate analysis variables were included that showed a p value < 0.1 in the univariate analysis. Table 4 showed that the %CO reduction, and tilt duration significantly predicted the %CBF reduction. The PetCO2 reduction showed a marginal contribution (p=0.011). All other variables did not significantly contribute to the model.

This is just in the patient group with the abnormal %CBF change.
The first sentence in that paragraph is a bit confusing - the %CBF reduction was not found to be correlated with all those factors. When they say 'related' they mean that they examined the relationship between %CBF and each of the factors. Table 3 gives the detail.

None of the following were correlated with % change in cerebral blood flow within the 'abnormal' patient group:
Gender, age, disease duration, height, weight, heart rate increase, mean arterial pressure increase

I think it might have been better to include the patients who didn't have an abnormal %CBF change in that analysis. Unfortunately the spread of disease durations doesn't cover the first two years - see Table 1, the range is 6 to 20 years. So we can't tell if there is a deconditioning effect going on here - patients are taking 12 years after onset on average to get to this specialist ME/CFS clinic. Neither weight nor height are remotely significant correlates.

Disease severity was associated with %CBF change, but its impact is tiny, perhaps suggesting that the %CBF reduction mostly isn't a result of sedentary behaviour.

%Cardiac Output reduction was by far and away the biggest factor able to predict %CBF change.

 

[Caroline Struthers]

@Caroline Struthers are there any drugs affecting cerebral blood flow that could be tested in your trailblazer trial?

Pyridostigmine does not cross the blood brain barrier but rivastigmine does. There was discussion on the Rob Wust paper thread about the possibility of acetylcholinesterase receptors being involved.

Triptans for migraine cause cerebral vasoconstriction but the gepant group doesn't. Would patients with both ME and migraine get better function on g epants, not just pain relief?

That's interesting. I would propose to set up a democratic process of some kind to create a shortlist of potential medications which could then be voted on by the community. A bit like what was set up by @Snow Leopard with outcomes here

https://www.s4me.info/threads/which-outcome-measures-are-most-important-for-clinical-trials.29829/

I think it might be important to have medications which can be combined (as with LIFT) in a 2x2 factorial way so there are four arms medicationa +medicationb: medicationa + placebo; medicationb + placebo; placebo + placebo

 

[Hutan]

To measure CBF we used extracranial Doppler due to the inherent limitations of transcranial Doppler (Castle-Kirszbaum, Parkin et al. 2022).

The flow was the sum from the carotid and vertebral arteries.

Stroke volume was the velocity of blood passing through the aorta in one heart beat multiplied by the (corrected) aortic valve area. So, the speed of the liquid and the size of the pipe.

Cardiac output (CO) was the stroke volume multiplied by the heart rate, to give a value expressed in litres/minute.

So, the percentage of cardiac output reduction predicts the percentage of cerebral blood flow reduction in the patients with an abnormal %CBF reduction. In the healthy controls, the cardiac output has much less to do with the cerebral blood flow - there is some mitigation going on to preserve cerebral blood flow.

The following paragraph relates to techniques used, and is relevant to replication studies:

The data of HC in the present study were compared with those in the review by Meng (Meng, Hou et al. 2015). The %CBF reduction in the five reviewed studies varied between -4 and - 19%, the %CO reduction between -18 and -44, while in our study the %CBF reduction was -6% and the %CO -10%. However, there are differences in techniques used for both the CBF (transcranial Doppler vs extracranial Doppler in our study) and the CO measurements (inert gas/acetylene rebreathing, finger plethysmography, and impedance cardiography vs suprasternal Doppler in our study). Also, the orthostatic stressor was different between our study (tilt test) and the previous ones (mainly lower body negative pressure (LBNP) and standing up). These differences in measurement techniques and stressors may account for the differences in obtained CO and CBF data. For example, in a direct comparison study between LBNP and a tilt test, the CBF reduction by LBNP in HC was significantly less than during tilt testing, which the authors attributed to differences in PetCO2 (Bronzwaer, Verbree et al. 2017). Also, we demonstrated that CO by finger plethysmography underestimates the CO changes during the tilt compared to suprasternal Doppler (van Campen, Verheugt et al. 2021).

