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

Jonathan Edwards said:
Compression socks wouldn't be that much use. It would need to be tights I think.
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I just want to mention that based on my personal experience (very severe OI), knee-high compression socks (class II, 23-32 mmHg) is enough to make a noticeable and useful difference, measurable by the blood pressure monitor as well. Thigh-highs are more effective, but the knee-highs really do help enough to be of actual use.

I have tried high-waisted compression tights too, as well as regular firm control "shapewear" for example very high-waisted shorts. Personally I find all these a bit too uncomfortable and restricting to wear on a daily basis. In my case they haven't made much of a difference compared to the thigh-highs.

@Jonathan Edwards Sorry if you find my repeated comments on this topic annoying :)
 
Perhaps salt water has a longer lasting effect than predicted for this reason:

My orthostatic symptoms are dependent on how long I've been upright and the type of stressor. Sitting is better than standing but worse than lying down. Riding a bike is better than walking. Standing is worse than walking. The worst thing is repeatedly alternating between squatting and standing.

The stress caused by this accumulates over the course of the day. Drinking salt water, even just once, may lead to a lower overall stress level at the end of the day even if by then blood volume is not different.

The best thing is to repeatedly drink salt water.
 
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Hoopoe said:
Perhaps salt water has a longer lasting effect than predicted for this reason:
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Yes, things may be pretty complicated over a longer period of say hours. And it may vary from person to person depending on whether they have a tendency to develop oedema, like my left leg and maybe @mango?, or maybe widened calf veins.

So it would be useful to have some proper measurements from a study.
 
Jonathan Edwards said:
Yes, things may be pretty complicated over a longer period of say hours. And it may vary from person to person
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Salt helps my OI, too, and generally makes me feel less unwell. I used to add a bit to food, till I stayed with someone who didn't use salt in their cooking and realised my muscles weren't on fire any more. It's so painful that OI's the lesser evil.

Next best is leg compression. It doesn't resolve the low-grade headache as completely as salt, but it does improve it—when the weather's cooled down enough to wear compression garments again, my head clears within seconds. It's one of those grumbling background things that's most obvious when it stops.
 
Caroline Struthers said:
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
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It doesn't seem to be used outside of Russia and other post-Soviet states, but within Russia, emoxypine is touted as increasing cerebral blood flow, treating endothelial dysfunction of some type, reducing oxidative stress, increasing ATP, among other things.

I have no stake in those particular claims and my Russian isn't good enough to make much sense of the academic publications on it, but I do wish someone would look into it, even if only to confirm it's overstated or irrelevant to ME/CFS.
 
Here’s a couple of studies on compression garments that might be of interest:

Compression Stockings Improve Cardiac Output and Cerebral Blood Flow during Tilt Testing in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) Patients: A Randomized Crossover Trial

Compression Garment Reduces Orthostatic Tachycardia and Symptoms in Patients With Postural Orthostatic Tachycardia Syndrome

The colourful illustrations (Figure 2) in the second paper always amuse me, for unknown reasons.

On a tangent, scientists have used a negative pressure vessel, a bit like an iron lung, to induce blood pooling in the lower body. I think Dr Blair Grubb discusses it in some of his lectures. He tried it out and described the experience as unpleasant.

On another tangent, this enterprising patient obtained a second-hand military g-suit to combat her blood pooling:
https://oiresource.com/pictures.htm
 
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On measuring blood volume:

There is a recently accredited medical device that can measure total blood volume quickly and easily:
https://detalo-health.com/

It uses carbon monoxide rebreathing (a tiny amount) as a tracer.

It is not a new method, but the ability to purchase it as an EU-accredited medical device is new as of 2023. It is much cheaper to purchase and operate than the older nuclear medicine technology.


There is also apparently a new and easy way to measure splanchnic (abdominal) blood pooling.

It’s mentioned in this clinical trial looking at post-prandial symptoms in POTS but I can’t find any further info on it:

Splanchnic Venous Capacitance in Postural Tachycardia Syndrome

“… an innovative technique to assess venous capacitance in humans, using segmental impedance to measure the effect of graded positive airway pressure (CPAP) on splanchnic blood volume.”

I tried emailing the lead researcher but I don’t think I got a reply.
 
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Nimodipine (calcium channel blocker) has been thought to increase cerebral blood flow by being selective for dilating cerebral blood vessels.

However, there has been further research in recent years questioning whether it is as selective as previously thought.

