Systrom, Scheibenbogen and others have has found evidence of microcirculatory problems in chronic fatigue syndrome (ME/CFS) and fibromyalgia, but what about the big blood vessels – the arteries?
An artery (from Wikimedia)
These muscular, but flexible, tubes transport oxygenated blood under high pressure from the heart to the organs and muscles. They need to be strong enough to withstand the highest circulatory pressures in the body and supple enough to quickly respond to changes in blood pressure and wind their way through the body.
Given the crucial role they play, it’s perhaps no surprise to find out that they are complex indeed. Composed of three layers of smooth muscle, connective tissue and collagen, they pulse or enlarge when the heart beats, and relax when the heart rests.
The Study
This New Zealand study chose to study something called “arterial stiffness”, which describes how elastic the arteries are and how well they comply or react to the changes in blood pressure they’re constantly experiencing. Increased levels of arterial stiffness have been shown to be a “strong predictor” of an increased risk of stroke, heart failure, atherosclerosis, heart attack, and coronary artery disease.
They used a measure called AIx to assess arterial stiffness. Higher AIx levels indicate increased arterial stiffness. The New Zealand study was very clever. Recognizing that exercise might induce a state of oxidative stress/ inflammation that resulted in arterial stiffness, they put people with ME/CFS and healthy controls on a bike, had them pedal to exhaustion, and measured their AIx before, and then 48 and 72 hours later. (Dr. Klimas has reported that extensive monitoring before, during, and after exercise indicates that exercise triggers a burst of inflammation and oxidative stress in ME/CFS.)
Thirteen years ago, Spence found evidence of arterial stiffness in ME/CFS, but no one until now has assessed it after exercise. Seventeen people with ME/CFS and 16 healthy controls engaged in a maximal exercise test. Some returned 48 hours later, and some 72 hours later, to assess their levels of arterial stiffness.
Results
As so often happens, the results were similar at baseline in the ME/CFS and healthy controls, but adding an exercise stressor changed things. Two days after exercise, the healthy controls’ AIx (or arterial stiffness) had actually declined i.e. indicating that the intense exercise had had a healthy effect on the healthy controls’ arteries. This is believed to occur when exercise-induced nitric oxide, prostaglandin and endothelin levels relax the arteries, allowing them to dilate more, and leaving them suppler and more responsive.
No change, however, was found in AIx in the people with ME/CFS after 48 hours; i.e. while their arterial stiffness didn’t increase, their arteries also didn’t receive any of the benefits from exercise that the healthy controls did. A big spike in oxidative stress and inflammation – and ultimately, arterial stiffness – brought on by a broken energy production system being pushed past its limits in ME/CFS seems to make total sense.
It’s not a definitive study – it was too small for that – but it’s another in a long stream of studies that find exercise – long thought to be a kind of universal healer – actually makes things worse in ME/CFS. While the study needs to replicated, finding a significant difference in arterial stiffness between people with ME/CFS and healthy controls two days after exercise was remarkable.
What’s clearly needed next are more comprehensive studies that measure arterial stiffness in the hours and days after an exercise stressor. Nobody would probably be shocked to see arterial stiffness dramatically increase shortly after exercise in ME/CFS, and then slowly wind back down to baseline levels. Assessing measures of oxidative stress and inflammation at the same time should, of course, be done as well.
This study comes about a year after Scheibenbogen’s team found evidence of endothelial dysfunction in about half of the ME/CFS patients. These endothelially challenged ME/CFS patients were functionally more limited and had more severe fatigue-related and immune-related symptoms (sore throat, painful lymph nodes). Scheibenbogen also believes that adrenergic antibodies may be interfering with blood vessel functioning, and she and Wirth have proposed that sympathetic nervous system activation is narrowing the arteries.
We also recently saw evidence of low blood flows to the brain upon standing – perhaps brought on by low CO2 levels – that are narrowing the arteries.
It seems the deeper researchers dive into the exercise issue, the more they find.
Increased Cardiovascular Risk?
This study also brings up the issue of what cardiovascular risks diseases like ME/CFS and fibromyalgia may pose.