 

[Hutan]

These paragraphs from the discussion are worth reading:

When comparing ME/CFS patients with a %CBF reduction in the normal range of HC and patients with an abnormal %CBF reduction, patients with a %CBF reduction in the normal range of HC had less severe ME/CFS and were more likely to be male than patients with an abnormal CBF and CO reduction. We have recently shown that disease severity, classified according to the ICC criteria (Carruthers, van de Sande et al. 2011), was related to the %CBF reduction: severe patients had a larger %CBF reduction during the tilt test than patients with a mild or moderate severity of the disease (van Campen, Rowe et al. 2023).

The association between increasing symptom severity and a larger %CBF reduction is strengthened by this study showing that patients with worsening symptoms over time (including those with initially a %CBF reduction in the normal range) had a larger %CBF reduction during the second tilt test (van Campen, Rowe et al. 2023). Furthermore, Streeten et al. and our group showed that the use of military anti-shock trousers/compression stockings improved both OI and ME/CFS symptomatology and CBF abnormalities in ME/CFS patients (Streeten, Thomas et al. 2000, van Campen, Verheugt et al. 2018, van Campen, Rowe et al. 2021).

It would be worth looking at these papers that have evaluated the use of compression garments. I'm not sure how you could blind such studies, and so any reported benefit would either need to be both sustained and substantial or accompanied by corroborating physiological measures to be convincing. Members here have provided anecdotes that compression garments on the lower body including abdominal binders do help.

Although there is an association between ME/CFS disease severity and the %CBF reduction, there is no evidence that there is a cause-effect relation. This is evident from this patient group without an abnormal CBF reduction, but with symptoms varying between mild and severe disease.

So they are suggesting that you can have ME/CFS without abnormal orthostatic cerebral blood flow (and perhaps without orthostatic intolerance).

The observation that males have less severe ME/CFS has been observed previously, reflected by less symptoms and a higher physical functioning scale than women (Buchwald, Pearlman et al. 1994, Tseng and Natelson 2004, Faro, Sàez-Francás et al. 2016). The mechanism of milder symptomatology in men is unknown, as is the observation of a lower prevalence of the disease in men.

Sex differences. I doubt this definitive claim that males have less severe ME/CFS. If true, it's not a hard and fast rule as is presented here, but only a tendency - it's easy to think of men who have severe ME/CFS. I can recall the opposite claim being made - that ME/CFS is less common but more severe in men. This is basic epidemiology, sex differences in ME/CFS severity is something that should be known with certainty by now - but I don't think that we have such certainty.

The largest group of ME/CFS patients are those with an abnormal %CBF reduction during the tilt. As shown in Figure 1 the %CBF reduction parallels the %CO reduction with a slope between the %CBF and %CO reduction that is near 1. In the subgroup analysis of patients in whom also PetCO2 data were available (n=440) clinical variables like disease severity and an abnormal PetCO2 (<30 mmHg) were associated with the abnormal %CBF reduction (see table 3). However, the multiple regression analysis showed that only the %CO reduction was significantly associated with the %CBF reduction. The other variables did not contribute significantly.

Reiterating what is covered in previous posts.

 

[Hutan]

On possible mechanisms

One may divide mechanisms that regulate CBF into four distinct components or adaptive responses: autoregulation, chemoregulation (also called vascular reactivity), neuronal regulation (including the neurovascascular coupling and the effects of autonomic and sensory nerves on the extraparenchymal segments of the cerebral vasculature), and endothelium-dependent regulation (Claassen, Thijssen et al. 2021, Silverman and Petersen 2024).

Autoregulation refers to how CBF responds to changes in blood pressure. In the present study there are minimal changes in DBP, DBP, and MAP, suggesting that autoregulation plays a minor role here.

