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Endothelial dysfunction in ME/CFS patients (Sandvik, Mella, Fluge et al, 2023)

SNT Gatchaman

Senior Member
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302
Location
New Zealand
Endothelial dysfunction in ME/CFS patients
Sandvik MK, Sørland K, Leirgul E, Rekeland IG, Stavland CS, Mella O, Fluge Ø

Objective: A few earlier studies have found impaired endothelial function in patients with Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS). The present study investigated large-vessel and small-vessel endothelial function in patients with ME/CFS.

Study design: The study was a substudy of the RituxME trial, a national, multicenter, randomized, double-blind, placebo-controlled phase III study on the effect of rituximab vs. placebo in ME/CFS patients in Norway. Flow-mediated dilation (FMD) and post-occlusive reactive hyperemia (PORH) was measured at baseline and after 18 months of treatment in 39 patients and compared with healthy controls. Other outcome measures were symptom severity and various physical function measures.

Results: ME/CFS patients had markedly reduced FMD compared to healthy controls at baseline (5.1% vs. 8.2%, p< 0.0001, adjusted for arterial diameter and sex), and significantly lower microvascular regulation measured by PORH than healthy controls (1354 PU vs. 2208 PU, p = 0.002). There were no differences between the treatment and placebo groups in symptom changes or vascular measures. As a group, the ME/CSF patients experienced a slight, but significant improvement in clinical symptoms after 18 months. PORH, but not FMD, was similarly improved (1360 to 1834 PU, p = 0.028). There was no significant correlation between FMD and PORH. There were non-significant tendencies towards associations between symptom severity/physical function measures and lower FMD and PORH, and a significant correlation between PORH and steps per 24 hours at baseline.

Conclusions: ME/CFS patients had reduced macro- and microvascular endothelial function, indicating that vascular homeostasis may play a role in the clinical presentation of this disease.

Link | PDF
 

Murph

:)
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1,802
Strong study that shows me/cfs patients have worse endothelial function (i.e. bloodflow) than healthy congtrols. They tried to fix it with rituximab and it didn't do anything. They have also tried to fix it with cyclophospamide and that didn't do anything either. The challenge for the next scientist is to see what can fix it.

Scheinbenbogen in Germany is the main person working on the answer to this. She has been collaborating with the Norwegians who did this study. She believes taking autoantibodies to adrenergic, cholinergic and muscarinic receptors out of the blood will help, using plasmapheresis. However, it is possible that if b-cell produced antibodies were a problem, then rituximab should have done something.

It's also worth noting a recent study that found scheinbenbogen's celltrend test doesn't distinguish patients from controls in POTS. That's concerning. I recently began putting a lot of hope in Scheinbenbogen after going on a drug (midodrine) that affects alpha-adrenergic receptors and seeing a big decrease in PEM. (beta blockers already help me) Her theory that these receptors matter makes a lot of sense to me. So I hope the test she relies on really works. If it doesn't, all her results are questionable !!

And there's a lot of such results. She's been very busy working on long covid, finding that covid severity is correlated with autoantibodies: https://pubmed.ncbi.nlm.nih.gov/36238301/
 

SNT Gatchaman

Senior Member
Messages
302
Location
New Zealand

Wishful

Senior Member
Messages
5,862
Location
Alberta
After taking a drug for over 18 months, I think there would likely be differences (slight, but significant?) in various parts of the body, so whatever effect they are measuring may not be due to their theoretical mechanism.

How expensive is 18 months of this drug for a "slight, but significant" improvement? Fisetin--or was it epigenin--gave me a slight, but noticeable reduction in my brainfog, so I was willing to buy more, but it was really cheap (under $5 for several weeks?) with no known risk of side-effects.

I don't feel like reading the paper; are their any conflicts of interest? Really, even a positive-looking outcome is beneficial to the researchers' careers, and thus a conflict of interest. Report "No difference between this drug and placebo", or fudge the figures/study a bit so that it shows a "slight, but significant" positive result? That's a real problem with studies today, and peer review doesn't guarantee a close inspection and critique.
 

SNT Gatchaman

Senior Member
Messages
302
Location
New Zealand
I don't feel like reading the paper; are their any conflicts of interest? Really, even a positive-looking outcome is beneficial to the researchers' careers, and thus a conflict of interest. Report "No difference between this drug and placebo", or fudge the figures/study a bit so that it shows a "slight, but significant" positive result? That's a real problem with studies today, and peer review doesn't guarantee a close inspection and critique.

I think you may have misunderstood the point of this paper.

Abstract said:
The present study investigated large-vessel and small-vessel endothelial function in patients with ME/CFS.

Abstract said:
There were no differences between the treatment and placebo groups in symptom changes or vascular measures. As a group, the [ME/CFS] patients experienced a slight, but significant improvement in clinical symptoms after 18 months.

