As we hoped, technologies are being used in COVID-19 and long-COVID research that would have taken years, if not decades, to show up in chronic fatigue syndrome (ME/CFS), fibromyalgia (FM) research. They’re accelerating insights into potentially critical issues in these diseases. None is more critical – particularly in ME/CFS – than the cause of the fatigue and lack of energy in these diseases.
Because blood vessels deliver oxygen to the mitochondria they need to provide free flows to them. It just makes sense that poor blood/oxygen flows to the cells is going to impede energy production. The interest in the role blood vessels and reduced oxygen delivery to the muscles plays in fibromyalgia, and particularly ME/CFS, dates back quite a ways. As far back as 2013, Health Rising was asking: “Are Oxygen Starved Tissues Causing Pain and Fatigue in Fibromyalgia and Chronic Fatigue Syndrome (ME/CFS)?”
Perhaps the strongest evidence that blood vessel problems exist in ME/CFS comes from David Systrom’s invasive exercise studies. Systrom’s ability to measure blood flows and oxygen levels before and after the blood gets to the muscles is the key.
- Because blood vessels deliver the “juice” (oxygen in the blood) the mitochondria use to produce energy, it’s critical they flow free and clear.
- David Systrom’s invasive exercise studies in chronic fatigue syndrome (ME/CFS), though, suggest they may not be, and that the blood vessels are failing in two different ways: in one group of patients, the blood is being diverted away from the muscles shortly before it gets to them. In another group, blood is being lost after it’s gone through the muscles – leaving the heart with less blood to pump.
- Recent attention in long COVID and COVID-19 has focused on the endothelial cells lining the blood vessels and the damage the SARS-CoV-2 coronavirus may have done to them as it entered them via the ACE-2 receptor. These cells dilate the blood vessels when needed, protect the blood vessels from leaking, and produce pro-inflammatory cytokines.
- Enough endothelial cell damage has been found thus far for some researchers to assert that long COVID is an “enodothelioapthy”; i.e. a disease of the endothelial cells.
- Both ME/CFS and fibromyalgia studies have suggested that damage to the endothelial cells lining the blood vessels is present. One FM study even suggested that endothelial cell damage might be diagnostic for that disease.
- An Isreali study that used umbilical cords as a stand-in for blood vessels found that no less than 70 percent of the proteins that the SARS-CoV-2 coronavirus produces negatively impact the blood vessels in one way or another.
- Another that used something called “evolutionary rate correlation” suggested that many of the proteins the virus produces affects the coagulation/clotting process in the blood.
- Several studies suggest that the virus’s ability to produce micro clots in the blood may be why it’s so much better than the flu at producing ME/CFS states such as long COVID. One study found nine times the level of micro clots in COVID-19 patients compared to flu patients.
- Another study suggested that high levels of amyloid (misfolded proteins) were implicated in the increased clotting found in COVID-19.
- That was interesting given the results of a 2005 ME/CFS cerebrospinal fluid proteome study, which highlighted the presence of amyloid proteins. It proposed that misfolded proteins embedded in the blood vessels of ME/CFS patients’ brains were causing small leaks.
- Avindra Nath’s finding of punctate hyperintensities that appeared to be causing leaky blood vessels in the brains of autopsied COVID-19 patients, in turn, brought us back to a 1992 finding of widespread punctate hyperintensities in ME/CFS patients’ brains.
- Deformed red blood cells could also be impairing blood flows. They have been found in COVID-19, but it’s ME/CFS researchers at Ron Davis’s Collaborative ME/CFS Stanford Research Center that are leading the charge. In order to assess if deformed red blood cells are causing problems, they’re developing cheap and effective ways to assess blood flows through the microcapillaries.
- Blood vessel leaks in different areas, micro clots, narrowed blood vessels, and deformed red blood cells could all be impacting the flow of blood, and therefore oxygen, to the mitochondria in long COVID and ME/CFS.