Several studies – including one large one – have found increased arterial stiffness in FM. One linked the arterial stiffness to more severe symptoms, and proposed that activation of the fight/flight or sympathetic nervous system played a role.
Two studies have also found a moderately increased risk (50%) of coronary heart disease in fibromyalgia. As a group, people with FM had more diabetes, hypertension, hyperlipidemia, congestive heart failure, cerebral vascular diseases, depression, and anxiety than the reference cohort they were compared to.
While those comorbid conditions were more common in FM, the good news was that people with FM who did not have those cardiovascular conditions (diabetes, hypertension, hyperlipidemia, congestive heart failure, cerebral vascular diseases) actually had a somewhat lower risk of heart disease than the reference population.
The authors suggested that chronic stress, including, in some patients, early lifetime stressors, increased sympathetic nervous system activity and reduced parasympathetic nervous system activity. They noted the reduced heart variability results found in FM, which are a known risk factor for heart disease.
The Gist
- Arteries are muscular tubes that need to be supple and elastic to respond to changes in blood pressure.
- Increased arterial stiffness increases the risk for cardiovascular conditions like heart disease and stroke.
- A 2008 study found evidence of increased arterial stiffness in ME/CFS.
- This small New Zealand study assessed arterial stiffness before, and 48 hours after, exercise in people with ME/CFS and healthy controls.
- No evidence of arterial stiffness was found at baseline in ME/CFS, but the 48 hours after-exercise ME/CFS patients’ arterial stiffness was increased relative to the controls.
- Exercise had increased arterial elasticity in the healthy controls but not in the people with ME/CFS.
- At least four studies have found evidence of arterial stiffness in fibromyalgia. Several studies pointed to increased sympathetic nervous system activation as a possible cause.
- Other studies have found increased levels of cardiovascular risk factor in both FM and ME/CFS, including high levels of oxidative stress, poor lipid profiles and reduced heart rate variability. People with ME/CFS/FM also tend not to exercise regularly and are under increased stress. ME/CFS/FM is not, on the other hand, usually associated with high blood pressure – a strong cardiovascular risk factor.
- Several studies have also found evidence of an increased risk of cardiovascular conditions in fibromyalgia.
- Larger studies are needed to more thoroughly assess arterial stiffness, particularly in the hours following exercise when oxidative stress and inflammatory factors may be at their peak in ME/CFS.
- Larger studies are also clearly needed to assess cardiovascular risk factors in both these diseases.
Increased levels of oxidative stress can impact the blood vessels and have been found in both fibromyalgia and ME/CFS. Plus high levels of oxidative stress factors and/or decreased levels of the protective antioxidants have twice been associated with increased symptoms in ME/CFS and FM.
Several studies have found “unfavorable lipid profiles” that could increase the risk of atherosclerosis in ME/CFS. Fibromyalgia. studies have had mixed results with several finding unfavorable lipid profiles and others not. Low levels of the healthy cholesterol (HDL-C) have been found in ME/CFS.
Several studies have found “unfavorable lipid profiles” that could increase the risk of atherosclerosis in ME/CFS. A 2005 study found increased levels of oxidized lipids and decreased HDL-C in ME/CFS patients with risk factors (high blood pressure and/or obesity).
Spence’s 2008 ME/CFS study found increased arterial stiffness and significantly increased markers of inflammation and oxidative stress (C-reactive protein, 8-iso-prostaglandin F, isoprostanes, oxidized LDL) which could be damaging the arterial walls. Spence concluded that “inflammation and oxidative stress may result in an increased risk of future cardiovascular events” in ME/CFS.
In 2009, Maes concluded that chronic low grade inflammation, increased oxidative and nitrosative stress, reduced levels of antioxidants and healthy fatty acids could predispose people with ME/CFS to cardiovascular issues.
A small 2012 study of women with ME/CFS found high levels of “bad” fats, low levels of the “good” fats and signs of oxidative stress (increased malondialdehyde levels).
Large epidemiological studies are clearly needed to assess cardiovascular risk in FM and ME/CFS. People with ME/CFS can help further our understanding in this (and other) areas by participating in the Solve ME/CFS Initiative’s You+ME Patient Registry.
