This new ME/CFS / long-COVID paper, “Endothelial Senescence and Chronic Fatigue Syndrome, a COVID-19 Based Hypothesis”, highlights something we’d hoped would occur with COVID-19: new eyes being placed on, and new perspectives being produced on chronic fatigue syndrome (ME/CFS).
The group that wrote this paper is an interesting case in point. Their June 2020 paper, “Intoxication With Endogenous Angiotensin II: A COVID-19 Hypothesis“, proposed that endothelial dysfunction was a key aspect of COVID – and linked it to high angiotensin II (Ang II) levels. They suggested that the high Ang II levels in COVID-19 had caused “premature vascular senescence”.
That was intriguing given the really interesting place that high Ang II levels, and something called the RAAS or RAS paradox, inhabits in the ME/CFS/POTS universe.
The paradox concerns the renin-angiotensin-aldosterone pathway that’s supposed to kick in when low blood volume levels occur. Even in context of the very low blood volumes found in ME/CFS/POTS, the pathway doesn’t kick in, and its critical endpoint, aldosterone, remains at normal or even low levels. This is despite the fact that the levels of Ang II – found in the middle of the pathway – tend to be very high.
Wirth and Scheibenbogen were the first, to my knowledge, to possibly explain the RAAS paradox. They proposed that balky B2AdR receptors and high bradykinin levels had interfered with two of the three major factors needed to stimulate the RAA pathway; i.e. the signal to increase blood volume in ME/CFS has gotten “annihilate(d)”.
The current authors brought a whole new perspective to the high Ang II levels found in ME/CFS/POTS. They proposed that high ANG II levels are knocking out the mitochondria in endothelial cells lining the blood vessels – reducing nitric oxide (N0) levels (inhibiting the blood vessels from dilating properly), and triggering something they called “vascular aging”.
They also believe high Ang II levels in the brain are producing cognitive and other symptoms. Abilify sprang to mind when they proposed that dopamine-enhancing antipsychotic drugs may be protective against the central nervous system effects of COVID-19. The exhausted cytotoxic T and NK cells found in COVID-19 provided another possible touchpoint with ME/CFS.
ME/CFS, however, was never mentioned.
The Gist
- In June 2020, researchers proposed that the renin-angiotensin-aldosterone system had become discombobulated in COVID-19, and that high Ang II levels were causing damage to the blood vessels and the mitochondria. Despite the fact that high Ang II levels are also found in ME/CFS, they did not mention it.
- One of the great mysteries in ME/CFS and POTS has been something called the renin-angiotensin-aldosterone (RAAS) paradox. The paradox lies in the fact that despite the very low blood volume levels in the disease, the RAA system – which is designed to increase them – is never activated.
- One part of the RAA system is, though. Angiotenson II levels are greatly increased. Wirth and Scheibenbogen provided a possible explanation for the paradox. Balky beta-adrenergic receptors and plus a vasodilator called bradykinin were “annihilating” the signal the RAA system needed to proceed.
- A year later, the long-COVID researchers were back with a hypothesis they believe explains both long COVID and ME/CFS. It was centered squarely on those high Ang II levels found in ME/CFS.
- Ang II levels, it turns out, can cause more problems than we knew. Besides possibly producing blood vessel and mitochondrial problems, they can damage the gut lining, jack up oxidative stress levels, interfere with cellular cleanup, and even damage telomeres.
- The authors proposed that the high Ang II levels were causing the guts of both long-COVID and ME/CFS patients to leak bacterial molecules into the bloodstream – triggering an immune reaction reaching all the way to the brain.
- The authors even believe that the adrenergic autoantibodies that have received so much attention in ME/CFS may have been produced to deal with the bacterial molecules making their way into the gut.
- The authors outlined a variety of possible treatments not currently being used in ME/CFS that might help.
- Time will tell whether the current flock of ME/CFS and long-COVID hypotheses will win out, but the fact that most (Systom, Wirth and Scheibenbogen, Fluge/Mella, Patterson, Sfera at. al.) involve problems with the blood vessels, and some are even focusing on the RAA system (which hasn’t gotten much attention in ME/CFS), is nothing if not encouraging.
Endothelial Senescence and Chronic Fatigue Syndrome
Jump forward a year and this group of researchers – hailing from California, Texas, France, and Mexico – have now become fully embedded in ME/CFS research. Their dense, technical paper, “Endothelial Senescence and Chronic Fatigue Syndrome, a COVID-19 Based Hypothesis“, attempts to link long COVID and ME/CFS together in several novel ways.
The really fascinating thing, though, is how much of the paper centers on and expands on a key part of ME/CFS – the renin-angiotensin-aldosterone system (RAAS or RAS) paradox, and those high Ang II levels in particular.
Ang II – A Key to ME/CFS and Long Covid?
