Endothelial Dysfunction in ME

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I've been researching the quality of lions mane beta glucans vs oat bran beta glucans thismorning as I've restarted lions mane beta glucans just in case they have higher NK cell effect than oat bran alone.

Thought to cross check NO increases from beta glucans and found a study about oat bran specifically which is often not the case. The results showed a big increase in NO levels following beta glucan intake. This might be another reason why Joshua's protocol can work for some - I'll be honest though the number of people that did his protocol who had CFS/ME was so low that I really don't think we can draw any conclusions. I am not talking about people on PR who did the protocol, I'm talking about the fact that Josh often included people with fatigue like symptoms who didn't have ME and they improved...making any assertions about his protocol's usefulness for ME completely redundant.

Anyway paper here: https://www.hindawi.com/journals/bmri/2014/481904/

and extract:

Introduction. Oats are high in soluble fibers and effective in reducing the risk of cardiovascular diseases (CVD). We assessed the effects of beta-glucan from oat bran on serum nitric oxide (NO) endothelial function in patients with hypercholesterolemia. Method. Sixty hypercholesterolemic patients were randomly divided to receive an experimental bread rich in beta-glucan from oat bran (intervention) or bread rich in wheat fiber (control) for four weeks. All subjects had the same diet for two-week baseline period and hypocaloric diet for four weeks of intervention. Serum NO concentration and flow-mediated dilation (FMD) were determined before and after the experiment. Results. Mean age of the participants was 51.1 ± 9.3 years and 65% () were female. After intervention, serum NO concentration increased by 50.2 ± 19.8 μmol/lit in the intervention group (), but no change was observed in the control group (17.5 ± 27.5 μmol/lit; ). No change of FMD was observed in the intervention (0.48 ± 0.78%; ) or in the control group (0.59 ± 0.92%; ). Conclusion. Consumption of oat bread for four weeks increases serum NO concentration but has no effect on FMD. Further studies are warranted in this regard.
Whilst I am sure that without adequate interferon levels (if even for a very brief time) the viruses just continue to grow, maybe the oat bran can at least dampen the viruses by increasing NO levels quite a lot?

One of the things I love about oat bran is it's like £2 for a 4 month supply. I only take a tablespoon in the AM, it certainly makes you feel worse for a few weeks, but that subsides and you do get some anti-PEM, anti-fatigue benefits later on.
 

Wishful

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I haven't noticed any benefit from oats, or even significant quantities of oat bran. I'd put the NO hypotheses as 'might apply to a subset of PWME'.
 
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Main points:
  • In this study, the authors found that when blood from a certain set of ME patients was added to regular endothelial cells (EC) in vitro, the endothelial cells had a harder time producing nitric oxide (NO), which is representative of one type of endothelial dysfunction.
  • This finding suggests that one type of endothelial dysfunction found in ME, where endothelial cells fail to release sufficient nitric oxide when necessary, may be due to either something in the blood or something lacking from the blood, but not necessarily any problem with the endothelial cells themselves.
Very interresting, any speculations what could cause this?
 

Pyrrhus

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some of the methods that are used to measure ED (such as FMD and peripheral arterial tonometry) involve measuring the change in blood flow to the arm after deliberately occluding forearm blood flow. This is possibly done with a cuff similar to what is used in a BP monitor machine.

Wouldn’t these measurements be compromised if there was a structural cause that was preventing normal blood flow to the arm? Thoracic Outlet Syndrome involves compression of the subclavian artery by the scalene muscles and the first rib. This lowers blood flow to the arm causing symptoms like cold hands.
That's certainly a very interesting question, thanks for sharing that.

To throw a wrench in the works, we can consider whether the Thoracic Outlet Syndrome might be related to a lack of vascular collagen, and ask:

What would be the effect on the different types of endothelial dysfunction if there is a lack of vascular collagen?


Very interresting, any speculations what could cause this?
My best guess is that the blood is missing one or more key nutrients needed by endothelial cells.
 

SWAlexander

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New Article.

An X-Factor in the Blood May Be Impairing Blood Vessel Functioning in ME/CFS

Excerpt:
Then there are the endothelial cells. These cells lining the blood vessels are responsible for opening them up to allow for more blood flows and also play a role in inflammation and coagulation, and have received increasing interest in ME/CFS, fibromyalgia, and long COVID. At least three recent studies have found evidence of endothelial cell dysfunction in ME/CFS, and several suggest it is present in FM, and/or long COVID. Bruce Patterson’s long COVID treatment plan, for instance, is focused on preventing immune cells from reacting with the endothelial cells lining the blood vessels.

The findings support the intriguing idea that a mystery factor in the blood is interfering with the ability of the endothelial cells to open up the blood vessels and move blood, oxygen, and nutrients to the muscles, brain, etc. Six years after independent labs using different methods came up with the x-factor idea, we still, however, don’t know what it is.
Continue: https://www.healthrising.org/blog/2022/02/11/x-factor-blood-vessel-chronic-fatigue-endothelial/

My comments: to me, these preliminary findings go in a direction which is known as ALD, an X-linked factor VLCFA (very-long-chain-fatty acid).
 

