Reduced endothelial function in ME/CFS - results from open-label cyclophosphamide intervention study Fluge & Mella 2021

John Mac

John Mac

Senior Member (Voting Rights)
Full title:
Reduced endothelial function in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome - results from open-label cyclophosphamide intervention study

Provisionally accepted

Abstract

Introduction
Patients with myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) present with a range of symptoms including post-exertional malaise (PEM), orthostatic intolerance and autonomic dysfunction.
Dysfunction of the blood vessel endothelium could be an underlying biological mechanism, resulting in inability to fine-tune regulation of blood flow according to the metabolic demands of tissues.
The objectives of the present study were to investigate endothelial function in ME/CFS patients compared to healthy individuals, and assess possible changes in endothelial function after intervention with IV cyclophosphamide.

Methods
This substudy to the open-label phase II trial “Cyclophosphamide in ME/CFS” included 40 patients with mild-moderate to severe ME/CFS according to Canadian consensus criteria, aged 18-65 years.
Endothelial function was measured by Flow-mediated dilation (FMD) and Post-occlusive reactive hyperemia (PORH) at baseline and repeated after 12 months.
Endothelial function at baseline was compared with two cohorts of healthy controls (N=66 and N=30) from previous studies.
Changes in endothelial function after 12 months were assessed and correlated with clinical response to cyclophosphamide.
Biological markers for endothelial function were measured in serum at baseline and compared with healthy controls (N=30).

Results
Baseline FMD was significantly reduced in patients (median FMD 5.9%, range 0.5-13.1, n=35) compared to healthy individuals (median FMD 7.7%, range 0.7-21, n=66) (p=0.005), as was PORH with patient score median 1331 p.u. (range 343-4334) versus healthy individuals 1886 p.u. (range 808-8158) (p=0.003).
No significant associations were found between clinical response to cyclophosphamide intervention (reported in 55 % of patients) and changes in FMD/PORH from baseline to 12 months.
Serum levels of metabolites associated with endothelial dysfunction showed no significant differences between ME/CFS patients and healthy controls.

Conclusions
Patients with ME/CFS had reduced endothelial function affecting both large and small vessels compared to healthy controls.
Changes in endothelial function did not follow clinical responses during follow-up after cyclophosphamide IV intervention.
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https://www.frontiersin.org/articles/10.3389/fmed.2021.642710/abstract
 
Jaybee00 said:
Maybe doesn’t provoke symptoms because it might be a minor component relative to other bigger factors that are treated by cyclophosphamide.
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Yep thats what im thinking. Still seems kinda weird to me as i would expext systematic reduced endothelial function to affect functioning level. Im no expert on the values found in the studies compared to healthy values though, but after rituxME and the high amount of placebo im open to the possibility that the reduced endothelial function is in fact causing reduced function, and that the responders are in fact still sick. Just playing devils advocate here
 
Marky said:
Im no expert on the values found in the studies compared to healthy values though, but after rituxME and the high amount of placebo im open to the possibility that the reduced endothelial function is in fact causing reduced function, and that the responders are in fact still sick.
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There's also the fact that clinical response doesn't necessarily equal recovery. We don't know the extent and nature of the response, but as with most drugs, it would be very surprising if it were remission of all symptoms.

The fact that PWME often have demonstrable cardiovascular irregularities (hypotension, low blood volume, POTs), together with the symptom profile of ME (brain fog, muscle function problems) suggests that something is amiss in this area, irrespective of whether it's causal or a downstream effect. Endothelial dysfunction needs to be ruled out, for sure.
 
MeSci said:
Would this explain the swelling of blood vessels when the hands are lowered in contrast to when they are raised?
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I guess, to me that is something that comes and goes.

Endothelial dysfunction is also associated with metabolic syndrome, diabetes, cardiovascular disease ++. Oxidative stress can be a problem, and the metabolomics study a few years ago found higher levels of free heme (pro-oxidant) in the ME/CFS group than controls. I also remember someone looking at levels of reduced vitamin C, but I don't remember details, I think there might have been <10 patients diagnosed with Fukuda.

Blood vessel dilation can be influence by diet (nitrate and/or arginine rich foods), and of course diet is an important source of antioxidants. Whole foods dietary patterns are associated with improved endothelial function in studies on heart diseases.
 
For example:
Circadian clocks and vascular function
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2848505/
The existence of a circadian rhythm in the function of human blood vessels has long been recognized
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Flow-mediated dilation of brachial artery, a widely used clinical index of endothelial function, displays diurnal variation when examined in healthy young men.
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So perhaps the patients were sampled at a different time of day than the controls. And/or the patients might have, on average, a delayed daily schedule compared to controls. That might have affected measures of endothelial function.
 
So could reduced FMD result in hypertension and/or possibly low blood volume, simply because the blood vessels are too constricted? Are all blood vessels affected, or just those of a certain size?

