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

[SNT Gatchaman]

If a further study were done, I would be interested in how it varied during the day. A little difficult to co-ordinate but potentially enlightening. Have the patient sleep on-site (via a sleep lab) and make measurements eg on waking, +2 hours, early-mid afternoon and early-mid evening.

My subjective n=1 view is that the endothelial dysfunction is part of the "unrefreshing sleep" experience. For me it seems to "burn off" 1-2 hours after waking, then baseline and active HR slowly rises over the day and then falls toward evening (I'm generally sitting or pottering at home). I think it's well established that POTS patients are often at their best later in the day.

I've also commented previously on the interrupted sleep-and-paradoxically-better-day phenomenon I've experienced, though I don't know if that's common for others. It might be possible to capture that with objective data following an overnight sleep (or in this case interrupted sleep) study.

As an aside — irritatingly, I have the skills to perform this sort of evaluation. Although practically I would have teamed up with one of my vascular sonographers and cardiology, respiratory/sleep and vascular surgery colleagues and trainees. I think ethics could have been gained for this and maybe funding. Sigh.

 

[Robert 1973]

For me, one of the interesting things about the study is that measuring flow-mediated dilation using ultrasound doesn't look enormously challenging or expensive to carry out. If the professionals think these results are genuinely interesting, it might be within the scope of an ME charity to fund a study on a larger cohort.

It wouldn't even require the administration of the drug to test patients' response to it; simply knowing whether or not reduced arterial dilation is a real feature in a substantial proportion of patients, but not in a matched control group, would be useful.

ME Research UK was set up by a an ME patient who was a vascular scientist (Vance Spence). From memory they have funded various studies looking at endothelial function. I believe Faisal Kahn (sp?) is still involved in ME/CFS and LC research. I’d be surprised if this isn’t something they are looking at.

 

[Kitty]

ME Research UK was set up by a an ME patient who was a vascular scientist (Vance Spence). From memory they have funded various studies looking at endothelial function. I believe Faisal Kahn (sp?) is still involved in ME/CFS and LC research.

Thanks, I hadn't even realised that.

I’d be surprised if this isn’t something they are looking at.

Hopefully they will, especially if these results have contributed worthwhile new evidence. Obviously it's quite hard for most of us to evaluate it, without an understanding of how a phenomenon like this might vary anyway between healthy patients and chronically ill ones, older and younger, active and non-active, etc.

 

[SNT Gatchaman]

See also comment in Urine Metabolomics Exposes Anomalous Recovery after Maximal Exertion in Female ME/CFS Patients (2023).

 

[Mithriel]

I have damage to my finger nails that I believe is due to vasculitis. and the tips of my fingers become smooth and then blister.

My nails are slightly spooned and a couple are blue at the bottom. One nail grows slowly in the middle so it is split and damaged. The bottom is always blue and if it is gently tapped against anything the pain is excruciating for a few minutes. It is a bit like when you rap your fingers when they are cold.

 

[Rain]

A member motioned that they had migraines i.e. which didn't respond to the normal (migraine) medication --- wonder if this would be a potential clue i.e. another route to migraines?

It is well documented that Migraine benefits from vasoconstriction and gets worse with vasodilation. And with ME-symptoms preferring the opposite, having both can be a never ending circle.

 

[Rain]

I have damage to my finger nails that I believe is due to vasculitis. and the tips of my fingers become smooth and then blister.

Have you been checked for Raynaud's?

 

[duncan]

Any one care to take a stab at figuring how low VEGF might play into this?

 

[Mithriel]

Have you been checked for Raynaud's?

My kids have Raynaud's and it isn't like that though the diabetes nurse says I have it in my big toe! It is definitely secondary probably because I have nerve damage and little feeling in my feet (but not due to diabetes because I have a strong pulse!)

 

[Simon M]

Comments

The two striking things about the study are that:
1. This is the strongest evidence yet for endothelial dysfunction in patients, and is an important finding.
2. Potentially, dysfunction plays an important role in the illness, but the evidence for this is much weaker.