Of course, this study only looked at people with a normal response to the tilt test in terms of heart rate and blood pressure. Blood pressure may be changing with posture in some people at least some of the time in order to try to maintain cerebral blood flow. I've seen my own blood pressure increase dramatically and take a long time to normalise after a period of standing.

Second, the chemoregulation by CO2 (vascular reactivity) is probably normal in these patients as in the univariate analysis the %CBF reduction was related to the PetCO2 reduction and the mean PetCO2 reduction was 8 mmHg and the %CBF reduction was -29%. This relationship is in line with a number of studies in HC, where a 1 mmHg reduction in PetCO2 was related to a 3-4% reduction in CBF (see review Hoiland et al. (Hoiland, Fisher et al. 2019). Nevertheless, in the multivariate analysis the PetCO2 reduction was marginally related to the %CBF reduction due to our choice to set the significance level to 0.01, to reduce false positive findings.

PetCO2 is end tidal carbon dioxide. I would have thought vascular reactivity depends on more than CO2 levels. But it does seem that abnormal CO2 levels aren't a driving factor in most the study participants.

Third, the neurovascular coupling describes the close temporal and regional linkage between neural activity and CBF responses, where an increase in neuronal activity leads to an increase in CBF by dilatation of upstream pial arteries and near-by arterioles and capillaries (Willie, Tzeng et al. 2014, Phillips, Chan et al. 2016). In humans the neurovascular coupling can be studied e.g. using a visual stimulation with an eye-open and eye-closed protocol. Although in our protocol leg muscle tone may increase during standing, thereby increasing regional CBF, the large reduction in CO and CO2, together with the assessment of global CBF prevents assessment of neurovascular coupling.

'Pial arteries' are in the pia mater. This is connective tissue that coats the outside of the brain and has many blood vessels. I'm not sure that I understand all of that paragraph, but faulty nerve signals, perhaps driven by signalling molecules on associated connective tissue are surely a contender in the pathology, given the suspicions that this may also be causing problems with muscle function.

Fourth, the cerebrovascular endothelium exerts a profound influence on cerebral vessels and cerebral blood flow via smooth muscle cell dilators and constrictors, like NO, and endothelin-1 (Andresen, Shafi et al. 2006, Bai, Yu et al. 2022). Even under conditions of high orthostatic stress cerebral flow regulation in HC is preserved, as a study of Brown et al. showed that a mean %CO reduction of -44% resulted in a %CBF reduction of -19% (Brown, Dütsch et al. 2003). Giving the observation that the %CBF reduction is almost 1:1 related with the %CO reduction in over 90% of the ME/CFS patients with a normal HR-BP response, it is most likely that endothelial dysfunction of the cerebral vasculature plays a dominant role in the abnormal cerebral flow regulation during orthostatic stress. As outlined in the introduction, the mechanisms of cerebral flow regulation in HC are complex, but in ME/CFS patients additional factors that may disturb cerebral flow regulation, like abnormal venous return, blood volume changes, venous distensibility, deconditioning, chronotropic incompetence, neuroinflammation, autoimmunity, and microclots, can also play a role.
...
In ME/CFS patients a number of studies have shown endothelial dysfunction using flow-mediated vasodilation/post-occlusive hyperemia (Newton, Kennedy et al. 2012, Scherbakov, Szklarski et al. 2020, Sørland, Sandvik et al. 2021, McLaughlin, Sanal-Hayes et al. 2023, Sandvik, Sørland et al. 2023). Our study, specifically targeting the cerebral vasculature, adds to evidence that endothelial dysfunction of the brain may be present in the majority of patients.

So, the authors are liking dysfunction in cerebrovascular endothelium as a major cause. Certainly, we've seen lots of talk about endothelial dysfunction in the ME/CFS literature. Presumably there could be a problem with endothelial reactivity in the lower body causing vein distension and blood pooling, as well as a problem in endothelial reactivity in the brain causing inadequate blood vessel dilation?