I don't know this to be true, but, if constricted blood vessels were to reduce blood volume, might you see effects usually associated with hypotension because of the lower amount of blood circulating (even though the pressure might look normal or even high)?

I recall Dr. Bell recounting the story of a patient with ME symptoms who came to him with very high blood pressure. I forget what made Dr. Bell suspect low blood volume, but he very carefully gave this patient an infusion of saline, which would normally be counter-intuitive (to say the least). The patient quickly felt better (I forget what happened to his BP, but Dr. Bell was monitoring it closely). Unfortunately, the improvement was not long lasting, as the saline was excreted in a matter of hours. I recall this being the case with blood transfusions also, but you obviously can't take repeated blood transfusions for such a transitory effect.
 
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I can't remember the exact details, but a retired doctor contacted Dr Bell and said that he had worked years before with patients who had low blood volume and their symptoms were very similar to how he described ME. They did some work together and found that people with ME did indeed have low blood volume. One of his newsletters said that some of his patients had blood volumes lower than that which caused the death of Princess Diana.

Because of these results he trialled giving volunteers saline solution to restore volume. The results were very good but did not last long. They had to have infusions every week. It was impossible to run trials because saline is normally used as a control of other treatments and people found their stents became infected so they had to stop. one woman was a lawyer who was able to work if she had the saline and she carried on much longer than anyone else but eventually even she had to stop.

It was a very promising finding but Dr Bell retired and the other doctor had been elderly when they started. Another ME finding that faded away.
 
I posted this on another thread about 3 years ago. It's a 2009 study that found that the low cardiac output seen in severe CFS patients was likely the result of low blood volume (which had been determined by measuring the dilution of injected radioactive markers). Nancy Klimas was one of the authors.


[University of Miami - 2009]

Clin Sci (Lond). 2009 Oct 19;118(2):125-35. doi: 10.1042/CS20090055.
Chronic fatigue syndrome: illness severity, sedentary lifestyle, blood volume and evidence of diminished cardiac function.
Hurwitz BE1, Coryell VT, Parker M, Martin P, Laperriere A, Klimas NG, Sfakianakis GN, Bilsker MS.

Abstract
The study examined whether deficits in cardiac output and blood volume in a CFS (chronic fatigue syndrome) cohort were present and linked to illness severity and sedentary lifestyle. Follow-up analyses assessed whether differences in cardiac output levels between CFS and control groups were corrected by controlling for cardiac contractility and TBV (total blood volume). The 146 participants were subdivided into two CFS groups based on symptom severity data, severe (n=30) and non-severe (n=26), and two healthy non-CFS control groups based on physical activity, sedentary (n=58) and non-sedentary (n=32). Controls were matched to CFS participants using age, gender, ethnicity and body mass. Echocardiographic measures indicated that the severe CFS participants had 10.2% lower cardiac volume (i.e. stroke index and end-diastolic volume) and 25.1% lower contractility (velocity of circumferential shortening corrected by heart rate) than the control groups. Dual tag blood volume assessments indicated that the CFS groups had lower TBV, PV (plasma volume) and RBCV (red blood cell volume) than control groups. Of the CFS subjects with a TBV deficit (i.e. > or = 8% below ideal levels), the mean+/-S.D. percentage deficit in TBV, PV and RBCV were -15.4+/-4.0, -13.2+/-5.0 and -19.1+/-6.3% respectively. Lower cardiac volume levels in CFS were substantially corrected by controlling for prevailing TBV deficits, but were not affected by controlling for cardiac contractility levels. Analyses indicated that the TBV deficit explained 91-94% of the group differences in cardiac volume indices. Group differences in cardiac structure were offsetting and, hence, no differences emerged for left ventricular mass index. Therefore the findings indicate that lower cardiac volume levels, displayed primarily by subjects with severe CFS, were not linked to diminished cardiac contractility levels, but were probably a consequence of a co-morbid hypovolaemic condition. Further study is needed to address the extent to which the cardiac and blood volume alterations in CFS have physiological and clinical significance.

https://www.ncbi.nlm.nih.gov/pubmed/19469714

[bolding mine]
 
The research team has written an article about this study for the Kavli Trust who has supported them financially over several years. The article is aimed at lay people.

For now it's only in Norwegian version, but the Kavli Trust often translates articles into English, so let's hope they'll do it this time as well.
Until then, there's Google translation..

Ny studie viser nedsatt evne til regulering av blodomløpet hos pasienter med ME/CFS
google translation: New study shows impaired ability to regulate blood circulation in patients with ME/CFS

Quote:

This study therefore concludes that there is an association between ME / CFS and reduced endothelial function, but that we can not see any direct correlation between endothelial function and the individual patient's symptom pressure. Regulation of blood circulation is a complex process, and we still have a lot to learn about circulatory disorders in ME / CFS and how they affect patients' symptoms.
 
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