1. Important finding of endothelial dysfunction

figure 1 show substantial differences



Flow mediated dilation (measures arterial vasodilation)
5.1% for ME/CFS patients versus 8.2% healthy controls (p < 0.0001).

Crucially, when glyceryl nitrate (GN) is given under the tongue there is no longer any significant difference in flow mediated dilation between patients and controls. (GN provides nitric oxide, NO, which is the vasodilator that endothelial cells normally produce. And this suggests that the cause of inadequate dilation is a lack of endothelial-derived nitric oxide.

Post-occlusion reactive hyperaemia
(measures capillaries/small, blood vessel vasodilation)
1354 PU in ME/CFS patients versus 2208 for healthy controls, p = 0.002

The study found no correlation between FMDand PORH in patients. But they point out, this isn't surprising since most studies, looking at these two measures find little or no correlation between them. The paper says that the exact mechanisms of regulation of macro (FMD) and micro (PORH) vasodilation are likely to be different.

overall
As the authors say:
It is a significant and important finding that our group of ME/CFS patients have such an markedly reduced vascular function compared to healthy individuals.
…This is an important discovery in a field with a scarcity of objective and measurable abnormalities.

The authors acknowledge the small sample size (39 patients) and we now need replication in larger samples.

I'm out of gas, but will comment later on the clinical importance and pathological significance of endothelial dysfunction (which I think is where things get interesting).

 

[John Mac]

Crucially, when glyceryl nitrate is given under the tongue there is no longer any significant difference in flow mediated dilation between patients and controls

Has anyone tried this? Is it safe to use?

 

[darrellpf]

In 2013/2014 the authors started a patent (withdrawn) for NO treatment of ME/CFS

Nitric oxide donor for the treatment of chronic fatigue syndrome

 

[SNT Gatchaman]

In 2013/2014 the authors started a patent (withdrawn) for NO treatment of ME/CFS

This patent application looks like stand-alone NO and in combination with the B-cell depletion. It was deemed to be withdrawn in Nov 2015 (which was around the time of the positive phase II Rituximab findings and long before the 2019 negative phase III trial). Unclear if extension not sought or actively withdrawn, but I guess this wasn't on the basis of thinking the B-cell depletion part of the application combo was invalid, so maybe the NO donor side wasn't looking as promising?

 

[Michelle]

Didn't they also do a patent app for Imdur? I remember we all talked about this back in 2018 or so. Some of us tried it to no avail.

I know there have been a few studies of Sildenafil over the years, but I can't remember the findings (which means they probably weren't too promising). But I have been wondering where it might fit into these findings.

 

[Wonko]

In 2018 I tried various NO supplements for several months, based partially upon the 2013/14 paper, with the aim of increasing vascular responsiveness.

There was a subjective improvement, small but there. At the level I operate at most of the time any improvement no matter how small can make a big difference in how much I can accomplish.

It was discontinued because of cost, the effort involved, and because it wasn't portable, in order to get the dosages I needed to have a effect I had to use powders mixed into shakes, quite a lot, in low sugar liquid, as I was getting through 3 shakes a day, and I'm diabetic, the sugar/carb components had an impact on their own.

But, sustained positive effect, for me, yes, just quite marginal, and after a while the sort of thing only noticed once it fades.

 

[kilfinnan]

Has anyone tried this? Is it safe to use?

I have a spray. I've tried it on a number of occasions hen feeling awful. It made no difference apart from a slight headache. That's obviously just my experience. On the other hand using an oxygen commentator 90 mins a day has changed my life.

 

[ukxmrv]

Has anyone tried this? Is it safe to use?

I think this is the same drug used in POTS tests?

During the Tilt Table test NTG is sometimes administered. Not sure how frequent this is as I have had the TTT with and without.

My expertise a TTT was that my BP went down and my HR up with NTG. I became very nauseous and faint. It felt the same for me as a bad POTS attack in hot weather.

 

[hinterland]

Would grape seed extract (GSE) be worth trying? This quote below is from marketing literature so apologies for that, but gives you the idea - in animal models GSE activated the enzyme (eNOS) that produces nitric oxide. The information is focused on blood pressure regulation but seems there is scope for broader effects.