SWAlexander

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ALD seems to be primarily a fatal children's disease that destroys the myelin sheath. Has any ME research turned up myelin damage?
I know some female adults who have it, but less serve. Males can have a real problem depending on the high phytanic acid results. In any case, diet has a big influence. No food should be consumed that comes from animals with a ruminant.
 

Pyrrhus

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New article:

Endothelial dysfunction and altered endothelial biomarkers in patients with post-COVID-19 syndrome and chronic fatigue syndrome (ME/CFS) (Haffke et al., 2022)
https://forums.phoenixrising.me/thr...onic-fatigue-syndrom-haffke-et-al-2022.87340/

From the article:
Fatigue, exertion intolerance and post-exertional malaise are among the most frequent symptoms of Post-COVID Syndrome (PCS), with a subset of patients fulfilling criteria for Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS). As SARS-CoV-2 infects endothelial cells, causing endotheliitis and damaging the endothelium, we investigated endothelial dysfunction (ED) and endothelial biomarkers in patients with PCS.
Peripheral endothelial function was assessed by the reactive hyperaemia index (RHI) using peripheral arterial tonometry (PAT) in patients and [healthy controls (HCs)].
Five of the 14 post-COVID ME/CFS patients and five of the 16 PCS patients showed ED defined by a diminished RHI (< 1.67), but none of HCs exhibited this finding.
 

halcyon

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The last sentence in that quote is interesting: it indicates that blood hemoglobin is a great scavenger of nitric oxide, so that even when you locally introduce NO into the lungs, the NO does not spread to other parts of the body. So it's effects remain local.
This is an interesting function of RBCs that I had never considered, but just came across recently looking at Ross Richards' work. In addition to their main function, RBCs can effectively be thought of as a disposable extra tissue sink for free radicals in order to draw damage away from other tissues (Richards et al., 1998; Hattangadi & Lodish, 2007). The downside of this is that they lack the ability to repair themselves, and taking a hit for the team causes alterations in their membranes which can lead to deformability issues.
 
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Quote from the recent westermeister paper posted earlier in this thread by Pyrrhus.
[...]
Finally, inhibitory eNOS phosphorylation at Thr495 was higher in HUVECs treated with ME/CFS-plasma compared to the same treatment with HC-plasma.

In conclusion, this study in vitro shows a decreased NO production in HUVECs exposed to plasma from ME/CFS patients, suggesting an unreported role of eNOS in the pathophysiology of this disease.
Could this phosphorylation at Thr495 be because the body is struggeling to maintain blood pressure? So it wont allow much NO production since it causes vasodilation.

I think there was a study that found reduced blood pressure variability in me/cfs.

Also iirc Wirth&Scheibenbogen wrote in one of their hypothesis papers that they strongly suspect that there is some ion channel dysfunction in mecfs. I cant remember exactly which one but i think it was the proton-sodium pump or the sodium-potassium pump.
 

SNT Gatchaman

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Could this phosphorylation at Thr495 be because the body is struggeling to maintain blood pressure? So it wont allow much NO production since it causes vasodilation.
Not sure. I did make a mental connection to the abnormally phosphorylated ATG13 affecting iNOS in microglia. I would be interested to see if the pATG13 abnormally affected HUVECs and eNOS production.

NO metabolism looks pretty complex to me, doing opposing things in different tissues and acting at short range and duration. I think it's: abnormal production of and/or response to NO that leads to failure of cardiovascular homeostasis, BBB integrity etc.

Here's the initial figure from the review article —

1655591180506.png

Figure 1
NOS–NO signalling in cardiovascular tissues. In the vessel wall, nitric oxide (NO) synthesis by endothelial nitric oxide synthase (eNOS) in endothelial cells regulates vascular smooth muscle cell (VSMC) relaxation, mediates angiogenesis, inhibits VSMC proliferation, and through its diffusion to the vessel lumen inhibits platelet aggregation and thrombosis. S-nitrosylation of haemoglobin and/or reduction of nitrites (NO2−) by deoxyhaemoglobin promotes NO release and subsequent NO-mediated relaxation in hypoxic tissues. Diffusion and bioavailability of NO in VSMCs are regulated by haemoglobin-α (Hb-α) at the myoendothelial junction and by cytoglobin (CYGB) in muscle cells. Synthesis of NO by neuronal nitric oxide synthase (nNOS) within VSMCs also contributes to regulate vascular tone. In cardiac myocytes, autocrine and paracrine effects of NO from eNOS and nNOS modulate cardiac contractility through regulation of excitation–contraction coupling (including in response to stretch and β1-adrenergic stimulation), relaxation, and mitochondrial respiration. nNOS expression in cardiac nerves and postsynaptic eNOS modulate the ortho–parasympathetic balance towards reinforced parasympathetic (vagal) transmission leading to reduced heart rate.