Conclusion
At least four studies have found increased arterial stiffness in fibromyalgia, and this is the second study to find altered arterial stiffness – a risk factor for cardiovascular disease – in ME/CFS. While baseline levels of arterial stiffness were normal, people with ME/CFS had elevated levels of arterial stiffness relative to a healthy control group 48 hours after exercise. Exercise decreased arterial stiffness – leaving the arteries more supple and responsive to blood pressure changes – in the healthy controls but not in the people with ME/CFS. The inability of exercise to improve arterial stiffness could contribute to post-exertional malaise.
Larger, more comprehensive studies are needed to validate the findings and to determine what happens to arterial stiffness in the hours and day following exercise in ME/CFS.
Increased arterial stiffness is a risk factor for cardiovascular diseases. Note that increased arterial stiffness was not found at baseline in this study – but was in an earlier study – and has been found several times in FM. Studies indicate that people with ME/CFS/FM also display a number of risk factors for cardiovascular illnesses such as increased oxidative stress, unfavorable lipid profiles, reduced heart rate variability, as well as low exercise levels and increased levels of stress. On the plus side, high blood pressure is rarely mentioned in connection with these diseases (but can be found in hyperadrenergic POTS – which is found in ME/CFS).
Several Taiwanese studies suggest people with FM may have a moderately increased risk of coronary heart disease and/or stroke. (Note, though, that an FM patient’s chance of having either is still quite low.)
Given the risk factors present, large epidemiological studies are needed in both ME/CFS and FM to assess cardiovascular risk. People with ME/CFS can, however, help further our understanding in this area by participating in the Solve ME/CFS Initiative’s You+ME Patient Registry.
I take a lot of salt to increase my blood pressure and have been afraid that it would stiffen my arteries. Any idea if salt has the same effect on us, people with ME, than other? Anyway, when I get anxious about it, I think ” better have a better quality of life now than supple arteries when/if I gel old! “
That’s a question I have myself. I have no idea. Thankfully there doesn’t seem to be much high blood pressure in ME/CFS/FM altho mine has been riding a bit high (130’s/80’s). I’m going to do more meditation and hopefully will bring it down.
HyperPOTS cohort…
orthostatic hypertension…
Yes, that was noted in the blog “On the plus side, high blood pressure is rarely mentioned in connection with these diseases (but can be found in hyperadrenergic POTS – which is found in ME/CFS).”
Hi Cort,
Thanks for your review. In my latest study, we show that blood pressure is incredibly high with even a small amount of exercise in some of our patient group in NZ…..
Interesting! Thanks and good luck with future studies.
@dr. Lynette Hodges:
I never heard about exercise hypertension. I did a very quick search on your name and the topic and it potentially offers a VERY interesting link to a rather large subgroup of ME cases.
Would the potential spiralling upwards of BP go hand in hand with:
* Happening shortly after the onset of anaerobic threshold?
* Happening only slightly delayed after a strong spike in blood lactate levels?
* The raise in exercise induced BP correlate well to the simultanious increase in (hyper)ventilation?
* The raise in exercise induced BP correlate well to the simultanious excessive increase in heart rate?
* Would patients who have this exercise hypertension have significantly reduced Heart Rate Variability compared to healthy controls in the time following it (spanning the immediate range of minutes to the “PEM range” of hours up to three days)?
In addition, if study would allow it:
* Something very similar (but plausible to a lesser extend) happening with brain activity induced exhaustion?
* Something very similar happening with ME patients when they awake at night bathing in sweat, breathing like a horse and have a very high and or irregular heart beat?
Also:
* Would patients with clear signs of muscle athrophy be exceptionally well represented in the group of people with exercise induced hypertension?
If the answer to many of these question is yes, then I might hold another rather important piece of that puzzle.
Note: from my quick search I assume that many of the answers to above question are not found in open literature, so if you would observed those that would sort of indicate that the underlying ideas leading to the above questions point in a good and possible rather important direction.
Kind regards,
dejurgen
Great blog. I thought this study found AS as well?
https://www.mdpi.com/2077-0383/9/8/2531
“It seems the deeper researchers dive into the exercise issue, the more they find”
Sorry to be cranky, but perhaps a class action lawsuit against Wellesley et al (PACE trial) is finally in order? His data (well, pre-fudging, of course) would have shown pretty clearly that exercise was harming (not only not helping, but actually injuring) his MECFS patients.
