Endothelial Dysfunction in ME

[Pyrrhus]

I thought I'd start a thread to summarize discussions about the different types of endothelial dysfunction that might be found in ME. Please feel free to add to this thread as needed.

What is "Endothelial Dysfunction"?

Blood vessels are enclosed by a layer of cells called endothelial cells, which are similar to a layer of skin surrounding a blood vessel. These endothelial cells are themselves surrounded by a layer of muscle tissue. The muscle tissue can squeeze the endothelial cells, constricting the blood vessel, or they can relax, allowing the blood vessel to dilate. This muscle tissue is generally controlled by autonomic nerves. Any dysfunction in the constriction or dilation of a blood vessel might be referred to as "endothelial dysfunction".

​

There are at least three different types of endothelial dysfunction that might occur in ME:

1. The autonomic nerves that control the muscle tissue can fail to constrict or dilate the blood vessel when necessary. This is a form of dysautonomia.
2. The endothelial cells can fail to release nitric oxide (NO) when necessary, which is a way that the endothelial cells force the muscle tissue to relax, thereby dilating the blood vessel. (This is what is most commonly referred to when someone uses the term "endothelial dysfunction".)
3. Deposits can build up inside the blood vessel, coating the endothelial cells with a stiff plaque. In the case of arteries, this is called "arterial stiffness". This stiff plaque prevents the blood vessel from easily constricting or dilating.

 

[Pyrrhus]

Large and small artery endothelial dysfunction in chronic fatigue syndrome (Newton et al., 2012)
David J Newton, Gwen Kennedy, Kenneth K F Chan, Chim C Lang, Jill J F Belch, Faisel Khan

A letter to the editor describing a study that found endothelial dysfunction in ME:
https://forums.phoenixrising.me/thr...unction-in-cfs-newton-et-al-heart-risk.13617/

This study used two techniques to measure endothelial dysfunction:

• Flow-mediated dilation (FMD)
• Post-occlusive reactive hyperemia (PORH)

FMD appears to only measure the ability of arteries (not veins) to dilate in response to nitric oxide (not in response to autonomic nerves).

PORH is a broader measure of endothelial dysfunction, which looks at microvascular tissue and may take into account input from the nervous system, but this broader approach might also make the resultant data harder to interpret.

 

[Pyrrhus]

Peripheral endothelial dysfunction in myalgic encephalomyelitis/chronic fatigue syndrome. (Scherbakov et al., 2020)
Scherbakov, Szklarski, Hartwig, Sotzny, Lorenz, Meyer, Grabowski, Doehner, Scheibenbogen.

A study by Carmen Scheibenbogen's group that used peripheral arterial tonometry to look at the ability of arteries (not veins) to dilate in response to nitric oxide (not in response to autonomic nerves).
https://forums.phoenixrising.me/thr...phalomyelitis-chronic-fatigue-syndrome.79425/

 

[Pyrrhus]

Reduced Endothelial Function in ME/CFS–Results From Open-Label Cyclophosphamide Intervention Study (Sørland et al., 2021)
Kari Sørland1,2*, Miriam Kristine Sandvik3, Ingrid Gurvin Rekeland1,4, Lis Ribu2, Milada Cvancarova Småstuen2, Olav Mella1,4 and Øystein Fluge1,4

A study from Øystein Fluge's group that also found endothelial dysfunction in ME:
https://forums.phoenixrising.me/thr...el-cyclophosphamide-intervention-study.83317/

This study used two techniques to measure endothelial dysfunction:

• Flow-mediated dilation (FMD)
• Post-occlusive reactive hyperemia (PORH)

FMD appears to only measure the ability of arteries (not veins) to dilate in response to nitric oxide (not in response to autonomic nerves).

PORH is a broader measure of endothelial dysfunction, which looks at microvascular tissue and may take into account input from the nervous system, but this broader approach might also make the resultant data harder to interpret.