It’s upon those high Ang II levels that much may hang in ME/CFS and long COVID.
At high levels, Ang II can produce a remarkably wide array of nasty effects. High levels of Ang II produce inflammation, fibrosis, inhibit muscle repair, damage the endothelial cells lining the blood vessels, produce vasoconstriction (narrowing) in the blood vessels, jack up oxidative stress levels – producing peroxynitrite, and reducing the levels of nitric oxide – an important vasodilator.
Ang II also inhibits the phagocytosis or swallowing of damaged and dead cells (efferocytosis) – possibly allowing damaged endothelial cells to accumulate – and the intestinal dysbiosis to worsen.
When phagocytic cells such as macrophages fail to cleanly envelop or swallow damaged cells, the contents of those cells (called damage-associated molecular pattern (DAMP)) can leak into the bloodstream, causing an immune response. High DAMP levels have been associated with unexplained fatigue, chronic pain, exhaustion, and muscle dysfunction in other diseases.
Let’s not forget telomere attrition. Three years after the CDC found telomere attrition in ME/CFS, telomere attrition was linked to high Ang II levels in COVID-19.
To the Gut We Go
In the current paper, the authors move from their focus on the blood vessels to the gut. The epithelial part of the intestinal barrier is a fragile one – a single layer of epithelial cells covered up with mucous.
Besides all the other things it can do, Ang II can apparently trigger the death of that fragile line of intestinal epithelial cells. It also may be able to alter the junction molecules (claudins) that control barrier permeability. Either way, the intestinal barrier breaks down, allowing bad actors like lipopolysaccharides (LPS) to move into the bloodstream – sparking an immune response that may reach all the way to the brain.
The authors write that the fact that:
“… a dysfunctional RAS can trigger barrier disruption, dysbiosis and amino acid malabsorption…(makes it) not surprising that COVID-19 and ME/CFS have been associated with both aberrant immune responses and dysfunctional intestinal permeability.”
Several studies suggest a leaky gut may be present in ME/CFS, including one which concluded that exercise exacerbated it.
One wonders if the authors missed a beat by not including fibromyalgia (FM) in their hypothesis. It’s taken longer to get to the gut connection in FM, but a recent study suggested similar bacterial problems occur in FM.
Finally, the authors bring in one of the key actors in the Wirth and Scheibenbogen and Fluge/Mella hypotheses – the autoantibodies directed at the cholinergic and beta 2 adrenergic receptors (B2AdR). Instead of the autoantibodies resulting from molecular mimicry, though, the authors propose these autoantibodies are being produced and aimed at the bacterial molecules escaping from the intestines.
Possible Treatments
The authors noted that several treatments (escitalopram, coenzyme Q10 and nicotinamide adenine dinucleotide (NAD), mildronate) used in ME/CFS can restore endothelial functioning, and suggested that angiotensin receptor blockers (ARBs) might be helpful.
Factors that improve short-chain fatty acids (SCFAs/fermented dietary fiber) may be able improve intestinal integrity. Fat globule membranes (MFGM) and b-glucan have been shown to do the same in mouse studies. B-glucan may also be able to damp down microglial activation in the brain. Fecal transplants haven’t been studied enough, but the early word on them in ME/CFS is pretty good. Metformin may be able to protect the gut barrier.
The authors also believe that a new field of drugs called senotherapeutics (dasatinib, hyperoside, quercetin, fistein, Navitoclax), which target cell death and aging, may present another as yet untested option.
Conclusion
Time will tell if these authors are right, but the encouraging thing is that the new eyes being focused on ME/CFS as a result of long COVID are already fashioning new hypotheses and adding new potential insights and treatment possibilities to the field.
We didn’t know, for instance, that the high Ang II levels found in ME/CFS/POTS might be damaging the mitochondria. While the connection between Ang II and the blood vessels had been made, the possible connection between Ang II and the intestinal barrier had not. Ditto with efferocytosis, telomere attrition, and the idea that the beta-adrenergic autoantibodies that have aroused so much interest in ME/CFS might be being produced in response to bacterial products that have leaked into the blood. Along with these insights came a new set of treatment possibilities.
Long COVID and ME/CFS hypotheses seem to be merging…Will it keep up?
Perhaps the most striking thing about this and other recent hypotheses, though, is a continuing focus on the blood vessels from different research groups.
Fluge and Mella believe autoantibodies are affecting blood vessel functioning via endothelial cell dysfunction. Wirth and Scheibenbogen believe the same, and add in vasodilators, and then potentially link the autoantibodies and the vasodilators to the RAAS paradox.
Systrom’s invasive ME/CFS exercise tests suggest blood vessel problems occur in different subsets of ME/CFS: just before the blood gets to the muscles, and in the veins after it’s left the muscles, something is hampering blood flows. Even Bruce Patterson, who is at this point fully focused on long COVID, believes blood vessel problems are at the very core of that condition.