Bad enough that he did that to the patients in his trial, but he went on to push his rubbish psychological ‘treatment’ world-wide. A woman I know was denied insurance coverage through her workplace unless and until she underwent GET. This was after it had already been documented and known that his treatment was harming patients.
Just sayin’ is all.
Dr Myhill has been campaigning for this.
Certainly understand the sentiment! It probably wouldn’t work because the GET studies don’t show many harms. It’s the surveys that do and researchers will defer to the studies. When I think of what Workwell has had to go through to get researchers to listen to them – it makes me wonder about researchers!
Hi Anne, I can see what you’re saying but I’ve been involved in making very valid complaints and it’s a brutal process. I’ve become a bit more sophisticated over the years and what I’ve learnt is that I had to prove that what happened was not following procedures, criteria etc. They weren’t interested in the consequences for me. It was a cold, isolating and miserable process. The other side were defensive and attempted to undermine my credibility. However, I stuck it out and the professional organisation upheld my complaint.
I’ve been using Vagus Nerve Stimulation with a TENS unit and ear clip for about six months now and have been surprised and pleased at how it has lowered my daily anxiety level. Especially when I have lots of things coming at me at once. I’m also having daily bowel movements with no supplement aids for the first time in my adult life. I can’t help but think that VNS would help with some of the issues of the heart being discussed here.
Absolutely. The reason the fight or flight system is so turned on in these diseases may be that the vagus nerve (or parasympathetic nervous system) – which is supposed to keep it under control – is failing to do so. That in turn may be interfering with the ability of the smooth muscles in the arteries to function properly. Lowering your anxiety level (fight/flight symptom) and having better bowel movements makes perfect sense with VNS.
Thanks for sharing your success. 🙂
Could low blood volume or dehydration play a part in arterial stiffness? Perhaps it’s a compensatory mechanism?
Somehow someone is going to have to figure how low blood volume – so little studied in ME/CFS – and the problems with the RAAS system – which I’ll bet occurs in FM as well – figures into this. It would make sense to me that low blood volume would result in a jacked up sympathetic nervous system – which some of the researchers believe is behind the arterial stiffness found.
Lisa, Could you please reveal what Vagus Nerve Stimulation and Tens unit system you use to lower your daily anxiety levels? I could certainly use that technique.
As you get older or are overweight, your veins also become stiffer. I think the cause in ME / POTS is that the smooth muscle can’t relax. Stiffness is also found in the heart. The cause lies in the sympathetic nervous system, as Professor Scheibenbogen says. Still, I think there is an increased risk of cardiovascular disease. The cardiovascular system is more likely to age in ME / POTS patients.
I would think the cardiovascular system – probably under a lot of stress in ME/CFS/FM/POTS – is not going to age particularly well. Since I don’t quite frankly experience ANYTHING relaxing in ME/CFS/FM – I wouldn’t be surprised if the smooth muscles linking the blood vessels aren’t either. 🙂
Cort, No confirmation neuroinflammation like study Japan.
No signs of neuroinflammation in women with chronic fatigue syndrome
or Q fever fatigue syndrome using the TSPO ligand ^11C-PK11195
https://assets.researchsquare.com/files/rs-348289/v1/3fa863c2-ddb4-4767-b6e8-02e0bb7c8616.pdf
My goodness look at that…Such a small study, though – and they used Fukuda.. I’ve been told that the bigger (and positive) Japanese study update is coming. Time will tell…Thanks for passing that on.
I often think that that looking at hEDS through the connective tissue lens has blinded/biased doctors to think that everything follows from faulty connective tissue, instead of seeing connective tissue as one of the things that is affected.
Funny – because the other types of EDS do have faulty connective tissue, but they don’t have the omni-systemic symptoms. Wouldn’t that make them stop for a second and wonder…
I am also left wondering when will FMS and ME/CFS shed the sympathetic system lens… and the central sensitization one (hint: look at quinolic acid for that one…)
I think when that does, they’ll see the diseases anew, instead of chopping them up into discrete systems and dysfunctions. Which is why I appreciate Naviaux and his big picture. Systems thinking.