I tried this GSE product a few years ago and noticed an increase in physical stamina that was meaningful - I was able to be more active physically without having to pace so carefully, but no improvement in cognitive function or flu-like symptoms so my functioning was still limited by that. After several months the GSE seemed to become less effective so I stopped taking it.

Mechanism of Action Edirisinghe I, Burton-Freeman B, Tissa Kappagoda C. Clin Sci (Lond). 2008; 114:331-7.
How does MegaNatural® -BP work?
Research using animal models indicates that it activates the enzyme nitric oxide synthase (eNOS) to produce nitric oxide (NO). NO is a gaseous compound that acts as a cellular messenger. When NO is present in the inner lining of the blood vessels, known as the endothelium, it causes the surrounding smooth muscle to relax. This endotheliumdependent relaxation of the blood vessels then supports healthy blood flow.

 

[SNT Gatchaman]

Haven't read, but various trials of grape seed extract in this context referenced in The impact of grape seed extract treatment on blood pressure changes: A meta-analysis of 16 randomized controlled trials (2021).

European Food Safety Agency published MegaNatural®-BP grape seed extract and maintenance of normal blood pressure: evaluation of a health claim pursuant to Article 13(5) of Regulation (EC) No 1924/2006 (2021). Concluding —

The evidence provided did not establish a plausible mechanism by which the food could exert the claimed effect in vivo in humans. The evidence provided is insufficient to establish a cause and effect relationship between the consumption of MegaNatural®-BP and maintenance of normal blood pressure.

 

[Simon M]

Comment — does endothelial dysfunction play an important role in the illness?

If replication shows that endothelial dysfunction is the norm in ME/CFS, that will be quite something. I'm not aware of any other objective markers linked to the illness.

The bigger question, though, is whether or not the findings matter – is endothelial dysfunction a cause of either the illness or its symptoms?

If endothelial dysfunction is driving this illness, it would be expected to correlate with illness severity, and the study looked for just that. (The analysis was restricted to measures taken at the start of the study.) 

Correlation between FMD/PORH and measures of severity.

1. Overall severity.
FMD : There was a correlation that fell severity just outside significance, p = 0.051.
PORH: None (P = 0.15, which might very generously be described as “marginal significance”).

2. Steps per 24 hours.

FMD: This is the one statistically significant coronation. Figure 2B gives this as r = 0.33, p = 0.042. (Oddly, the text reports this as a slightly bigger effect: r = 0.39, p = 0.014).

PORH: none (P = 0.29).

3. SF 36 physical function scale.
There was no correlation for either FMD or PORH (P = 0.53, P = 0.46)

How much weight should we put on these findings?

So, that’s one statistically significant findings (PORH steps in 24 hours), one marginal finding (overall severity and FMD) and one non-significant finding (overall severity and PORH) that could very generously just be described as marginal .

It's possible that both FMD and PORH do indeed correlate with severity measures, and these "true" effects were missed because of measurement issues and/or a small size of the study, meaning it lacks the statistical power to find some true associations.

On the other hand, if endothelial dysfunction is really driving the illness, then we should expect a strong association with severity measures, and a study of even this size should probably pick that up.

However, I think there is a bigger concern. The idea is that endothelial dysfunction means not enough oxygen gets to tissues and that's why people with ME don't have enough energy. Specifically, without enough oxygen, the body can't burn fuel efficiently and produces lactate as a result.

Unfortunately, the evidence of people with ME producing more lactate is weak at best.

Some single maximum studies find a small increase in lactate in patients versus controls, while other studies fail to find it. Crucially, the CDC multi – site study (Dane Cook, can't find the reference) found no difference in lactate levels between patients and controls when they were matched on (metabolic) fitness. That doesn't really fit with endothelial dysfunction/insufficient bloodflow being a major issue.

The conclusion of the study restricts itself to claiming that endothelial dysfunction is part of the clinical presentation of this disease, and I think that’s fair.

However, I don’t think the date yet justifies the assertion in the discussion that the findings are clinically important.

But the data is intriguing. As the authors say, we need a lot more research in this area.