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The Scheibenbogen Effect

Thus far this year, Scheibenbogen has co-authored 5 ME/CFS studies.

With the studies pouring out, it’s getting hard to keep up with Carmen Scheibenbogen and friends in Germany. Scheibenbogen has co-authored no less than five papers on chronic fatigue syndrome (ME/CFS) in 2020. With Klaus Wirth coming on board, the autoantibody testing lab there, and Scheibenbogen and company in a publishing frenzy, Germany – out of which virtually nothing on ME/CFS came for decades – has now become quite a hub of research. The one constant in all of this appears be Scheibenbogen, who has co-authored 17 papers on ME/CFS since she appeared on the scene in 2014. Such is the impact one dynamic researcher can have.

The hunt seems to be circling mainly around two factors: autoimmunity and the blood vessels. This study tackles one of the most intriguing possibilities in ME/CFS – impaired circulation. ME/CFS has been thought of as an immune disease, a hormonal disease, and a metabolic disorder, and indeed it seems to have aspects of all of these, but what about ME/CFS as a cardiovascular disorder? What quicker way to impair energy than to inhibit the flow of oxygen-rich blood through the small blood vessels?

The Study

ESC Heart Fail. 2020 Jun;7(3):1064-1071. doi: 10.1002/ehf2.12633. Epub 2020 Mar 10. Peripheral Endothelial Dysfunction in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome. Nadja Scherbakov 1 2 3 4Marvin Szklarski 5Jelka Hartwig 5Franziska Sotzny 5Sebastian Lorenz 5Antje Meyer 1 3 4Patricia Grabowski 5Wolfram Doehner 1 2 3 4Carmen Scheibenbogen 1 5

In this study, lead author Nadia Scherbakov, senior author Carmen Scheibenbogen and other researchers, working out of Berlin, focused on the thin line of endothelial cells which line the blood vessels and which help to control whether they are open or constricted. They also produce immune and blood clotting factors.

First, they used a non-invasive technique called “Peripheral Arterial Tonometry (PAT)” to measure changes in the “vascular tone”. During the test a blood pressure cuff reduces blood flows to the hand for five minutes.  After the cuff is opened the amount of blood flowing to the fingers is measured.

The EndoPat test, which can be done in a doctor’s office, can be used to quickly assess risk factors for cardiovascular diseases such as heart failure, stroke, and pulmonary arterial hypertension.

In contrast to other cardiovascular tests, PAT assesses microvascular functioning; i.e. the functioning of the peripheral arterioles found just before the capillaries. These arterioles, which are lined with smooth muscles, are where most of the blood flow regulation occurs. If not enough nitric oxide (NO), a vasodilatory substance,  is produced, the arterioles will not be able to dilate enough to let sufficient amounts of blood through to the capillaries which transmit nutrients to the tissues.

The German researchers assessed something called reactive hyperemia, which occurs when the flow of blood through the veins gets blocked, lowering oxygen levels (producing ischemia) and causing a buildup of metabolic waste. The doctor in the video below reports that a result above 2.0 is normal.

The Gist

  • Using a non-invasive approach (Endo-Pat) featuring a blood pressure cuff and a finger monitor, German researchers assessed the functioning of the small blood vessels called arterioles.
  • The arterioles, which are located between the arteries and the capillaries, regulate blood flows by producing nitric oxide, a blood vessel dilator.
  • The study assessed something called a “reactive hyperemia index” (RHI). An RHI below 2 is considered a cause for concern. It suggests that damage to the endothelial lining to the blood vessels has occurred, which is blocking the flow of blood. Endothelial dysfunction is often the first sign of cardiovascular disease.
  • The small study found that about 50% of people with ME/CFS had low RHI’s.  Attempts to find a metabolic or immune cause including B2 adrenergic antibodies were unsuccessful, however.
  • A small substudy involving 6 patients with increased levels of B2 adrenergic antibodies, however, did find that immunoadsorption resolved the small blood vessel issues in 5 of them.
  • Dr. Scheibenbogen reported that another small follow-up immunoadsorption study has produced similar results to the first one. (The first one produced excellent results in a subset of patients.)
  • Three studies using the Endo-Pat technology have been done in ME/CFS – two have found endothelial dysfunction and one has not.
  • Larger studies are needed to validate this study’s intriguing finding indicating that narrowed small blood vessels in large subset of people with ME/CFS may be reducing blood flows to the tissues.
  • Other studies, but not all, have found reduced blood flows to the brain and/or muscles in ME/CFS. David Systrom’s large studies indicate that reduced oxygen delivery (i.e. energy) to the muscles is present in this disease.
  • Systrom believes three factors – one of which involves the microcirculation – may be causing the oxygen delivery problem.
  • As endothelial dysfunction is found in many diseases, it cannot by itself explain what’s causing the fatigue and exertion problems in ME/CFS. Wirth and Scheibenbogen have proposed impaired blood vessel functioning that results in dramatic increases in pain and fatigue producing vasodilators is present in ME/CFS. They are working on a second hypothesis they believe may explain the energetic problems in ME/CFS.
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Results