β1, adrenergic receptor β1; ACh, acetylcholine; m2, muscarinic acetylcholine receptor m2; NA, noradrenaline; SNO, S-nitrosothiol; SR, sarcoplasmic reticulum; T-tubule, transverse-tubule.
 
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Quote from the recent westermeister paper posted earlier in this thread by Pyrrhus.


Could this phosphorylation at Thr495 be because the body is struggeling to maintain blood pressure? So it wont allow much NO production since it causes vasodilation.
This experiment is in test tubes so the actions of those cells in terms of processing extra eNOS is triggered by something in the plasma rather than any other conditions that apply to them. But if you mean, could the thing in the me/cfs plasma be a signalling molecule telling the endothelium to process that eNOS before it creates vasodilation, then perhaps!

I speculated the other day that possibly one way a virus survives undetected in the peripheral tissues of a human body is by hijacking the bloodflow system to suit its needs and prevent immune cells (which are large) from accessing the peripheral tissues (where they are served by small vessels). This is pure speculation but if that *was* the case the removal of that signalling molecule might improve the chances of the immune system accessing the furthest reaches and reducing viral reservoirs.

I was inspried in this theory by an illustration I saw that showed mec/fs blood flow sort of short-circuiting and going back to the heart before it got to the deepest reaches of the body. I think it was a graphic taken from work by David Systrom perhaps? I wish I could find that illustration again, or be reminded of the right technical terms that would permit me to google it up again and re-read the paper it comes from.
 
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This experiment is in test tubes so the actions of those cells in terms of processing extra eNOS is triggered by something in the plasma rather than any other conditions that apply to them. But if you mean, could the thing in the me/cfs plasma be a signalling molecule telling the endothelium to process that eNOS before it creates vasodilation, then perhaps!
Yep, im thinking there is something in the plasma that signals to inhibit the enzyme.

I speculated the other day that possibly one way a virus survives undetected in the peripheral tissues of a human body is by hijacking the bloodflow system to suit its needs and prevent immune cells (which are large) from accessing the peripheral tissues (where they are served by small vessels). This is pure speculation but if that *was* the case the removal of that signalling molecule might improve the chances of the immune system accessing the furthest reaches and reducing viral reservoirs.
Thats a nice theory, fits very well in here. Probably a long shot though like everything else at this point.

I was inspried in this theory by an illustration I saw that showed mec/fs blood flow sort of short-circuiting and going back to the heart before it got to the deepest reaches of the body. I think it was a graphic taken from work by David Systrom perhaps? I wish I could find that illustration again, or be reminded of the right technical terms that would permit me to google it up again and re-read the paper it comes from.
Do you mean arterio-venous shunting? Where the capillaries are omittet because the blood somehow found a less resistant path. I also think it was Systrom talking about this...
 

Pyrrhus

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New paper:

Serum of Post-COVID-19 Syndrome Patients with or without ME/CFS Differentially Affects Endothelial Cell Function In Vitro (Flaskamp et al, 2022)
https://forums.phoenixrising.me/thr...-function-in-vitro-flaskamp-et-al-2022.88309/

A proportion of COVID-19 reconvalescent patients develop post-COVID-19 syndrome (PCS) including a subgroup fulfilling diagnostic criteria of Myalgic encephalomyelitis/Chronic Fatigue Syndrome (PCS/CFS). Recently, endothelial dysfunction (ED) has been demonstrated in these patients, but the mechanisms remain elusive.

Therefore, we investigated the effects of patients’ sera on endothelia cells (ECs) in vitro. PCS (n = 17), PCS/CFS (n = 13), and healthy controls (HC, n = 14) were screened for serum anti-endothelial cell autoantibodies (AECAs) and dysregulated cytokines. Serum-treated ECs were analysed for the induction of activation markers and the release of small molecules by flow cytometry. Moreover, the angiogenic potential of sera was measured in a tube formation assay.

While only marginal differences between patient groups were observed for serum cytokines, AECA binding to ECs was significantly increased in PCS/CFS patients.

Surprisingly, PCS and PCS/CFS sera reduced surface levels of several EC activation markers.

PCS sera enhanced the release of molecules associated with vascular remodelling and significantly promoted angiogenesis in vitro compared to the PCS/CFS and HC groups.

Additionally, sera from both patient cohorts induced the release of molecules involved in inhibition of nitric oxide-mediated endothelial relaxation.

Overall, PCS and PCS/CFS patients′ sera differed in their AECA content and their functional effects on ECs, i.e., secretion profiles and angiogenic potential. We hypothesise a pro-angiogenic effect of PCS sera as a compensatory mechanism to ED which is absent in PCS/CFS patients.
(emphasis and spacing added)