- COVID-19 is doing precisely what we had hoped it would do: it’s jumpstarted research into areas of critical concern in ME/CFS/FM, and is producing new technologies, insights, and even treatment possibilities (e.g. Bruce Patterson’s attempts to solve the blood vessel problem).
His studies suggest two different blood vessel problems are occurring in ME/CFS:
- One group of ME/CFS patients has higher than expected oxygen levels in the venous blood. That suggests that a microcirculatory problem is shunting blood away from the muscles – depriving the mitochondria of oxygen. The inability of the mitochondria to get a hold of this oxygen during exercise results in higher-than-normal oxygen levels in the venous blood. It’s very easy to potentially explain the fatigue/PEM in this group – their muscles are simply not getting the fuel they need for their aerobic energy production system to kick in.
- Another group with normal venous oxygen levels, but with reduced amounts of blood returning to the heart (low preload), appears to have sprung some leaks in their venous circulatory system. This group simply doesn’t have enough blood reaching the heart for it to provide normal amounts of blood to the muscles.
While the cause is different in the two groups, the end result is the same – not enough blood (i.e. oxygen) is getting through to the muscles for the aerobic energy production system to fully kick in. Note that both problems feature leaky blood vessels – either right before the blood reaches the muscles or afterward.
Besides Systrom, Shungu’s reduced brain blood flows, Visser’s reduced oxygen uptake, ACE-2 problems in COVID and ME/CFS, and several hypotheses (Wirth/Scheibenbogen, Fluge/Mella, Shungu) all question whether blood vessel problems are present.
Similar questions are being raised in fibromyalgia as well. A 2019 study, in fact, proposed that a marker of endothelial cell dysfunction might prove to be diagnostic for FM. Other studies have found reduced oxygen uptake during exercise, and stiffened arteries (in both ME/CFS and FM).
Given all that it was interesting to see a recent COVID-19 study, “Effect of SARS-CoV-2 proteins on vascular permeability“, use an approach that took the blood vessel issue in COVID-19, long COVID, and perhaps even ME/CFS, to a whole new level.
Leaky Blood Vessels, Leaky Gut, Leaky Brains?
2020 saw the emergence of SARS-CoV-2 coronavirus, which just happens to attack the same endothelial cells lining the blood vessels that some researchers believe have gotten whacked in ME/CFS. Blood vessel problems are now believed to play such a big role in COVID and long COVID that some researchers believe it is as much a vascular disease as a respiratory disease.
In fact, as time goes on and the damage to the lungs clears up – but the fatigue, cognitive and other problems remain – more COVID-19 researchers are turning to the blood vessels to attempt to explain the mysterious long-term issues the long-COVID patients are dealing with.
Bruce Patterson’s long-COVID treatment protocol is a case in point. Patterson uncovered evidence of unusual clotting in long COVID a year ago. His treatment protocol banks on the idea that endothelial cell dysfunction is the be all and end all in long COVID. He believes a similar process may be occurring in ME/CFS/FM and post-Lyme disease.
Endothelial cells keep the blood vessels from leaking, dilate the blood vessels when more blood flow is needed, and produce inflammatory factors that cause clotting and other issues.
In October, Irish researchers proposed that a persistent “endotheliopathy” – a disease of the endothelial cells – is causing breathlessness, fatigue, and exercise intolerance in long COVID.
COVID-19 researchers believe they’ve already identified three sequential stages in which endothelial cell damage occurs in that disease.
First, the direct hit from the virus on the endothelial cells (it enters them through the ACE-2 receptor) causes an immune response that interferes with their functioning. The subsequent death of those cells causes the angiotensin I-converting enzyme 2 (hACE2) to activate the kallikrein–bradykinin, and renin–angiotensin pathways, which then results in increased vascular permeability; i.e; leaky blood vessels.
That’s a really intriguing model as a similar model for ME/CFS was proposed by Wirth and Scheibenbogen hypothesis pre-COVID.
Finally, an immune system overreaction damages the junctions between the endothelial cells, allowing the blood vessels to leak and a hypercoagulable state to form.