The study, which used 35 people with ME/CFS and 20 (age and BMI matched but not sedentary) healthy controls, found evidence of peripheral endothelial dysfunction in 51% of the ME/CFS patients. The endothelially challenged ME/CFS patients were functionally more limited and had more severe fatigue-related and immune-related symptoms (sore throat, painful lymph nodes) than the patients without apparent endothelial issues.

The researchers appear to have identified a sicker group with more endothelial issues. They were, unable, however – at least with regards to the lab tests – to determine why. Given the beta-adrenegic antibodies Scheibenbogen’s found in other studies, one might have expected elevations to be present, but they weren’t. (Dr. Scheibenbogen suspects these antibodies only play a role in a subset of patients and other factors are likely also responsible for blood flow issues.)

None of the immune or metabolic markers (C‐reactive protein, albumin, hemoglobin, creatinine, aspartate transaminase, alanine transaminase, gamma-glutymytransferase, hemoglobin A1c, basal thyrotropin, immunoglobin A,G, M, IL-8, sIL-2, soluble V and ICAM, β2‐adrenergic receptor antibody, M3 acetylcholine receptor antibody) were either elevated or reduced in the patients with endothelial dysfunction.

But then came a clue.  An immunoadsorption trial that attempted to rebalance their immune systems caused the endothelial problems to disappear in five of the six sicker patients.

Similar to plasmaphoresis, immunoadsorption is a blood purification technique which removes IgG autoantibodies and other pathogenic substances from the blood. It’s an expensive treatment (about $20,000) sometimes used in multiple sclerosis and other autoimmune diseases.

Every one of the six patients getting immunoadsorption had elevated levels of antibodies to the beta-adrenergic receptors found on the blood vessels (these receptors also play a key role in vasodilating the blood vessels). The immunoadsorption appeared to open their blood vessels – allowing blood to reach their tissues – and presumably reducing the hypoxia and metabolic wastes that were building up.

The authors didn’t say how much the health of these patients improved, but a study on the effects of immunoadsorption on ten ME/CFS patients found that 7 rapidly approved and three had moderate to marked improvements lasting 6-12 months. Much larger studies are needed, but the increase in endothelial functioning was promising, and the trial’s success suggested that a focus on the immune/cardiovascular interface made sense.

Conclusions

The idea of ME/CFS being a kind of cardiovascular disease affecting the small blood vessels seems to make perfect sense but has been surprisingly little explored. This appears to be the third time that PAT has been used in chronic fatigue syndrome (ME/CFS). Back in 2012, Newton did find evidence of endothelial dysfunction in ME/CFS, but in 2018, the Moneghetti /Montoya study, which matched ME/CFS patients to healthy sedentary controls, did not.

In contrast to the Montoya study, which used sedentary controls – and did not find diminished endothelial functioning in ME/CFS – this study did not use sedentary controls. The Scheibenbogen study did, however, appear to have a more endothelially challenged group, and perhaps a sicker group as well, as over 50% of their patients had a low reactive hyperemia index (RHI) (<1.81).

Arteries, arterioles, capillaries

The EndoPat measured the ability of the arterioles to dilate and pass blood through to the tissues.

Montoya’s ME/CFS group, on the other hand, had a much higher average RHI of either 2.21 or 2.44 (the paper did not indicate which number referred to which group.)  Montoya’s ME/CFS patients also had similar exercise results as the healthy controls.

