Part II: ME/CFS, Sepsis and Glycocalyx
To recap from the previous blog post “Part I: Blood Flow in Sepsis & ME/CFS”, ME/CFS looks like a lot like sepsis and sepsis is an inflammatory illness of blood vessels. The blood vessel problems in sepsis interfere with oxygen delivery to cells.
The particular kind of blood flow problem that you find in sepsis is often described as “heterogeneous perfusion.” In heterogeneous perfusion, blood flow is normal through some capillaries, but in neighboring capillaries, blood flow might be slowed or stopped.
In both ME/CFS and sepsis, we say that there is a problem with “oxygen extraction.” Cells have trouble accessing and using oxygen from the blood to make energy. Heterogeneous perfusion is known to cause problems with oxygen extraction.
Glycocalyx, an important material that lines the inside of blood vessels, is destroyed during sepsis and destruction of glycocalyx leads to heterogeneous perfusion.
The loss of glycocalyx might unite seemingly disparate aspects of chronic fatigue syndrome, like the fact that the illness seems to have so many different causes. There may also be an intersection between mast cell activation syndrome and glycocalyx. Glycocalyx loss could shed light on the connection between low blood volume and ME/CFS.
A material called glycocalyx that lines the interior of blood vessels is extremely important for preventing heterogeneous perfusion. Glycocalyx is lost because of inflammation during sepsis and its loss is directly related to problems with capillary function that you find in sepsis.
Glycocalyx is a fuzzy, loose, jelly-like substance. For a long time, until imaging techniques improved, we had no idea that glycocalyx took up so much space inside blood vessels. When we saw how much space it actually takes up, we concluded that it must be there for a purpose and we set about trying to discover what the purpose was exactly.
As blood moves through a capillary, glycocalyx turns that movement into a signal for the blood vessel to dilate to allow blood to flow through. Without healthy glycocalyx, blood vessels don’t stay open reliably. In a dynamic process, blood vessels with damaged glycocalyx open and close and open and close in a way that denies cells a reliable delivery of oxygen.
When blood vessels fail to stay open to allow blood to pass, heterogeneous perfusion is the result. Some vessels will be open, but some will be closed and others will flow slowly. When you remove glycocalyx experimentally, you can reproduce the blood flow patterns that you see in sepsis.
Glycocalyx is also home to various antioxidant enzymes that stand ready to quell oxidative stress inside blood vessels. When glycocalyx falls away, these enzymes are no longer present and oxidative stress in blood vessels can multiply and get out of hand, increasing glycocalyx damage.
One of these embedded enzymes is superoxide dismutase (SOD). SOD is responsible for preventing the formation of peroxynitrite, a particularly damaging free radical long thought to be elevated in ME/CFS.
Red Blood Cells and Glycocalyx
Last month, Ron Davis and the Open Medicine Foundation published a paper showing that people with ME/CFS have red blood cells that are harder than normal. Red blood cells are larger than capillaries and are meant to be squishy so that they squeeze through the smallest blood vessels. Hardened red blood cells that have lost their squishiness are unable to fit through many capillaries and this causes flow problems that can lead to heterogeneous perfusion.
Conversely, glycocalyx loss and heterogeneous perfusion can also cause a loss of red blood cell deformability. As red blood cells pass through low oxygen zones in slow blood flow capillaries, their oxidative stress increases which results in a loss of deformability.
Glycocalyx and Nitric Oxide
Glycocalyx keeps blood vessels open by releasing nitric oxide. Nitrix oxide dilates blood vessels. In my last article, we talked about how I respond well to methylfolate and potassium. These increase nitric oxide and visibly increase my blood flow, causing my skin to “pink up”. These supplements increase my energy, my ability to exercise without getting sick and improve my autistic symptoms.
Norwegian researchers Øystein Fluge and Olla Mella patented agents that increase nitric oxide as potential treatments for ME/CFS after observing a remission in a patient after she took a nitric oxide donating drug called Imdur for chest pain.
Do we, as ME/CFS patients, have a problem with damaged glycocalyx? When I take things that increase nitric oxide, am I supplementing the ability of my damaged glycocalyx to produce nitric oxide? Does external nitric oxide from supplements or drugs “pinch hit” for damaged glycocalyx?
Glycocalyx and the Many Causes of ME/CFS
People are known to get sick with ME/CFS after infections of various kinds, after physical injury, and after high emotional stress. After we get sick, additional “crashes” can be triggered by surgery, infections, accidents, or stress. How could we all end up with the same illness from so many different causes? How could so many different things make us feel worse?
A unifying theory might be that all of these events can trigger glycocalyx damage.
Glycocalyx is a delicate substance and many events can trigger its destruction.
Inflammation is one cause of glycocalyx damage. More severe infections seem to be more likely to lead to ME/CFS. Perhaps this is because more severe infections cause more severe inflammation. When we see clustered outbreaks of ME/CFS, we could be looking at infections that happen to cause an unusual amount of damage to blood vessels and glycocalyx.
David Bell, in his book Cellular Hypoxia and Neuro-Immune Fatigue, wrote about a patient of his that was one of many in an outbreak of ME/CFS in his town in upstate New York. He saw this patient two days before a flu-like illness would leave the patient with ME/CFS. This patient’s cheeks were bright red. Dr. Bell proposed that ME/CFS is a vasculopathy, a word that means that there is something wrong with the blood vessels. Bell observed other patients as well who had red cheeks before they developed a flu-like illness and ME/CFS.