They are specifically saying that all patients experienced a slight improvement over the investigation period, whether they took the drug or not. This paper is not about the therapeutic effect of Rituximab — that has already been reported on, as a negative result.

In 2019 Fluge and Mella said:
Conclusion:
B-cell depletion using several infusions of rituximab over 12 months was not associated with clinical improvement in patients with ME/CFS.

This paper also confirms no improvement in vascular function, corroborating other outcome measurements previously made. It's looking at non-invasive measurements of endothelial dysfunction and replicating findings starting from 2012. This is useful and shows that ME is associated with endothelial dysfunction that can be non-invasively demonstrated. Please see the links in my post #3.

Abstract said:
Conclusions: ME/CFS patients had reduced macro- and microvascular endothelial function, indicating that vascular homeostasis may play a role in the clinical presentation of this disease.
 

lenora

Senior Member
Messages
4,992
Where is Pyrrhus and many of our other males? I assume they aren't on a long winter's vacation, although they could use one.

If you're in another group with them, kindly pass along that they're missed and we hope things are going better for them.

Thank you for the information, it's most definitely appreciated. Yours, Lenora
 

Murph

:)
Messages
1,802
This study replicates the 2012 study (Large & Small Artery Endothelial Dysfunction in CFS), posted by @Pyrrhus

While there may be subsets in ME, findings may relate less to autoantibodies and more to impaired production of NO via endothelial NOS for other reasons. See also thread Endothelial Dysfunction in ME, particularly this post on Decreased NO production in endothelial cells exposed to plasma from ME/CFS patients.

I wouldn't see the autoantibody theory and the NO theory as mutually exclusive. They are complementary.

Scheinbenbogen writes the following about beta-adrenergic and muscarinic receptors:

ß2AdR are important vasodilator receptors in the heart, brain and skeletal muscles, and are expressed on endothelial cells to release nitric oxide and on vascular smooth muscles cells to cause direct vasodilation. M3-muscarinergic receptors release nitric oxide from endothelial cells

This is not to say she's right. There could be other reasons vasodilation / vasoconstriction is failing.
 

Murph

:)
Messages
1,802
Where is Pyrrhus and many of our other males? I assume they aren't on a long winter's vacation, although they could use one.

If you're in another group with them, kindly pass along that they're missed and we hope things are going better for them.

Thank you for the information, it's most definitely appreciated. Yours, Lenora
Pyrrhus is on mastodon these days. i'm won't link to him but with such a rare name you can find him!
 

Wishful

Senior Member
Messages
5,862
Location
Alberta
I think you may have misunderstood the point of this paper.

Yup. Bad brain day.

There could be other reasons vasodilation / vasoconstriction is failing.

I believe most ME symptoms can somehow be linked to neural dysfunction (possibly due to glial dysfunction, since they are important for neural function). Vascular function is controlled by neurons. Some neurons receive and process information from various receptors that sense stretch, chemical levels, etc. Others send signals that result in the vessels constricting or relaxing. Thus it seems logical for ME to interfere with those functions. Maybe someone can model the effects of neural dysfunction on vascular (dys)function.
 

lenora

Senior Member
Messages
4,992
These terms have been tossed around since I began this trek. Just so you know, people have been confused by this and actually are trying to make a difference to our lives. Someday someone will cry Bingo!....and we'll win the jackpot. Have hope.

I do believe countries are finally realizing that there is a steady source of income being lost by people in their productive years being bedridden. Will it make a difference? We hope. Yours, Lenora
 

pattismith

Senior Member
Messages
3,972
Endothelial dysfunction is probably what explain the positive effect some ME sufferers find with pentoxifylline;

I found this link on the american ME society, it helps with fatigue:

Pentoxifylline – American ME and CFS Society (ammes.org)

In Germany they are testing a drug called Vericiguat from Merck. Which should dilate blood vessels. It is already FDA apporoved. Maybe this help these subgroups.
that's interesting!
 

SNT Gatchaman

Senior Member
Messages
302
Location
New Zealand
I have called this vascular " asthma" as a way to describe it to people.

Great comment. I might want to steal that in due course!

There has been an uptick in asthma diagnoses post Covid (children and adults). Pre-existing asthma was also recognised quite early on as a risk for developing Long Covid. The explanation may "simply" lie in immune dysregulation, but I have been wondering whether there could be a link between bronchial smooth muscle cell and vascular smooth muscle cell dysfunction and particularly their signalling, that partly explains symptoms. This might include the NO pathway.

---
Soluble Guanylate Cyclase Agonists Induce Bronchodilation in Human Small Airways (2019)
Airway smooth muscle proliferation and inflammation in asthma (2018)
β-Agonist-mediated relaxation of airway smooth muscle is protein kinase A-dependent (2014)
Nitric oxide induces airway smooth muscle cell relaxation by decreasing the frequency of agonist-induced Ca2+ oscillations (2010)
 
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