Time will tell whether nature will, as Robert Phair puts it, brush aside these “beautiful hypotheses” or whether they will stand up to the test of time. It’s encouraging though, to see common themes emerge so very early in the hunt for the cause of long COVID.
They proposed that high ANG II levels are knocking out the mitochondria in endothelial cells lining the blood vessels – reducing nitric oxide (N0) levels (inhibiting the blood vessels from dilating properly),
With regard to men with ME/CFS…..I wonder if this could be a contributing factor to erectile disfunction?
That is a very interesting question. I don’t know but I would imagine the blood vessels have to be working properly for everything to proceed correctly.
Never had an erectile dysfunction, even in the worst periods of completely bedridden situation, unable to drink even water(age 59), so probably not. But knowing it is very complex condition is hard to to do an uniform rule.
Hey George,
since when do you have CFS and is it post viral?
The first time hit me at age 54 and i spent 4 months bed-bound but in 2 months i did recover 100%. 5 years later hit me for the second time and kind a stronger ,i’m 1 year bed and home bound now mostly . Really don’t know, newer been sick, can’t really see the reason but i believe it is autoimmune- i have hashimoto since 2000(at least). then i developer from nowhere very severe urticaria(don’t know the reason for) in 2010 an until the beginning of this crisis i was on med. for it and once this happened now the urticaria disappeared totally
Its not just men having problems downstairs. I was just told by my lady doctor that my issues might be due to my nervous system. She wouldn’t recognize my me/cfs but would acknowledge what my neurologist said, “A virus hit your central nervous system”.
Glad somebody speaks openly. Thank you for that. It’s not only men. Or some men? It’s (some) women too. The before (multi…) and after (nothing), on those very rare occasions I was able to be intimate? Mindblowing difference. Never spoken about but that too has been a major loss. Always felt it’s a ‘bloodflow or nerve conduction’ thing, Can’t be anything else. Like a 4 lane high speed highway that turned into a muddy narrow long road with lots of turns and no final destination. Ugh.
I’ve been on Sildenafil (Viagra) for a couple of years now. I find it eases brain fog slightly and reduces shortness of breath a little. It’s no panacea (not a cure all) though, just a small help.
It’s been successfully used in stroke patients to regain brain blood flow. Also used in premature babies for lung development. It’s used for increasing peripheral blood flow in Raynaud’s disease. And in adults is found to sooth the heart ‘thump’ at rest. So I figured it should help ME/CFS
There was an ME/CFS Sildenafil study started but I never found the published results
It’s also being studied in acute Covid for lung function to see if it gets more oxygen into the blood (I’m yet to find those results)
I drink a lot of water with it to also increase blood volume, and wear compression tights, and find I get more upright time (no pun intended) I take half strength slow release aspirin to thin the blood too.
I take 30-40mg of Sildenafil 3 x daily
Seems to give a 10% improvement physically and 20% cognitively. I find I wake up faster if I take the Sildenafil in the morning with a coffee and a large glass or two of water
The generic version of Sildenafil is about NZD$2 for a 100mg pill so affordable
Many chemists sell it over the counter for erectile dysfunction. But the Men’s clinics sell it cheaper in bulk
Note: NEVER take with other ‘NITRATE’’ medications like heart or blood pressure meds as the combination dangerously drops blood pressure.
I do however take propranolol with it but a low 10-20mg dose
I remember a Sildafenil study at UCLA in Los Angeles years ago. I don’t know if it ever got finished. What an interesting idea, though. Glad it helps a bit.
The angiotensin II connection is interesting. My neurologist has put me on Atacand which is an angiotensin II blocker for my chronic vestibular migraine. It works sometimes and we have to keep bumping the dose up.
Interesting. Is it possible that Ang II – which despite its role in the RAA paradox received very little interest in ME/CFS – might be a key player?
In fact, apart from a few studies, the RAA paradox has received almost no interest. Until Wirth and Scheibenboggen came along nobody that I’m aware of tried to explain it. Yet, blood volume is big issue in these diseases.
Perhaps it’s partly because the POTS researchers that have clued in on the RAA paradox aren’t molecular biologists…I don’t know.
This paper collaboration is very good news indeed:
“ Jump forward a year and this group of researchers – hailing from California, Texas, France, and Mexico – have now become fully embedded in ME/CFS research.”
Exactly what the ME field needs – I am grateful to them. Let’s hope the push from long covid will result in major breakthroughs.
And thank you for your superb analysis tying in all the blood vessel findings!
Thanks. It was great to see this diverse group of researchers – none of whom had studied ME/CFS before – putting forth an ME/CFS and long COVID hypothesis. It shows a) that ME/CFS has not been lost in the rush to understand long COVID and b) that long COVID researchers have something to learn from this disease as well.