Not a rash, exactly. “It was flushing,” Bell said. “Dilated blood vessels of the cheeks that would alternate with pallor, a sickly pale color.”
Bell proposed that the outbreak in his town was due to a parvovirus that caused blood vessel inflammation.
Local injuries can also potentially lead to widespread glycocalyx loss. If you have a major tissue injury from an accident or you undergo significant surgery, damage occurs to local blood vessels wherever there is tissue damage. Glycocalyx particles break away from the walls of blood vessels at the site of an injury.
These particles act as Damage Associated Molecular Patterns, or DAMPS. DAMPS are inflammatory molecules that originate inside the body and trigger noninfectious inflammation. DAMPS that come from glycocalyx can potentially flow through the blood and trigger inflammation and further glycocalyx damage elsewhere in the body.
In fact, the DAMPS that come from glycocalyx activate the same receptors that bacterial infection activates in sepsis: the TLR4 and TLR2 receptors. Activation of these particular receptors by bacterial infection initiates the inflammatory response that destroys glycocalyx in sepsis.
Activation of these receptors can not only cause inflammation, but can also cause immune suppression, a symptom often seen in ME/CFS.
These glycocalyx-sourced DAMPS have been proposed to serve as a cause of Systemic Inflammatory Response Syndrome, or SIRS. SIRS is just like sepsis, except SIRS doesn’t have to have an infectious cause. Sepsis is a kind of SIRS, one that is begun by bacterial infection.
Thus, a condition that involves an elevated release of glycocalyx particles from blood vessel walls stands a decent chance of looking rather like sepsis.
At the 2017 Open Medicine Foundation Symposium at Stanford, Wenzhong Xiao, Ph.D., presented evidence that the gene expression in ME/CFS resembled SIRS more than any other illness.
Adrenaline is a stress hormone released during emotional and psychological stress. It may also be an efficient destroyer of glycocalyx. I wonder if one of the effects of psychological stress is to increase adrenaline release and increase the destruction of glycocalyx.
If we get sicker during stress, there are some in the psychiatric community who would say that this proves that our illness is psychologically caused. What if, in our bodies, stress translates to damaged blood vessel function and worsening blood flow, effects that could never be helped with psychological therapies?
Mast Cell Activation Syndrome and Glycocalyx
When I developed ME/CFS, one of my earliest symptoms was hives accompanied by severe flushing in my cheeks, nose and ears. This was due to mast cell activation syndrome (MCAS), a condition in which an immune cell called a mast cell activates chronically and inappropriately. A lot of people with ME/CFS have MCAS as well.
I will write a longer blog on the intersection of mast cell activation syndrome and ME/CFS, but one possible connection is that mast cells live alongside blood vessels all over the body and they activate when blood flow is not working correctly and also in response to DAMPS.
Mast cells release enzymes and inflammatory mediators that destroy glycocalyx.
When you have a condition that involves chronic mast cell activation, like I do and like many of us with ME/CFS do, one consequence might be chronic damage to blood vessels that looks rather like sepsis.
Like Slow, Chronic Hemorrhage
A consistent finding with ME/CFS patients is that we have chronically low blood volume. Our blood volume is low enough that it seems to result in our hearts being smaller than normal, presumably because they do less work to push a smaller amount of blood around the body.
A sudden loss of blood through hemorrhage triggers glycocalyx damage that is nearly indistinguishable from the damage that occurs in sepsis. In fact, hemorrhage is a non-infectious trigger of SIRS.
Dr. David Bell said that ME/CFS resembled slow, chronic sepsis. Might our condition also resemble a slow, chronic hemorrhage?
Is Our Glycocalyx More Fragile Than Normal?
Robert Naviaux, Ph.D., is a researcher at the University of California San Diego. Dr. Naviaux is working with the Open Medicine Foundation to find answers for ME/CFS patients.
In studying the metabolism of patients, Dr. Naviaux identified a class of fatty compounds called sphingolipids as the point of greatest differentiation between healthy controls and people with ME/CFS. Sphingolipids were markedly downregulated in ME/CFS patients.
Albumin is the most abundant protein in the blood and its presence is the most important protective factor for the health and stability of glycocalyx. The part of albumin that stabilizes glycocalyx is a sphingolipid called sphingosine-1-phosphate (S1P). Without S1P, albumin does not protect glycocalyx.
In a study published in October 2018, researchers found that S1P preserves glycocalyx integrity and function during hemorrhage.
If we have a global reduction in the sphingolipid compounds, is our S1P sphingolipid also low? If our albumin is low in S1P, might ME/CFS patients be unusually sensitive to glycocalyx damage from any cause including inflammation or chronic low blood volume? If this were the case, would intravenous albumin be a possible treatment for improving blood vessel function? Intravenous albumin is derived from the blood of other people and would presumably contain normal amounts of S1P.
Like blood vessels, glycocalyx is present in every square inch of the body and its presence plays a powerful role in determining how and whether blood reaches cells. It is known to be damaged by the same events that trigger and worsen ME/CFS. If damaged glycocalyx is contributing to ME/CFS, this should allow us to identify logical new treatments.