 

[Pyrrhus]

Effects of Post-Exertional Malaise on Markers of Arterial Stiffness in Individuals with ME/CFS (Bond et al., 2021)
Joshua Bond, Tessa Nielsen and Lynette Hodges

A study from New Zealand that measured "pulse wave velocity" and found arterial stiffness in ME:
https://forums.phoenixrising.me/thr...ndividuals-with-me-cfs-bond-et-al-2021.83489/

 

[Diwi9]

Thanks for this primer, @Pyrrhus. I had some form of endothelial dysfunction for years prior to full-on ME/CFS.

 

[Hip]

There are at least three different types of endothelial dysfunction that might occur in ME:

Very interesting summary.

Ever since I caught the Coxsackie B4 virus which triggered my ME/CFS, I developed cold hands and feet (which I think is due to poor blood circulation in these peripheries). Interestingly, some friends and family who caught my virus also developed cold hands and feet, even though they did not develop ME/CFS.

I was curious to measure the temperature of my hands and feet, to see how cold they actually are.

When I placed a digital thermometer probe into my elbow pit and closed my elbow around the probe, the temperature measured around 35°C, just slightly less than the standard core body temperature of 37°C.

But when I placed the thermometer probe on the balls of my feet (gently pushing the probe into the skin using a small plastic vitamin jar), the temperature was around 25 to 27°C, varying slightly from day to day. So my foot surface temperature is around 10°C colder than my core body temperature.

That certainly suggests something is amiss with blood flow to my hands and feet.



I always wondered whether the high amounts of nitric oxide deployed by the immune system when fighting pathogens might interfere with the nitric oxide used for vasodilation.

ME/CFS patients can have a chronic enterovirus infections in their skeletal muscles. If the immune system is constantly releasing nitric oxide in the muscles in order to control this infection, then possibly the blood vessel system will down-regulate its sensitivity to nitric oxide, thereby leading to endothelial dysfunction.



It's interesting that the nitric oxide secreted by the immune system (via the enzyme iNOS) is absolutely critical for protecting against viral infection should the interferon system fail, according to this paper:

In the presence of an intact interferon system, nitric oxide plays a minor but significant role in antiviral protection. However, in the absence of an interferon system, nitric oxide is critical for the protection against DNA viruses.

There have been some suggestions that interferon is unable to do its job in the case of the chronic non-cytolytic enterovirus infections found in ME/CFS, which if true, may mean that the immune-secreted nitric oxide is the only thing keeping the viral infection in check. Thus you might expect the immune system to chronically secrete nitric oxide for this purpose.



Professor Martin Pall's peroxynitrite theory of ME/CFS may also come into endothelial dysfunction:

Martin Pall believes that in ME/CFS, the enzyme nitric oxide synthase (NOS), which creates nitric oxide, becomes partially uncoupled from its substrates and cofactors, and thus no longer produces sufficient nitric oxide.

Uncoupling of an enzyme means there is insufficient substrates or cofactors available for the enzyme, so it cannot synthesize its desired product (nitric oxide in this case).

The enzyme NOS requires arginine and BH4 in order to synthesize nitric oxide, but if these are in short supply, the NOS will produce superoxide instead, which then reacts with any nitric oxide present to form the toxic oxidant peroxynitrite.

So basically NOS uncoupling leads to peroxynitrite being created in place of the desired nitric oxide.


Pall says this uncoupling becomes a vicious circle, as peroxynitrite itself oxidizes and depletes BH4, thereby leading to the production of even more peroxynitrite.

In this vicious circle, you get a partial uncoupling of all three NOS enzyme (eNOS, nNOS and iNOS), including the eNOS enzyme responsible for creating nitric oxide for blood vessel vasodilation.

Source: The NO/ONOO-Cycle as the Central Cause of Heart Failure

 

[sb4]

ME/CFS patients can have a chronic enterovirus infections in their skeletal muscles. If the immune system is constantly releasing nitric oxide in the muscles in order to control this infection, then possibly the blood vessel system will down-regulate its sensitivity to nitric oxide, thereby leading to endothelial dysfunction.

