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

"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."

Thanks for pointing that out - haven't looked carefully at the paper - could it be due to heterogeneity i.e. not a single pathology?

EDIT - "There was a near-significant association between FMD [Flow-mediated dilation] at baseline and disease severity assessed as mild/moderate versus moderate versus moderate/severe (p for trend = 0.051, Fig 2, panel A), but no significant correlations between FMD and either SF-36 Physical Function (p = 0.60, panel B) or steps per 24 hours (p = 0.22, panel C)."
"SF-36 Physical Function" I'd discount [subjective - questionnaire]
"steps per 24 hours" - measured by?

 

If the endothelial dysfunction that they found was part of the core pathology of ME/CFS, I would expect a correlation with the SF-36 physical function.

 

The lack of correlation with severity could be done to multiple factors, individual to the patient, and independent of ME

These factors may not even meet the threshold of treatable or detectable cardiovascular disease to researchers but the scientific process continues.

But this vascular theory may explain the continuum of orthostatic intolerance, orthostatic hypotension and maybe POTS, but that is still unknown.

The problem is we also we do not have physiological data on more severe patients, because them through this testing would be ethically unsound.

Returning to endothelial function, we do need to understand the exact pathological mechanism to this, to use a medication (otherwise it could be unsafe and harmful playing around with a pwME’s homeostatic mechanisms of cardiovascular control (neurological and hormonally related).

Also with people after long periods of severity, there could be additional alterations in many parameters that affect cardiovascular health, especially if their musculature has wasted away as our movement of muscles helps with blood flow and organ function.

If there is widespread damage to endothelial function, this could have many ramifications, firstly locally at tissue level. Feedback systems back to the regulatory centres in the brain could be getting the wrong information about micro and macrovascular status and adjusting the autonomic system in response which has a myriad of physiological effects and subsequent symptom production.

If the endothelium is not functioning properly it may affect tissues in the neurological system (in the brain, homeostatic feedback loops within the brain, in regulatory nerves and peripheral nerves, but especially cardiovascular control via the sympathetic/parasympathetic nervous system. (And then there is cardiac tissue itself and basically any tissue including the endothelium because they have a microcirculation themselves maintaining their function.)

All gets pretty complex and much is still largely unknown (because of lack of research, but quite a few studies show what main organ systems are working, for most people, and what is not, once other illnesses are excluded (and there are many and they are often missed) but this vascular theory does give some explanation of the variety of symptoms pwME have.

 

To add a small anecdote about blood perfusion and cold water. Today, 4 hours after cold water immersion my feet are still feeling different and well perfused. It was about 5 repetitions of immersing my feet up to the knees into about 12 °C water for 30-60 seconds, with small pauses inbetween because the cold begins hurting.

If exercise as method for improving vascular health is not possible or only to a limited degree, maybe this sort of thing is an alternative.

 

So you're arguing that mild patients were in worse PEM during the test compared to the more severe ME/CFS patients? I doubt that would have such a big influence because for severe patients a trip to the doctor is also extremely taxing even if they don't have to do any physical activity to get there.

Anyway, I wouldn't dismiss the results because of the lack of correlation with sf-36 and other disability measures but IMHO it does make it less plausible that it is a significant finding.

 

Contrast this with the finding of reduced cerebral blood flow in ME/LC on tilt table.

Furthermore they later found similar degrees of CBF reduction in severe patients with a sitting, rather than standing provocation (as in mild/moderate ME).

I agree. The measurements shown by this technique at this interrogation site may be only reflecting part of the endothelial dysfunction story, and are a proxy for reduced NO availability, which might have a different effect size around the vasculature. Probably influenced by my subjective self-observations, I'm keen on the idea of endothelial dysfunction as a core part of the disease, though downstream of eg immune dysregulation.

Probably there wouldn't be a good correlation between the reduced flow-mediated dilation in the upper limbs of this study and the reduced cerebral blood flow in head/neck of the van Campen, Rowe and Visser studies.

For more detail on the technique of Flow-Mediated Dilation, see —

Expert consensus and evidence-based recommendations for the assessment of flow-mediated dilation in humans (2019, Eur Heart J).

 

Thanks very much for your summary. I found this diagram in an image search (ref). I think this is what Sandvik et al did, isn't it? Helps to see the visual representation.

 

See also the relationship between PDE10A, NO signalling and vascular tone control, with a rare potentially ME/CFS-related SNP found in males only, via GWAS.

ETA: Per Chris Ponting's post, "the male PDE10A signal did not replicate" via 23andMe's data (DecodeME data awaited).

 

Uninformed question, but I’m just wondering if there is enough data on genes which are associated with NO production/release to make it worth looking at the UK Biobank data to see there is any correlation with self-reported CFS?

 

Falling to my knees (or worse falls) from orthostatic hypotension was also present relatively early, although I don't remember any such events in the first year. Mild orthostatic hypotension is considered normal in my family so that I can't remember such events in the first year might just mean it was considered normal.

 

I think it's pretty well established on this site that I'm no medical expert. But as a lay-man my question with regards to severity would be, couldn't it simply be that this is causative but the downstream effects build up over time or in some cases very quickly making someone severe?

If I could make an analogy of water carving through rock, the initial stream might be the same but it would carve out more and more of the rock as the water would keep on streaming through. In a similar sense, the longer the process described by the researchers occurs the more severe your symptoms become? Or that some people are more susceptible to it's effects making them severe quickly?

 

I sometimes think we worry too much about deconditioning being the reason for abnormal results. I did not do much sports while I was still well enough to leave the house, but I was up and down stairs, shopping, cleaning, walking briskly for at least an hour a day. Didn't know about ME or PEM so I had the odd day in bed and felt bad every night but I was fit.

If someone is still managing to leave the house I would think they would be best classed as sedentary and that is what they try to get in controls.

The people in most trials are not severe as it is too hard for them to do it so that is not the image we should have. Just a thought.

It is the BPS who keep going on about us being deconditioned.

 

In my case it was the same. When I got sich I was professional football player. After getting pneumonie (possibly mononucleosis) I have never recovered. I got immediately muscle weakness, felt strong lactic acid accumulation like never before, trembling of muscles, higher heart rate...this couldnt be explaining by decondition.

 

See also this thread: Vericiguat [drug for heart failure mentioned by Prof Schiebenbogen]

Potentiates soluble guanylate cyclase in the NO-sGC-cGMP pathway in vascular smooth muscle cells.

 

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.