There's more about the patients who had worsening symptoms over time and who showed increasing %CBF reduction in the tilt test, reported in another study:

This observation is strengthened by our previous study where patients with worsening symptoms showed a substantial further reduction in %CBF (van Campen, Rowe et al. 2023). Twenty-five of these patients with worsening symptoms (n= 71) initially had a %CBF reduction in the normal range of HC. In this subgroup the initial %CBF reduction was -6% (SD 4%) but changed to -25% (SD 5%), a value well beyond the cut-off value of -15%. Possibly one of the above-mentioned mechanisms in ME/CFS may become operational (venous return, hypovolemia, deconditioning, sympathetic activation, chronotropic incompetence, neuro-inflammation, auto-immunity, endothelial dysfunction, and micro clots), but this needs to be studied further.

 

[Hutan]

Limitations/ future research ideas:

Moreover, we only selected those patients with a normal HR and BP response during tilting. The same analysis should be performed in patients with POTS and orthostatic hypotension. Individuals with ME/CFS have been reported to have variable function from day to day and week to week. Future studies can evaluate whether the CBF and CO measurements differ on “good” versus “bad” days. Our focus was on the prevalence of reductions of CBF and CO and therefore mechanisms of CBF and CO changes and regional cerebral blood flow differences were beyond the scope of this study. These topics would be important to investigate further.

Yes, good ideas:

• undertake the analysis in all ME/CFS patients, not just those reporting orthostatic symptoms and not just those with a normal HR and BP response to tilt testing.
• compare CBF and CO measurements on good and bad days
• investigations into the mechanisms of the CBF and CO reductions

I'd add

• investigations of possible treatments, including compression garments and drugs with a plausible mechanism

Ah, yes, the authors say in Conclusions

These data suggest that circulatory improvement by increased water and salt intake, compression garments, and medications targeted to improve CO are the primary targets to improve orthostatic intolerance. This needs to be prospectively assessed in randomized, placebo-controlled trials.

The authors say:

Finally, the use of extracranial Doppler flow to measure cerebral blood flow must be replicated by others and in different patient groups.

So

• validate the CBF measurement technique of extracranial Doppler flow
• replicate the study using different methods of measurement of CBF

It is unclear how much the orthostatic intolerance of ME/CFS patients differ from other forms of circulatory dysfunction.

There's that one line in a paragraph about CBF measurement technique that warranted a bit more discussion I think. I think they are saying that there might be problems with blood flow in the body generally, not just in response to an orthostatic stress. I think that is very possible, and presumably it is easier to study than cerebral blood flow. Also, if lower body blood pooling is part of the cause of orthostatic intolerance, then there are a lot of easy experiments that could be done to confirm that e.g. measurement of belly and calf circumference before and after standing, and on good and bad days.

• more studies on non-cerebral blood flow in relation to orthostatic stress and good day/bad day comparisons.

And there's the epidemiology research:

• differences in severity in males and females

 

[Hutan]

I think this was an interesting paper, making good use of retrospective data. It seemed to me to be well done, with good recognition of the limitations. Thanks to the authors for their ongoing interest in ME/CFS.

 

[mango]

Thank you @Hutan, very helpful

 

[Jonathan Edwards]

It would be worth looking at these papers that have evaluated the use of compression garments. I'm not sure how you could blind such studies, and so any reported benefit would either need to be both sustained and substantial or accompanied by corroborating physiological measures to be convincing.

An interesting problem.

You might be able to measure volume reduction to the lower limbs by compression garments using an entirely non-invasive optical method as used for building customised shoes. You scan the person in the compression tights using a LASER beam and compute the exact 3D shape from which the volume can be calculated.

The blinding problem might best be overcome by a dose-response study using compression garments designed to produce a range of volume reductions (maybe three or four levels) but with different shapes such that sensed compression did not correlate directly with reduced volume. (Some tights with very tight calves but sloppy thighs maybe, as well as all-over tight ones and loose ones.) You would want a tights-knitting machine that knitted precise shapes but modern technology should do that easily enough and probably already does for TED stockings.