While the authors don’t mention it, note that leaky gut linings are also an issue in long COVID, ME/CFS, and fibromyalgia, and that the same ACE-2 receptor implicated in COVID-19, ME/CFS, and POTS is also found in the gut. This could conceivably be causing or contributing to the IBS-like symptoms often found in COVID-19, long COVID as well as ME/CFS, FM, and POTS.
Could problems with this receptor be causing problems in the blood vessels, the gut, and the brain in all these diseases? Except for a few small studies and the recent attention given it by Wirth/Scheibenbogen, this receptor has received very little study or interest in ME/CFS and POTS.
Endothelial Cell Breakdown Explained?
The endothelial cells, though, are receiving a lot of interest in COVID-19, – so much so that in “Effect of SARS-CoV-2 proteins on vascular permeability“, an Israeli research group turned to umbilical cords to study them. Using umbilical cords as a blood vessel model, the Israelis introduced the SARS-CoV-2 (the coronavirus) proteins into the model to see how they affected it.
Remarkably, almost 70% of the coronavirus proteins negatively impacted the endothelial cells lining the blood vessels. The Israeli researchers proposed that a system-wide problem of leaky blood vessels might be causing the multiplicity of symptoms and conditions associated with the virus. In their latest hypothesis paper, “An attempt to explain the neurological symptoms of Myalgic Encephalomyelitis/Chronic Fatigue Syndrome“, Wirth and Scheibenbogen reported that no less than 5 studies have found damage to the endothelial cells in long COVID.
Another study went so far as to use something called “evolutionary rate correlation” to uncover proteins that co-evolved with the ACE-2 receptor. The goal was to uncover proteins that were interacting with that receptor. The study distinguished several coagulation pathway proteins, the immune response proteins, and proteins associated with the androgen receptor.
If you’ve never heard of “evolutionary rate correlation”, or using umbilical cords to study the effects of proteins on the blood vessels, don’t feel bad. No ME/CFS/FM studies have attempted to do anything like that – and aren’t likely to in the near future. In fact, we’re going to have to get used to new technologies popping up that we’ve never heard of or even conceived of before. It’s a coronavirus thing.
Micro Clots and Amyloidic Proteins, Oh My…
Speaking of clotting, The Irish study mentioned above, which went far beyond any assessment of clotting thus far done in ME/CFS/FM, found a variety of “pro-thrombotic changes” had occurred; i.e. it suggested that long-COVID patients are predisposed to produce blood clots.
The coronavirus’s propensity for producing micro clots could also help explain why COVID-19 is so much better at producing ME/CFS-like states such as long COVID than the flu is at producing them. Back in July 2020, a study that found 9 times the level of small blood clots in the lungs of people with COVID-19 compared to people with the flu may have stumbled upon a key feature in lingering, post-infectious disease states.
In August a South African study, “Persistent clotting protein pathology in Long COVID/Post-Acute Sequelae of COVID-19 (PASC) is accompanied by increased levels of antiplasmin“, found that people with both acute and long COVID were having difficulty breaking down the plasma proteins in their blood.
This “pathological fibrinolytic system” appeared to result in “persistent anomalous (amyloid) micro clots”. The apparent inability of long-COVID patients to get rid of their misfolded folded proteins (i.e. micro clots) appeared to be gumming up their blood. The authors speculated that this might have been caused by a prolonged inflammatory state. Unfortunately, it didn’t seem to be going away over time.
It did, however, make Baraniuk’s 2005 cerebrospinal proteome study finding that much more interesting. Baraniuk reported that the ME/CFS “proteome was remarkable for the number of proteins associated with protein misfolding and cerebrovascular amyloidosis syndromes.” Evidence of amyloid deposition in the blood vessels, and a weakening of the blood vessels walls, was found. Baraniuk speculated that localized bleeding caused by amyloid deposition into the blood vessels might be occurring throughout ME/CFS patients’ brains.
The micro clot findings and the breakdown in the fibrinolytic system designed to get rid of them are intriguing given the hypercoagulation found in both ME/CFS and fibromyalgia about 20 years ago.
