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

[SNT Gatchaman]

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

 

[Sean]

There was no significant correlation between FMD and PORH.

That is interesting.

 

[hibiscuswahine]

Very interesting, thanks for sharing.

Another brick in the wall for the vascular theory for ME/CFS ….

now wondering how that might have flow on (pun) effects on the cardiovascular and neural control, both centrally and peripherally,

And the microcirculation at tissue level…..what is happening to the endothelium….lots of options….

 

[JemPD]

If anyone has energy to give a layman's summary of this, i for one would be very grateful. I know very little about vascular systems.

Am i right in thinking that we already know this was a high quality study from previous reporting of the negative ritux results..?
so we can treat these results as reliable?

 

[SNT Gatchaman]

We measured [flow mediated dilation] in 12 ME/CFS patients in 2014 and found that 10 out of 12 patients had low FMD values (in 5 out of 12 < 2%, median value 2.8%) compared to previous studies on healthy subjects in appropriate age groups. All ME/CFS patients had normal dilation responses after administration of sublingual glyceryl nitrate. This led us to suspect that reduced availability of endothelial-cell derived NO, with subsequent inadequate autoregulation of blood flow according to the metabolic demand of tissues, could be a symptom-causing mechanism for ME/CFS patients.

See
Decreased NO production in endothelial cells exposed to plasma from ME/CFS patients (2022)
Nitric oxide signalling in cardiovascular health and disease (2018)

Also
Nebivolol: an effective option against long-lasting dyspnoea following COVID-19 pneumonia - a pivotal double-blind, cross-over controlled study (2022)
Oxidative stress-induced endothelial dysfunction and decreased vascular nitric oxide in COVID-19 patients (2022)

 

[SNT Gatchaman]

If anyone has energy to give a layman's summary of this, i for one would be very grateful. I know very little about vascular systems.

Briefly, cos it's late here

They put an ultrasound probe on the upper arm, 5-10 cm above the elbow, looking at the brachial artery. They measure the vessel diameter at rest and following blowing up a blood pressure cuff on the forearm (enough to stop arterial blood flow below where the probe is). This should make the brachial artery above the temporary occlusion dilate up. Healthy controls do, ME/CFS don't (so much). Then repeated after a rest, with GTN spray under the tongue (as if for angina). This then makes ME/CFS artery dilate up as well as HC. This indicates that the artery is capable of dilating it's just not getting the right signal. Nitric oxide is thought to be that signal and GTN provides NO, so the assumption is that availability of NO is reduced in ME/CFS.

There's more, particularly on the small rather than large vessels, but that's a start.

Their concluding remarks are —

We think our findings of reduced endothelial function, both micro- and macrovascular, are of clinical importance. [...] Our study supports growing evidence that ME/CFS patients have a markedly reduced endothelial function compared to the normal population. This is an important discovery in a field with a scarcity of objective and measurable abnormalities.

Our study does not answer the question of why these patients have reduced endothelial function. Reduced endothelial function might be an associated symptom rather than a central mechanism of the disease. However, we suspect that in ME/CFS the endothelial dysfunction is related to an abnormal immune response, and may be a factor in the pathomechanism.

 

[Hoopoe]

I'm seeing some symptom improvement by immersing feet or better the body in cool water. It appear to trigger a beneficial response in the body. Nothing major but it seems a clear enough hint that my vascular function is not ideal and positively influenced by this stimulus.

 

[JemPD]

Briefly, cos it's late here

They put an ultrasound probe on the upper arm, 5-10 cm above the elbow, looking at the brachial artery. They measure the vessel diameter at rest and following blowing up a blood pressure cuff on the forearm (enough to stop arterial blood flow below where the probe is). This should make the brachial artery above the occlusion dilate up. Healthy controls do, ME/CFS don't (so much). Then repeated after a rest, with GTN spray under the tongue (as if for angina). This then makes ME/CFS artery dilate up as well as HC. This indicates that the artery is capable of dilating its just not getting the right signal. Nitric oxide is thought to be that signal and GTN provides NO, so the assumption is that availability of NO is reduced in ME/CFS.

There's more, particularly on the small rather than large vessels, but that's a start.

Their concluding remarks are —

Thank you!

So this finding could be significant then?

 

[duncan]

"However, we suspect that in ME/CFS the endothelial dysfunction is related to an abnormal immune response...."

Why abnormal? Why not simply an immune response. There are several infections that can target endothelial cells, not the least of which is Covid:

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7172722/

 

[InitialConditions]

ME/CSF

[A little in-joke I have with myself...] Madness that no co-author, reviewer, editor, or typesetter caught this, especially as it's in the abstract.

 

[InitialConditions]

[A little in-joke I have with myself...] Madness that no co-author, reviewer, editor, or typesetter caught this, espeically as its in the abstract.

Also suprised to see this paper only had one reviewer. I don't think one reviewer is ever sufficient.

 

[Mij]

Why abnormal? Why not simply an immune response. There are several infections that can target endothelial cells, not the least of which is Covid:

It's definitely not ME/CFS or Covid immune response specific.

 

[Mij]

It was 22 years ago that I had an 'immune response' from taking immune modulators (Imunnovir) that reactivated HHV6 and EBV, it hit me suddenly one day but I didn't have time to assess what was occurring so I went out shopping. After a couple of hours my legs froze, stiffened and turned ice cold. I could no long walk and was stuck on a downtown street asking strangers for assistance.