You could then use subjective measures of benefit and see how they correlate with actual volume reduction and with spurious measures like sensed tightness. You could probably use a cross-over design to reduce patient numbers needed and ensure (self)matched groups. Maybe you could get each subject to choose an optimum pair of tights and see if the modal choice had a well defined volume reducing profile.

It could be funded by Marks and Spencer or Versace.

 

[Jonathan Edwards]

Compression garments would seem to be a good place to start in validating ideas about relative blood flow with a therapeutic intervention. The physiological effect would be far easier to interpret with non-invasive methods than saline infusion or drugs. And if drugs made a big difference I think we would know by know. A number of members have reported that they find compression garments useful. That is less clear for drugs.

Compression garments also have an effect on much more than just the vascular compartment. They prevent gravitational pooling of extravascular fluid, as in oedema. I have used a compression stocking for my left leg under certain circumstances with very reliable local results for ten years. (I have denervation from a lumbar disc problem which means that the left leg does not clear lymph as well as the right and it swells on journeys or above 30 degrees of heat.)

 

[Hoopoe]

My personal experience is that loading up on fluid and salt has a fairly strong positive effective when certain symptoms are bad and especially in hot weather. I'm talking about a reduction in symptoms of about 50-75%. At othert times the effect isn't as pronounced but still meaningful and more than compression socks which I'm not sure has any real effect.

If theory says this cannot happen then maybe the theory is wrong.

 

[Jonathan Edwards]

more than compression socks which I'm not sure has any real effect.

If theory says this cannot happen then maybe the theory is wrong.

Compression socks wouldn't be that much use. It would need to be tights I think.

Maybe the theory is wrong. But loading up with fluid and salt in hot weather would be expected to make people feel better, just by keeping hydration good. That isn't necessarily anything to do with blood volume. My scepticism is that you can alter blood volume with IV saline supplementation better than just drinking.

 

[SNT Gatchaman]

So, the percentage of cardiac output reduction predicts the percentage of cerebral blood flow reduction in the patients with an abnormal %CBF reduction. In the healthy controls, the cardiac output has much less to do with the cerebral blood flow - there is some mitigation going on to preserve cerebral blood flow.

That mitigation in HCs being taking the foot of the brake pedal of CBF regulation in response to the decreased CO. So I wonder if the problem in patients is the combination of loss of peripheral cardiovascular homeostasis and the overactivity of mechanisms that act to limit cerebral blood flow.

As summarised in the paper, those mechanisms are –

One may divide mechanisms that regulate CBF into four distinct components or adaptive responses: autoregulation, chemoregulation (also called vascular reactivity), neuronal regulation (including the neurovascascular coupling and the effects of autonomic and sensory nerves on the extraparenchymal segments of the cerebral vasculature), and endothelium-dependent regulation (Claassen, Thijssen et al. 2021, Silverman and Petersen 2024).

Claasen et al is Regulation of cerebral blood flow in humans: physiology and clinical implications of autoregulation (2021, Physiological Reviews)

Silverman and Petersen is Physiology, Cerebral Autoregulation (StatPearls)

See also the section on Effects of standing from supine position to upright position at Deranged Physiology —

• Venous return decreases, thus RV and LV stroke volume is decreased
• Carotid sinus baroreceptor pressure decreases because of:
  • Elevation above hydrostatic indifference point
  • Decreased cardiac output
• Baroreceptor reflex is activated, which:
  • Increases heart rate by decreasing vagal tone (immediately)
  • Increases peripheral vascular resistance (with a slight delay)
• Cerebral perfusion pressure also decreases;
  • Cerebral vessels vasodilate to preserves blood flow
• The net effects are:
  • Increased heart rate
  • Increased blood pressure
  • Decreased stroke volume
  • Stable or slightly decreased cardiac output
  • Stable cerebral perfusion
• In an awake patient standing up voluntarily, lower limb muscle pump activity ameliorates the decrease in venous return