If I am understanding this correctly then something like BH4 wont help, as the issue isn't too much BH4 being used up to make nitric oxide; it's too much nitric oxide leading to down-regulated sensitivity.

I find this interesting as damn near all my symptoms could be explained by poor blood flow issues. Just trying to decide whether or not shelling out £140 for a weeks worth of BH4 is worth a try or not.

 

[Hip]

If I am understanding this correctly then something like BH4 wont help, as the issue isn't too much BH4 being used up to make nitric oxide; it's too much nitric oxide leading to down-regulated sensitivity.

That's only my speculation that NO from the immune system could desensitize the NO system in the blood vessels; but I have not found any studies which indicate this.

Nitric oxide relaxes the smooth muscles surrounding the blood vessels, and in this way causes the blood vessels to widen, increasing blood flow and lowering blood pressure.

From a quick Google, the actual mechanism appears to be this (from Wikipedia):

Nitric oxide ... relaxes vascular smooth muscle by binding to the heme moiety of cytosolic guanylate cyclase, activating guanylate cyclase and increasing intracellular levels of cyclic-guanosine 3',5'-monophosphate, which then leads to vasodilation.

When inhaled, nitric oxide dilates the pulmonary vasculature and, because of efficient scavenging by hemoglobin, has minimal effect on the vasculature of the entire body.

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.

I guess this would be the same for NO locally induced by the immune system (via iNOS) to target an infection in a particular body organ: the NO will not spread much further than that organ, because of the hemoglobin. So NO locally created by the immune system would appear not to have any major systemic effects.

However, if like in ME/CFS you have a low-level infection throughout the body tissues, then maybe the NO produced by the immune system might have systemic effects which mess around with the NO system in the blood vessels.

 

[Hip]

I find this interesting as damn near all my symptoms could be explained by poor blood flow issues. Just trying to decide whether or not shelling out £140 for a weeks worth of BH4 is worth a try or not.

I think it would be worth trying if you had the GCH1 mutation which affects BH4 synthesis. Here is what an ME/CFS patient with that mutation reported about taking BH4:

When I started taking BH4 it was a revelation. I found out what it meant to be "normal" instead of insanely moody - and nearly suicidal when I was doing the Cutler protocol.

That first dose completely brought me back to good in 30 minutes. Besides depression, BH4 alleviates anxiety, improves concentration and even helps me to prevent crashes. I took BH4 during an exercise stress test and failed to crash.

 

[Pyrrhus]

Low-grade inflammation and arterial wave reflection in patients with chronic fatigue syndrome (Spence et al., 2008)
Vance A Spence, Gwen Kennedy, Jill J F Belch, Alexander Hill, Faisel Khan
https://pubmed.ncbi.nlm.nih.gov/18031285/

A study from 2008 that looked at the arterial stiffness marker Alx75 of blood vessels and the amount of the inflammation marker CRP in the blood and found that patients with CFS had higher markers of arterial stiffness and higher markers of inflammation in the blood than controls.
Discussion:
https://forums.phoenixrising.me/threads/uk-study-pediatric-cfs.6201/#post-130421

Excerpt:

Some of the symptoms reported by people with CFS (chronic fatigue syndrome) are associated with various cardiovascular phenomena. Markers of cardiovascular risk, including inflammation and oxidative stress, have been demonstrated in some patients with CFS, but little is known about the relationship between these and prognostic indicators of cardiovascular risk in this patient group.

In the present study, we investigated the relationship between inflammation and oxidative stress and augmentation index, a measure of arterial stiffness, in 41 well-characterized patients with CFS and in 30 healthy subjects.

