Preprint cerebral blood flow relation is abnormal in most ME/CFS patients with a normal heart rate and blood pressure response, 2024, van Campen et al

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

 

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.

https://www.youtube.com/watch?v=GdiRC5Fmuzg

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

 

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.

 

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.

 

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.

 

@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

 

Thank you @Hutan, very helpful

 

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.

 

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.)

 

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.

 

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.

 

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 –

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