There’s good stuff in this one: https://www.frontiersin.org/articles/10.3389/fmed.2021.628029/full
Thanks Cort. This is another interesting piece of the puzzle and Vance Spence, who you also mention in this article, has produced some incredibly insightful research on ME/CFS and the circulatory system. Much of Spence’s research involved looking at the relationship between acetylcholine (a neurotransmitter) and blood pressure. As both a patient himself and a researcher, I can understand why both his instincts and intellect steered him to following this lead. For me too, the scientific evidence and personal experience also points toward a broken cholingergic system. Conversely, in the hundreds of research papers I have read over the years, I haven’t seen any evidence to refute this possibility.
Unlike most diseases, where the acetylcholine response is blunted Vance found that acetylcholine response is enhanced in ME/CFS. I personally believe that this is because the vagus nerve does not effectively transmit acetylcholine, either due to structural damage caused by injury or connective tissue failure or auto-immune attack on the muscarinic receptors that help regulate the parasympathetic nervous system. I suspect that spinal issues might be particularly complex and debilitating.
While the relationship between acetylcholine and the circulatory system is fascinating, with implications for oxygen delivery and heartrate, the relationship between acetylcholine and the gut is also interesting. The vagus nerve innervates the gut and moderates immune response and inflammation. If acetylcholine cannot effectively do its job in the gut then it stands to reason that inflammation will increase, and many researchers have noted that ME/CFS shares some similarities with inflammatory bowel disease, certainly for a subset that includes myself.
Both stress and exercise increase intestinal permeability. Shukla found much higher concentrations of LPS in the bloodstream of ME/CFS patients following exercise than controls. Perhaps an under-researched aspect of this illness is what damage that LPS causes once it hits the bloodstream and the blood-brain barrier. LPS could potentially trigger a form of very mild septic shock creating a temporary drop in blood pressure, increased arterial stiffness (as found in this study), sickness response and a host of other unpleasant symptoms. Younger has also found that patients’ symptoms track with leptin, and elevated leptin is now thought to increase gut permeability. Leptin release is stimulated by overeating, stress, high insulin, serotonin and estrogen.
@debsw, Learner1:
To much TMAO or Wikipedia(Trimethylamine_N-oxide) can cause both hypertension and impair Nitric Oxide production (but according to studdies only in parts of the body).
See the paper with title “Trimethylamine-N-oxide Specifically Impairs Endothelium-Derived Hyperpolarizing Factor-Type Relaxation in Rat Femoral Artery” saying
” In endothelium-derived hyperpolarizing factor (EDHF)-mediated relaxation under nitric oxide synthase (NOS) and cyclooxygenase (COX) inhibitions by… …TMAO specifically impairs the relaxation in femoral arteries but not in the superior mesenteric arteries. Under the inhibitory actions of NOS…”
What has that to do with acethylcholine? Acethylcholine requires dietery choline. From the above linked Wikipedia page “The order Clostridiales, the genus Ruminococcus, and the taxon Lachnospiraceae are positively associated with TMA and TMAO levels.”
A further search learns that bad bacteria like Clostrodium Difficile (often mentioned in a bad way by ME sufferers) can convert dietery carnitine and choline to TMAO. That would give people with a latent or active Clostrodium Difficile infection higher TMAO and lower choline in their blood. That would be a double whammy on NO production.
Too high TMAO is also related to reduced recovery from ischemia. With our poor bloodflow and oxygenation, I believe that we risk recurrent partial hypoxia and ischemia. See a paper with title “Trimethylamine N-oxide impairs perfusion recovery after hindlimb ischemia”.
Note that some TMAO helps with adaption to blood pressure changes. So a minimum (and or stable) amount might help protect against things like POTS. It sure is complicated!
From Wikipedia(Flavin-containing_monooxygenase_3):
The FMO3 gene converts (among others) epinephrine (better known as adrenaline), norepinephrine, phenethylamine, trimethylamine and tyramine to their oxides.
FMO3 also converts TMA, produced by gut bacteria from carnitine and choline, to TMAO. BUT, TMA is the trimethylamine listed in above list.