AIx@75 (augmentation index normalized for a heart rate of 75 beats/min) was significantly greater in patients with CFS than in control subjects (22.5+/-1.7 compared with 13.3+/-2.3% respectively; P=0.002). Patients with CFS also had significantly increased levels of CRP (C-reactive protein) (2.58+/-2.91 compared with 1.07+/-2.16 mug/ml respectively; P<0.01) and 8-iso-prostaglandin F(2alpha) isoprostanes (470.7+/-250.9 compared with 331.1+/-97.6 pg/ml respectively; P<0.005).

In patients with CFS, AIx@75 correlated significantly with logCRP (r=0.507, P=0.001), isoprostanes (r=0.366, P=0.026), oxidized LDL (low-density lipoprotein) (r=0.333, P=0.039) and systolic blood pressure (r=0.371, P=0.017). In a stepwise multiple regression model, including systolic and diastolic blood pressure, body mass index, CRP, tumour necrosis factor-alpha, interleukin-1, oxidized LDL, high-density lipoprotein-cholesterol levels, isoprostanes, age and gender, AIx@75 was independently associated with logCRP (beta=0.385, P=0.006), age (beta=0.363, P=0.022) and female gender (beta=0.302, P=0.03) in patients with CFS.

The combination of increased arterial wave reflection, inflammation and oxidative stress may result in an increased risk of future cardiovascular events. Assessment of arterial wave reflection might be useful for determining cardiovascular risk in this patient group.

 

[Pyrrhus]

There are at least three different types of endothelial dysfunction that might occur in ME:

1. The autonomic nerves that control the muscle tissue can fail to constrict the blood vessel when necessary. This is a form of dysautonomia.

I just realized that I described papers describing 2 of the 3 types of endothelial dysfunction, but I didn't link to any papers that discussed the first one: dysautonomia of the autonomic nerves that control constriction of the muscle tissue surrounding blood vessels.

Here's one:

Insights from Invasive Cardiopulmonary Exercise Testing of Patients with ME/CFS (Joseph et al., 2021)
by the team of Phillip Joseph, Anne Oaklander, and David Systrom
A study that used iCPET to look at blood circulation during exercise and nerve dysfunction in the lower leg.

Discussion:
https://forums.phoenixrising.me/thr...patients-with-me-cfs-joseph-et-al-2021.82907/

 

[godlovesatrier]

I also found that Ginseng increases nitric oxide levels in endothelium https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3659627/

While ginseng makes a lot of people worse, I find this particular herb works well for me (at least once I've got past the side effects). I can't take it anymore as it makes me very angry and very impatient. But for the first two years I relied on this completely and my quality of life was way way better for it, of course couldn't use it forever due to the aforementioned issues. I've been trying to understand why ginseng used to and andrographolide now does help me to feel so much better. Nitric oxide for ginseng and calcium channel blocking and h2 blocking capability of andrographolide have both popped up in numerous research papers.

Hopefully this is interesting.

 

[Pyrrhus]

Postural Orthostatic Tachycardia Syndrome (POTS) is a type of dysautonomia that is a common symptom of ME.

Here is a new paper that looked at endothelial dysfunction in people with the symptom of POTS:

Impaired Endothelial Function in Patients With Postural Tachycardia Syndrome
https://pubmed.ncbi.nlm.nih.gov/33486983/
by Abby H Chopoorian 1, Amr Wahba 2, Jorge Celedonio 2, Victor Nwazue 2, Emily C Smith 2, Emily M Garland 2, Sachin Paranjape 2, Luis E Okamoto 2, Bonnie K Black 2, Italo Biaggioni 2 3, Satish R Raj 4, Alfredo Gamboa

Main points:

• Three techniques were used to assess endothelial dysfunction:
  • Flow-mediated dilation (FMD)
  • Peripheral arterial tonometry
  • "Post-ischemic leg blood flow", which appears to be a type of Post-occlusive reactive hyperemia (PORH).
• Flow-mediated dilation (FMD) was lower in patients compared to controls.
• Peripheral arterial tonometry showed no significant differences between patients and controls.
• "Post-ischemic leg blood flow" showed no significant differences between patients and controls.