Also, it will lower blood pressure, so would be contraindicated for anyone with low blood pressure, and test subjects with normal blood pressure would have to be monitored.

(My daughter is currently trying nimodipine to see whether it is more effective than her previous regime of amlodipine and candesartan. She has abnormal cerebral vasoconstriction and mild hypertension that seems to be co-morbid.)
 
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Jonathan Edwards said:
My scepticism is that you can alter blood volume with IV saline supplementation better than just drinking.
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Dr Satish Raj (and others) found abnormalities in the renin–angiotensin–aldosterone system (RAAS) in POTS patients. It has been called the renin–aldosterone paradox.

https://www.ahajournals.org/doi/10.1161/01.CIR.0000160356.97313.5D?url_ver=Z39.88-2003&rfr_id=ori:rid:crossref.org&rfr_dat=cr_pub 0pubmed

The RAAS regulates blood volume.

I think RAAS abnormalities have also been found in ME/CFS patients.

The possible mechanism for IV saline working better than consuming water and salt is that the IV saline bypasses the RAAS, and it takes it a while to catch up and reset the body to the abnormal low level of blood volume that it mistakenly targets.

Hence the person receiving the IV fluids experiences a period of increased blood volume and improved symptoms that dissipates over perhaps a few days.

As always, more research is needed. It’s an interesting angle and I hope some new researchers take another look at it.

Dr Raj has given a lecture on this topic:
Understanding Blood Volume & Hemodynamics in POTS
 
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Published
https://www.mdpi.com/2227-9032/12/24/2566

The Cardiac Output–Cerebral Blood Flow Relationship Is Abnormal in Most Myalgic Encephalomyelitis/Chronic Fatigue Syndrome Patients with a Normal Heart Rate and Blood Pressure Response During a Tilt Test
by
C (Linda) M. C. van Campen
1,*,
Freek W. A. Verheugt
2,
Peter C. Rowe
3and
Frans C. Visser
1


1
Stichting Cardio Zorg, Kraayveld 5, 1171 JE Badhoevedorp, The Netherlands
2
Department of Cardiology, Onze Lieve Vrouwe Gasthuis (OLVG), 1091 AC Amsterdam, The Netherlands
3
Department of Paediatrics, John Hopkins University School of Medicine, Baltimore, MD 21205, USA
*
Author to whom correspondence should be addressed.
Healthcare 2024, 12(24), 2566; https://doi.org/10.3390/healthcare12242566
Submission received: 13 October 2024 / Revised: 16 December 2024 / Accepted: 18 December 2024 / Published: 20 December 2024
Browse Figure
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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 (HCs), the regulation of CBF is complex and cardiac output (CO) is an important determinant of CBF: a review showed that a 30% reduction in CO results in a 10% reduction in CBF. In previous and separate ME/CFS studies, we showed that CO and CBF decreased to a similar extent during tilt testing. The aim of the study: to test the relationship between CBF and CO, which seems to be abnormal in ME/CFS patients and is different from that in HCs.

Methods:

In this retrospective study we analyzed this relationship in a large group of patients. To compare the patient data with those of HCs, 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. A total of 534 ME/CFS patients and 49 HCs underwent tilt testing with measurements of HR, BP, CBF, CO, and end-tidal PCO2. To measure CBF, extracranial Doppler flow velocity and vessel diameters were obtained using a GE echo system. The same device was used to measure suprasternal aortic flow velocities. End-tidal PCO2 was recorded using a Nonin Lifesense device.

Results:

In 46 (9%) patients, CO and CBF changes were in the normal range for HCs, and in 488 (91%) an abnormal CO and CBF reduction was found. In patients with abnormal CO and CBF reductions, the slope of the regression line of CO versus CBF reduction was almost 1. The multiple regression analysis of the latter group showed that the CO reduction for the most part predicted the CBF reduction, with a limited role for the PETCO2 reduction.

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 for HCs and those with an abnormal CO and CBF reduction during the tilt (91% of patients). In the latter group of patients, an almost 1:1 relationship between the CO and CBF reduction suggests the absence of compensatory vasodilation in the cerebral vasculature. This might indicate endothelial dysfunction in most ME/CFS patients and may have clinical and therapeutic implications.