Back to the Future? A 1992 ME/CFS Study
The amyloid finding, though, brought us back to an even earlier finding in ME/CFS – the 1992 finding of widespread punctate hyperintensities in the brains of people with ME/CFS. These hyperintensities are thought to be the result of chronic microvascular disease.
Back then the researchers didn’t know what to do with that finding, but in 2020 Avindra Nath found evidence of similar thinned, leaking blood vessels (“punctate hyperintensities”) in the brains of COVID-19 patients.
Nath suggested that a series of small strokes had occurred across the brains of COVID-19 patients and even proposed that these lesions could be producing problems with heart rate, breathing, etc. Nath subsequently undertook a neurological study of long-COVID patients that could tell us much.
Deformed Red Blood Cells?
Then there’s red blood cell deformability – ME/CFS’s potentially unique contribution to the long-COVID field. If an inflammatory milieu around the red blood cells exists, it could have consequences for the red blood cells themselves. It doesn’t appear that red blood cell deformability is gathering much interest in long COVID.
A Russian study, though, found massive damage to the red blood cells, stacked, aggregated erythrocytes (red blood cells) capable of clogging the “microvascular bed” and diminishing the oxygen supply to the tissues in, get this, mild COVID-19 patients. It suggested that anti-thrombotic drugs be used. Dr. Holtorf has remarked that he’s found heparin to be useful in some people with ME/CFS.
The red blood cell deformability project funded by the Open Medicine Foundation at the ME/CFS Collaborative Research Center at Stanford University, though, began before long COVID reared its head, and it continues to evolve.
The RBC deformability saga in ME/CFS began with a finding by San Jose State University researchers, and moved over to Stanford. Recently, the University of California at Davis researchers have joined the show.
The project’s continued evolution suggests that deformed red blood cells could be impeding blood flows in that last, most crucial juncture – the microcapillaries that deliver blood to the muscles.
Unfortunately, the idea that this might be a problem seems to have escaped medical researchers before now and the technology to properly assess them was lacking. So, Ron Davis did what Ron Davis does – he, in collaboration with the Stanford and UC Davis teams, began to develop a microfluidic device that can do that.
Davis expects that this instrument will fit a couple of nice parameters: it’ll be inexpensive, easy to operate in different clinical settings, and produce results in a short time.
With the increased emphasis on clotting and oxidative stress, the red blood cells, and the microcirculation, this project comes at an excellent time – not just for ME/CFS but potentially for long COVID as well.
Different Roads Leading to Rome…
The saying went “all roads lead to Rome” simply proposes many different ways exist to get to your location; in this case to the fatiguing, exercise-challenged states of ME/CFS/FM, long COVID, etc. Leaky blood vessels found before or after the blood vessels, micro clots, amyloidal deposits, massive vasodilator release, and/or deformed red blood cells could all contribute.
These studies – coming from the U.S., Ireland, South Africa, and other countries – display a remarkable array of new technologies that have been pressed into service to understand COVID-19 and long COVID. More than anything, it’s new technologies that will likely get at the genesis of complex, multi-systemic diseases like ME/CFS.
If a multisystem origin is what you want, the blood vessels are a great place to start. Before the long-COVID saga is done, it’s clear that much will be learned about the endothelial cells, the blood vessels, the red blood cells, and the microcirculation – all potentially vital issues in ME/CFS. If long COVID turns out to be an endothelial disease, these studies will surely provide roadmaps that will be used in ME/CFS/FM.
Long COVID, then, is already doing what people with ME/CFS/FM wanted it to do. It’s bringing new technologies and new researchers to the study of post-infectious disease states, as well as an increased focus on factors that we already believe may play a significant role in these diseases, and is already providing potential insights into them.
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At Health Rising we try our best to put the pieces together and explain them. Sometimes that means reaching way, way back. I remember, back in 2005 being excited and kind of appalled by the finding that amyloidal fragments (amyloids!) might be causing problems in ME/CFS. Jump forward 16 years, though, and here they are popping up in long COVID, as well.
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