Excerpt:

The purpose of this study is to evaluate endothelial function in postural tachycardia syndrome (PoTS), a poorly understood chronic condition characterized by a state of consistent orthostatic tachycardia (delta heart rate ≥30 beats per minute) upon standing without orthostatic hypotension. Nineteen patients with PoTS and 9 healthy controls were studied after 3 days of a fixed, caffeine-free, normal sodium (150 milliequivalents/day) diet.

All participants underwent autonomic function testing, including sinus arrhythmia, valsalva maneuver, hyperventilation, cold pressor, handgrip, and a standing test with catecholamine measurements, followed by endothelial function testing. We analyzed 3 measures of endothelial function: percent brachial flow-mediated dilation, digital pulsatile arterial tonometry, and postischemic percent leg blood flow.

Flow-mediated dilation was significantly lower in patients with PoTS (6.23±3.54% for PoTS) than in healthy controls (10.6±4.37% for controls versus, P=0.014). PoTS and controls had similar digital pulsatile arterial tonometry (1.93±0.40 arbitrary units for controls versus 2.13±0.63 arbitrary units for PoTS). PoTS had similar but suggestive percent leg blood flow to controls (313±158% for PoTS versus 468±236% for controls, P=0.098). Patients with PoTS have significantly reduced flow-mediated dilation compared with healthy controls, suggesting that PoTS is characterized by endothelial dysfunction in conduit arteries.

(spacing and emphasis added)

 

[Pyrrhus]

And now for something completely different!

Altered endothelial dysfunction-related miRs in plasma from ME/CFS patients (Blauensteiner et al., 2021)
J. Blauensteiner, R. Bertinat, L. E. León, M. Riederer, N. Sepúlveda & F. Westermeier
Published: 19 May 2021
https://www.nature.com/articles/s41598-021-89834-9

Main points:

• Despite the title, this study did not measure endothelial dysfunction.
• This study compared a few selected micro-RNA's in the blood of ME patients to that of controls.
• The study found that five micro-RNA's are increased in ME patients compared to controls.
• The authors suggest that these micro-RNA's are biomarkers for the ability of endothelial cells to release nitric oxide (NO) when necessary.

Excerpt:

Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a complex disease characterized by unexplained debilitating fatigue. Although the etiology is unknown, evidence supports immunological abnormalities, such as persistent inflammation and immune-cell activation, in a subset of patients.

Since the interplay between inflammation and vascular alterations is well-established in other diseases, endothelial dysfunction has emerged as another player in ME/CFS pathogenesis. Endothelial nitric oxide synthase (eNOS) generates nitric oxide (NO) that maintains endothelial homeostasis. eNOS is activated by silent information regulator 1 (Sirt1), an anti-inflammatory protein. Despite its relevance, no study has addressed the Sirt1/eNOS axis in ME/CFS.

The interest in circulating microRNAs (miRs) as potential biomarkers in ME/CFS has increased in recent years. Accordingly, we analyze a set of miRs reported to modulate the Sirt1/eNOS axis using plasma from ME/CFS patients.

Our results show that miR-21, miR-34a, miR-92a, miR-126, and miR-200c are jointly increased in ME/CFS patients compared to healthy controls. A similar finding was obtained when analyzing public miR data on peripheral blood mononuclear cells. Bioinformatics analysis shows that endothelial function-related signaling pathways are associated with these miRs, including oxidative stress and oxygen regulation. Interestingly, histone deacetylase 1, a protein responsible for epigenetic regulations, represented the most relevant node within the network.

In conclusion, our study provides a basis to find endothelial dysfunction-related biomarkers and explore novel targets in ME/CFS.