Also from Wikipedia(Flavin-containing_monooxygenase):
“The majority of drugs function as alternate substrate competitive inhibitors to FMOs (i.e. good nucleophiles that compete with the drug for FMO oxygenation)”
That IMO means that the FMO enzymes are easily overwhelmed and the majority of FMO inhibitors work by overwhelming this enzyme. In more plain words: adding something that also can be oxidized by the FMO enzyme can easily reduce the availability of FMO enzyme for doing other needed things.
Looking at the picture labeled “Norepinephrine is synthesized from dopamine in the human body by the dopamine β-hydroxylase (DBH) enzyme.” in Wikipedia(https://en.wikipedia.org/wiki/Norepinephrine), you’ll find *ALL* of the chemicals “epinephrine (better known as adrenaline), norepinephrine, phenethylamine, trimethylamine and tyramine” as listed above in that picture, *except* for trimethylamine. That is however this TMA that can be produced from carnitine and choline by gut bacteria like Clostrodium Difficile.
So basically: there is a fairly high chance that a high (spike in) production of TMA in the gut can overwhelm the FMO enzymes and hence interfere with dopamine, tyramine, nor-epinephrine (aka noradrenaline) and epinephrine (adrenaline).
There are many other chemical processes that interfere with dopamine, tyramine, nor-epinephrine (aka nor-adrenaline) and epinephrine (adrenaline), but dopamine has vassodilator properties and (nor-)epinephrine has vassoconstricting properties. Dopamine is an important brain chemical and related in movement and neurodegenerative diseases like Parkinson. (Nor-)epinephrine is a key component in our fight or flight response.
So a chemical (TMA) possibly overwhelming the FMO enzyme could be a big deal. Possibly worse, it could overwhelm it depending on what you ate that day and how your digestion reacts to it as both the amount of carnitine and choline in the food AND how quick you digest your food AND how strong your immune system reacts against diverse gut microbes likely will influence and let swing the amounts of TMA / TMAO in our blood a lot. Having C. Diff or some similarly bad bugger in your gut will likely make things even worse.
On top of that, there is a relation between TMAO and NO, NO and BH4 and BH4 and seratonin and dopamine and (nor-)epinephrine synthesis…
FMO also operates on (a wide range of different) sulfides. Overwhelming FMO might impact digestion and tolerance of sulfur rich foods. Conversaly, overwhelming FMO with sulfur rich food might impact it’s effects on TMA, dopamine, tyramine, nor-epinephrine (aka nor-adrenaline) and epinephrine (adrenaline).
Agreed that it is complicated! If it wasn’t I imagine that this mystery illness would have been solved years ago 🙂
The reason why I find acetylcholine interesting is because it acts on the muscarinic receptors that various groups have found autoantibodies to. It is also the major neurotransmitter in the PNS and the spinal cord is clearly implicated in some cases. However, there is also evidence of beta adrenergic autoantibodies in some patients and norepinephrine is the key neurotransmitter that activates those receptors and subsequent nitric oxide release in the blood vessels. Maybe I’m wrong, but if the SNS and PNS aren’t working in harmony then it is harder to maintain system balance.
Like Learner pointed out, research studies do not exist in a vacuum and, thus far, no single piece of research can fully explain this illness, even though there must be some genesis somewhere. All carefully conducted and reliable research must surely link together eventually to create a broad understanding of the illness.
Nitric oxide regulates arterial stiffness. Maes and Morris have written about nitrosative stress in ME/CFS. It is frustrating how so much doesn’t get linked in ME/CFS research.
One can get some Humann or similar nitric oxide test strips. Most NE/CFS patients I know who have done so have found their nitric oxide levels yo be low to non-existent.
One can take nitric oxide boosters, something like the Berkeley Life product, but probably not arginine which might promote herpes viruses, and this can raise nitric oxide. Raising nitric oxide can increase the ability to exercise and relaxes blood vessels, lowering blood pressure in hyper POTS.
I’ve also found that taking Kuvan (sapropterin or BH4 or tetrahydrobiopterin) can also raise nitric oxide levels and cause relaxing of stiff blood vessels.