 

[Robert 1973]

See
Decreased NO production in endothelial cells exposed to plasma from ME/CFS patients (2022)
Nitric oxide signalling in cardiovascular health and disease (2018)

Also
Nebivolol: an effective option against long-lasting dyspnoea following COVID-19 pneumonia - a pivotal double-blind, cross-over controlled study (2022)
Oxidative stress-induced endothelial dysfunction and decreased vascular nitric oxide in COVID-19 patients (2022)

See also:

Peripheral endothelial dysfunction in myalgic encephalomyelitis/chronic fatigue syndrome, 2020, Scherbakov et al: https://www.s4me.info/threads/perip...fatigue-syndrome-2020-scherbakov-et-al.13992/

Altered endothelial dysfunction-related miRs in plasma from ME/CFS patients, 2021, Blauensteiner et al: https://www.s4me.info/threads/alter...-cfs-patients-2021-blauensteiner-et-al.20598/

Large and small artery endothelial dysfunction in chronic fatigue syndrome (2011): https://www.internationaljournalofcardiology.com/article/S0167-5273(11)01904-8/fulltext

 

[John Mac]

https://me-pedia.org/wiki/Endotheli...t=In 2021 a group of,other symptoms of ME/CFS.

 

[FMMM1]

"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."

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? Are migraines more common in people with ME/CFS? Part of the DecodeME questionnaire?

Also, perhaps the GWAS [Chris Ponting] study would pick this up i.e. if it were common?

Seem to recall that @Snowleopard had an interest in endothelial [dys]function - correct?

 

[Robert 1973]

See also:

Peripheral endothelial dysfunction in myalgic encephalomyelitis/chronic fatigue syndrome, 2020, Scherbakov et al: https://www.s4me.info/threads/perip...fatigue-syndrome-2020-scherbakov-et-al.13992/

Altered endothelial dysfunction-related miRs in plasma from ME/CFS patients, 2021, Blauensteiner et al: https://www.s4me.info/threads/alter...-cfs-patients-2021-blauensteiner-et-al.20598/

Large and small artery endothelial dysfunction in chronic fatigue syndrome (2011): https://www.internationaljournalofcardiology.com/article/S0167-5273(11)01904-8/fulltext

Also:

Endothelial dysfunction in COVID-19: an overview of evidence, biomarkers, mechanisms and potential therapies (2022):
https://www.nature.com/articles/s41401-022-00998-0

Disappointing that it doesn’t seem to mention ME/CFS or any of the above studies (as far as I could see).

There is a thread here but no comments yet: https://www.s4me.info/threads/endot...-therapies-2022-suo-wen-xu.30062/#post-442557

 

[FMMM1]

I was thinking this comment might be described as devils advocate - could this be deconditioning? Strikes me that we need the results of the GWAS study i.e. since genes are hard wiring i.e. not affected by the environment/previous infections ----

EDIT - also if this is downstream consequence, then I guess we need upstream cause --- infection or whatever i.e. to treat --- GWAS may provide clues to cause!

 

[SNT Gatchaman]

could this be deconditioning?

Probably not.

From Vascular and Microvascular Dysfunction Induced by Microgravity and Its Analogs in Humans: Mechanisms and Countermeasures (2020, Front Physiol) —

Physical Inactivity and the Reactivity of Conduit Arteries
At the leg level, brief inactivity, such as that induced by a few hours of sitting, decreases endothelium-dependent vasodilation capacity as estimated by flow mediated dilation (FMD). Similarly, reducing daily physical activity by taking <5,000 steps/day decreases FMD response at the popliteal level, whereas basal popliteal diameter is unchanged. In both cases, intermittent application of maneuvers increasing blood flow, such as fidgeting or foot heating to 42◦C, preserves popliteal FMD. However, prolonged advanced inactivity does not change even increases FMD of leg arteries, which may be explained by inward remodeling of arterial vessels at the lower limb level.

Smooth muscle vasodilator functions of large arteries are not impaired and may be enhanced after physical inactivity. At the brachial level, no significant changes in sensitivity to nitric oxide (NO) are observed after 5, 7, 49, or 56 days of bed rest. Changes at the lower limb level are less homogenous. Vasodilation in response to nitroglycerin is unmodified after 25 days of horizontal bed rest or 56 days of HDBR, tends to increase after 49 days of HDBR and increases after 28 days of unilateral lower limb suspension or 52 days of horizontal bed rest.

As for inflight reactivity of large arteries, endothelium-dependent and –independent vasodilation at brachial artery level is not substantially modified with long-term flight, while brachial diameter is unchanged (n = 13, measurements at d15, d60, d160).

Referencing earlier works:
Enhanced flow-dependent vasodilatation after bed rest, a possible mechanism for orthostatic intolerance in humans (2001, Eur J Appl Physiol)
Preserved contribution of nitric oxide to baseline vascular tone in deconditioned human skeletal muscle (2005, J Physiol)

 

[ME/CFS Skeptic]

Interesting findings but it was rather disappointing that the abnormalities did not correlate well with disease severity measures. This make it hard to argue that these abnormalities are part of the core pathology of ME/CFS.