Like this Harvard prof advocating for ME/CFS and long COVID. Never heard of her before – yet she wrote a powerful piece on the historical neglect of ME/CFS.
https://blog.petrieflom.law.harvard.edu/2021/07/29/long-covid-chronic-illness/?fbclid=IwAR2q93prvPPPCe-GKIKQCRb-1VM_PM25Q0MoH6bmgaIJEXd_KhXH4spPUqk
The author proposes escitalopram (Lexapro) as a treatment option to restore endothelial functioning. What is the logic behind this? Would other SSRIs work?
apparently SSRIs affect endothelial functioning, see https://pubmed.ncbi.nlm.nih.gov/19004511/
Doesn’t appear to be specific to Lexapro, maybe they just give that as an example of an SSRI that’s well-tolerated.
Yes, they appear to have searched far and wide for any drug that can affect endothelial functioning. It’s not at all uncommon, though, for a drug to affect a lot of things it was not designed for.
I agree the Renin-Angiotensin-Aldosterone system is involved. The problem that brings that system into play is the Adrenal glands. Two hormones produced by the Adrenal glands which set up the process is firstly low Cortisol which brings about low blood pressure which then the kidneys release Renin beginning the flow on affect from the liver and lungs to produce Angiotensin 11 which acts directly on blood vessels stimulating vasoconstrition and also acts on the adrenals to release Aldosterone. When the Adrenal glands are damaged (from viruses and inflammatory responses from the immune system) they no longer produce enough Cortisol to keep blood pressure stable or enough Aldosterone to maintain fluid volume. With low blood pressure,low fluid volume,and vasoconstrition there is definitely a problem with blood circulation especially microcirculation contributing to thick blood. Viruses are known to hide in these glands and in the beginning of reactivation the immune response actually inflames the gland to produce high Cortisol and no Aldosterone problems but as the virus spreads the Adrenals become more compromised from the immune response and become damaged from inflammation. The virus can also be in any glands or body organs causing inflammation and mitochondrial damage. Also oxidative stress problems from blood flow problems in micro circulation thick blood. One must have good blood flow and pressure to supply nutrients to tissues and remove waste from tissues to function normally. Viruses are the problem also inflammation from immune response damaging glands and organs and causing blood flow problems.
Thanks Dennis for commenting on one of my favorite parts of the ME/CFS mystery. Thanks for the reminder of the potential strong adrenal connection. The possibility of high initial cortisol output is fascinating and I hope long COVID researchers look into this.
Oxidative stress is potentially a big player as well and we should have more on this soon.
Maybe why low dose hydrocortisone helps some people with CFS. Helps to maintain blood pressure and get better blood flow. But also must stop viral replication to stop inflammation from immune system which then allows the Adrenal glands a break from quelling the inflammation. But which antiviral therapy is best and least toxic. Have seen encouraging reports on the use of Famvir antiviral and Celebrex anti inflammatory daily use over 6months with good outcomes.
Cort, I am dealing with a lot of suffering since having had the COVID injections. I was wondering if I have had CFS all along and it was never fully addressed. Could having the injections do the same thing as it did to me that is described in this article that CFS patients seem to have when they contract COVID? I am awaiting my blood test results through Dr. Bruce Patterson’s group due to your articles. I am hoping I get some answers.
I think a correction is needed. This article refers to “very low blood volumes found in ME/CFS/POTS”. The wording “very low” is misleading. Anyone with very low blood volume would have to be severely dehydrated or going into shock from blood loss. The blood volume depletion shown in research on these conditions has been around 10 to 15%. It is certainly clinically and statictically significant, but it is not “very low”. In this video, Dr Satish Raj describes his research on volume depletion in a small study of POTS patients. It was an average of 13%.
https://vimeo.com/283559045
I found this paper the other day and found it fascinating, as I recently had gut microbiome analysis and intestinal permeability testing done. Well, I have a “very leaky” gut and quite a bit of bad bacteria! (gram-negative, and LPS levels were too high). So I think there’s definitely something to the idea that the microbiome and permeability issues are at play. I hope more people add to this line of research. In addition to their recommendations to address the gut issues (including probiotics, HP guar gum, l-glutamine, etc), I’m now interested in looking into additional supplements: fisetin, b-glucan, and maybe something like this: https://www.lifeextension.com/vitamins-supplements/item02223/pro-resolving-mediators?gclid=Cj0KCQiAr5iQBhCsARIsAPcwRONGHTQxq1JipWpAeyb8K43wwY7OkADNHKnzxt-Kdy0cAYZ7qQwrQUsaAjUqEALw_wcB
As for that last one, I just googled what efferocytosis was and if there are any supplements to improve it – that’s what popped up! I’m sure there are more, and I wonder if something along those lines will become more common in ME supplement protocols.