Interestingly one can have high peroxynitrites but be low in nitric oxide, neither of which is a good thing.
High peroxynitrites, which Maes and Morris have written about, damage mitochondrial membrane and impair mitochondrial complex I.
This is all interrelated.
And then there is the acetylcholine piece. Both Mestinon and the supplement Huperzine A increase acetycholine which reduces the impact of the dysfunctional adrenergic system driving dysautonomia.
Would love yo see the researchers out all this together rather than just telling us we have stiff blood vessels
“Interestingly one can have high peroxynitrites but be low in nitric oxide”
That’s IMO to be expected. Nitric oxide and oxidative stress are both rather reactive. When oxidative stress (H202) is rather high, it forms a chemical reaction with NO to form peroxynitrites. That leaves you with few NO and much rather aggresive (often even more so then oxidative stress) peroxynitrites.
“I’ve also found that taking Kuvan (sapropterin or BH4 or tetrahydrobiopterin) can also raise nitric oxide levels and cause relaxing of stiff blood vessels.”
Would you take the highly dosed prescription version or the far lower dosed (but expensive) supplement version that I saw offered prescription free?
That BH4 thing is of interest as its needed to make dopamine and seratonin in the body. The metabolic trap theory says that we have the kyurenic pathway being diverted to much higher seratonin production. That would recude highly inflammatory stuff like quinolic acid, which may be a good thing in our condition. But it also would help deplete BH4, possibly compromising dopamine (and with it noradrenaline) production. It would also hamper NO production and with it blood vessel dilation.
One of the places where EBV lives, are the endothelial cells. While looking into Wikipedia(Endothelial_NOS) once more, I did find:
“The binding of the cofactor BH4 is essential for eNOS to efficiently generate NO.[17] In the absence of this cofactor, eNOS shifts from a dimeric to a monomeric form, thus becoming uncoupled.[18] In this conformation, instead of synthesizing NO, eNOS produces superoxide anion, a highly reactive free radical with deleterious consequences to the cardiovascular system.”
Getting EBV as an adult is suspected among patients to increase chances to get ME. So I wondered if it involves EBV being found often in endothelial cells and EBV increasing oxidative stress in those cells. So maybe mutations in eNOS?3? increases chances of eNOS to produce free radicals or maybe EBV blocks one of the many components to make NO rather then free radicals. If so, that could be game changing.
Following that lead, I did find a single research paper:
“Reversing Splenomegalies in Epstein Barr Virus Infected …”
https://isom.ca/wp-content/uploads/2020/02/JOM_2006_21_2_06_Reversing_Splenomegalies_in_Epstein_Barr_Virus_Infected-.pdf
“The Cause of Splenomegaly in EBV
The decrease of lymphocyte movement in EBV is caused by the generation of nitric oxide (NO) from another nitric oxide synthase enzyme, endothelial nitric oxide synthase (eNOS). The properties of eNO are different from the properties of iNOS product in that eNOS nitric oxide”
EBV seems to mess with eNOS (meaning it seems to reduce nitric oxide generation reducing vassodilation and to increase oxidative stress by switching / flipping the function of eNOS)???
On a related note, about ten weeks ago I had my annual physical exam, and was complaining to my GP about my muscle cramping problem since I acquired ME almost 30 years ago. We decided to do a trial of pentoxyffiline (generical Trental) to see if it helped. It can take up to 8 weeks to work. I’m 10 weeks in and I feel no change at all. It is supposed to make blood vessels and blood cells more flexible. This request was prompted by the research done at a California university a few years ago that came to the conclusion that our red blood cells don’t flatten as well as they should to get into our capillaries.
The longer I have had CFS the more I can’t exercise without having severe relapse with one exception. I have discovered that I have no post-exertional malaise and no relapse when I exercise laying down. I exercise daily,sometimes twice a day. I’m stretching my legs, lots of leg movement by getting in a variety of positions. Get whole torso involved via rolling from side to side. Do every kind of position I can think of working different muscles. I do all this with my cpap mask on because I have a tendency to stop breathing when I exercise. I also do some arm movements with bungee cord while standing that improves my posture and reduces neck pain. This is done very briefly. I have had no negative reactions to doing this. Have been doing for over a month.