(spacing added for readability)

 

[Murph]

Thanks for this thread @Pyrrhus . Long before I was diagnosed with ME/CFS, I knew I could generate a fatigue event (PEM) with a certain amount of either exercise or alcohol, and a big fatigue event by combining them in even small doses. It took me a while to figure it out, but the common factor in almost all the things that trigger PEM in me is vasodilation. (I also vividly remember an intense fatigue event after going to an onsen in Japan. All that hot water and steam!) So I'm especially interested in theories of ME/CFS that include vasodilation and the endothelium.

 

[Pyrrhus]

Altered endothelial dysfunction-related miRs in plasma from ME/CFS patients (Blauensteiner et al., 2021)
J. Blauensteiner, R. Bertinat, L. E. León, M. Riederer, N. Sepúlveda & F. Westermeier
Published: 19 May 2021
https://www.nature.com/articles/s41598-021-89834-9

Main points:

• Despite the title, this study did not measure endothelial dysfunction.
• This study compared a few selected micro-RNA's in the blood of ME patients to that of controls.
• The study found that five micro-RNA's are increased in ME patients compared to controls.
• The authors suggest that these micro-RNA's are biomarkers for the ability of endothelial cells to release nitric oxide (NO) when necessary.

An update from these same authors:

Decreased NO production in endothelial cells exposed to plasma from ME/CFS patients (Bertinat et al., 2022)
https://forums.phoenixrising.me/thr...exposed-to-plasma-from-me-cfs-patients.86883/

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.

Abstract:

Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a debilitating disease characterized by severe and persistent fatigue. Along with clinical studies showing endothelial dysfunction (ED) in a subset of ME/CFS patients, we have recently reported altered ED-related microRNAs in plasma from affected individuals. Inadequate nitric oxide (NO), mainly produced by the endothelial isoform of nitric oxide synthase (eNOS) in endothelial cells (ECs), is a major cause of ED.

In this study, we hypothesized that plasma from that cohort of ME/CFS patients induces eNOS-related ED in vitro. To test this, we cultured human umbilical vein endothelial cells (HUVECs) in the presence of either plasma from ME/CFS patients (ME/CFS-plasma, n = 11) or healthy controls (HC-plasma, n = 12). Then, we measured the NO production in the absence or presence of tyrosine kinase and G protein-coupled receptors agonists (TKRs and GPCRs, respectively), well-known to activate eNOS in ECs.

Our data show that HUVECs incubated with ME/CFS-plasma produced less NO either in the absence or presence of eNOS activators compared to ones in presence of HC-plasma. Also, the NO production elicited by bradykinin, histamine, and acetylcholine (GPCRs agonists) was more affected than the one triggered by insulin (TKR agonist). 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.

(spacing added for readability)

EDIT: Added link to new discussion

 

[bread.]

Thank you @Pyrrhus, as always!

Just wanted to point out that it's not certain that the Endothel is not structurally damaged (in this subset of) ME patients.

We can derive from these findings that yes, there is smthg or the absence of smthg in the blood, but this does not automatically mean that the Endothel of patients isn't damaged.

One could derive that patients with damaged Endothel are even more likely to have factor(s) in the blood that make these cells dysfunctional, but this is speculation obviousLy.

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 t loophe blood or something lacking from the blood, but not any problem with the endothelial cells themselves.

 

[Pyrrhus]

Just wanted to point out that it's not certain that the Endothel is not structurally damaged (in this subset of) ME patients.

We can derive from these findings that yes, there is smthg or the absence of smthg in the blood, but this does not automatically mean that the Endothel of patients isn't damaged.

Yes, thank you for pointing that out!

 

[Bowser]

My understanding of endothelial dysfunction is limited, but from what I can understand after glancing at these studies, 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.

TOS can also cause intracranial hypertension, as the blood that is prevented from flowing towards the arm retrogrades to the brain via the carotid artery and vertebral artery. This phenomenon is called TOS-CVH — a TOS-induced cerberovascular hyperperfusion phenomenon. There is only one paper that has ever been written on this, and it is here: https://www.apicareonline.com/index.php/APIC/article/view/1230/2037