Keywords:
stroke volume; cardiac output; cerebral blood flow; tilt table test; orthostatic intolerance; chronic fatigue syndrome (CFS); myalgic encephalomyelitis (ME); healthy controls

https://twitter.com/user/status/1870826614524969293
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As the HCs studied in the present study showed a normal heart rate (HR) and blood pressure (BP) response during the tilt test, we only analyzed the ME/CFS patients with a normal HR and BP response during the tilt and excluded those with postural orthostatic tachycardia syndrome (POTS), orthostatic hypotension (OH), or a (near)-syncope.

Disease severity in patients was scored according to the international consensus criteria (ICC), with severity scored as mild, moderate, severe, and very severe [29]. Very severe patients (bedridden patients) were not studied here because they were not able to undergo a tilt test.
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Based on the distribution of the %CO reduction versus the %CBF reduction (see Figure 1) we decided to separate patients into a group where the %CBF reduction was in the normal range of the healthy controls, and a group of patients with a %CBF reduction below the lower limit of normal for the healthy controls (a cut-off value of %CBF reduction of −15%).
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upload_2024-12-22_14-28-59.png

What's going on with that chart? They decided to use the range of HCs as a reference, with 15% cerebral blood flow reduction as the cutoff to compare ME/CFS similar to HC (green) and those with larger %CBF reductions (red).

Why is it such a perfect split between the patient groups if they divide at 15%? It seems too clean. I feel like it should be a smoother/messier transition.

Maybe I'm not understanding the chart.

Other interesting snippets:
it is most likely that endothelial dysfunction of the cerebral vasculature plays a dominant role in abnormal cerebral flow regulation during orthostatic stress. As outlined in the introduction, the mechanisms of cerebral flow regulation in HCs 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. Endothelial dysfunction in the brain has been described in a variety of cerebral diseases like Alzheimer disease [52], cerebral small-vessel disease [50], in multiple sclerosis [53], and possibly in Parkinson’s disease [54]. In ME/CFS patients, a number of studies have shown endothelial dysfunction using flow-mediated vasodilation/post-occlusive hyperemia [18,55,56,57,58]. Our study, specifically targeting the cerebral vasculature, adds to evidence that endothelial dysfunction of the brain may be present in the majority of patients.
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Twenty-five of these patients with worsening symptoms (n = 71) initially had a %CBF reduction in the normal range of HCs. 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.
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I used WebPlotDigitizer to pull out the coordinates of all the points I could make out for just ME/CFS. The tiny red dots show the ones I got coordinates for. Pretty much all the green ones I could see and all the ones around the edge of the red blob.
upload_2024-12-22_11-10-9.png

Here's the plot of just ME/CFS that I made from those coordinates:
vancampenchartpoints.png

That's what a random sample of people with ME/CFS looks like? That much room between the big blob of patients with low blood flow/cardiac output and the ones that are similar to healthy controls?

Edit: I filled in all the space in the middle of the big blob. The exact coordinates of the ones in the interior don't really matter, I'm just trying to match the shape to the paper's plot. (and I got a couple green ones I missed.)
upload_2024-12-22_12-26-1.pngvancampenchartpoints.png
 
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If there were two distinct clusters, which would be a bit surprising in itself, then the tail end of the blob near the bottom left is what I'd expect on the top right end of the blob. Where it slowly becomes less dense as it fades out. Instead the top right almost looks chopped off.

I guess maybe it's possible some sort of all or nothing mechanism gets flipped and there is no in between?
 
Interesting results. I suspect the healthy controls are part of a spectrum, whereby there is an element of changing CO and CBF mechanisms in the general public and want to remove the "noise" of this.

They do acknowledge this is a retrospective study, does not include people with severe ME and came from a select group of GP referrals for investigation for orthostatic symptoms. It may not be generalisable to entire ME/CFS population and does not include pwME/CFS with POTS or confirmed OH at this stage. They also note there are more men in the ME/CFS group than normal gender representation.

It is a strong relationship between CO/%CBF reduction, they are intending to do more studies on this. They are also advocating for more studies on increasing water and salt intake, the use of compression stockings and medications in the hope of alleviating this.
 
hibiscuswahine said:
I suspect the healthy controls are part of a spectrum, whereby there is an element of changing CO and CBF mechanisms in the general public and want to remove the "noise" of this.
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If you're referring to the two clusters I was talking about, it's not the healthy controls I'm looking at. It's that it seems odd that a quite large ME/CFS group (n=534) split cleanly with a large gap into two subtypes. One subtype almost indistinguishable from the healthy controls, and the other with a quite high correlation between the two variables.
 
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