While few studies have actually studied endothelial dysfunction in ME/CFS and FM, the idea that it may be present appears to fit well with what we know. Shungu’s brain lactate, Scheibenbogen’s mRNA findings, several, (but not all), brain blood studies suggest something may be wrong with blood delivery in ME/CFS.

Several, but not all, studies suggest that oxygen delivery to the muscles may also be impaired in ME/CFS.  After earlier exercise studies suggested oxygen delivery issues were impairing energy production during exercise, Systrom’s more recent, and much larger, invasive exercise studies seem to have settled that issue: oxygen delivery is indeed an issue for a large subset of patients.

Similarly, Staud’s finding that greater cerebral blood flows and higher heart rate variability levels (lower sympathetic nervous system (SNS) activity) were associated with reduced fatigue in ME/CFS made perfect sense given the role the SNS plays in squeezing the blood vessels. Dr. Natelson has proposed that some of the cognitive symptoms in ME/CFS derive from an “episodic cerebral hypoxia“; i.e. episodic declines of blood delivery to the brain.

The possible presence of stagnant hypoxia in ME/CFS and POTS provides yet another clue that oxygen delivery in ME/CFS and related diseases may be a problem. Stagnant hypoxia occurs when the oxygen content of the blood is normal, but the blood is moving too slowly to deliver sufficient amounts of blood to the tissues.

Stagnant Hypoxia – Where Chronic Fatigue Syndrome and Hyperadrenergic POTS Meet?

Arterial stiffness – an expected outcome of endothelial dysfunction – was found in one ME/CFS study, but not in a pediatric one.

Finally, Wirth and Scheibenbogen’s recent hypothesis – that a breakdown between vasoconstrictor and vasodilator forces in the blood vessels results in a massive upregulation in pain-producing vasodilating substances – puts a new twist on the blood delivery issue in ME/CFS.

It’s not just ME/CFS, though.  At least as early as 2006, researchers were suggesting that muscle ischemia caused by low blood flows could be contributing to the pain fibromyalgia (FM) patients experience.  They asserted that next step was to determine what happens to capillary blood flows (i.e. the microcirculation) in FM during exercise.

Low Energy Production and Pain in Fibromyalgia – Is Your Microcirculation To Blame?

While most studies are small, the possibility that small blood vessel oxygen delivery problems to the muscles and brains of people could be causing or contributing to ME/CFS, and perhaps FM, appears to be growing.

Cause?

What might be causing it is another matter. Factors like high blood pressure and high blood glucose have not been found in ME/CFS.  High levels of lipoproteins, oxidative stress and inactivity have been.

Nitric oxide synthase – the study suggested that the small blood vessels in a significant subset of ME/CFS patients may not be producing enough NO.

Systrom proposed the oxygen delivery problem could be caused by mitochondrial issues, hyperventilation and problems with the oxyhemoglobin dissociation curve – and/or microcirculatory problems. This small German study suggest the microcirculatory problems might be a big deal for a large subset of patients. Its results suggested that reduced nitric oxide production by the endothelial lining of small blood vessels (arterioles) was at least, in part, contributing to the fatigue and other symptoms in about half of the ME/CFS study group.

Because endothelial dysfunction can occur in many diseases, if it’s present in ME/CFS other factors must come into play that produce fatigue, post-exertional problems, etc.  (The “Blood Vessel Crunch” describes a blood vessel hypothesis that is unique to ME/CFS.  The authors, Wirth and Scheibenbogen, are working on the second part of that hypothesis which seeks to explain the energy production problems in this disease.)

While the lab results couldn’t uncover why the small blood vessel shutdown was occurring, a small immunoadsorption trial which reversed the small blood vessel problems, suggested that the problem could in the immune system, and possibly in antibodies that affect the beta adrenergic receptors found on the small blood vessels. Much larger studies, of course, are needed to validate their findings, and it should be noted that Montoya’s study did not find evidence of endothelial dysfunction. Dr. Scheibenbogen reported that a small, second as yet unpublished immunoabsorption ME/CFS study had results similar to the first one.

The study did not report on natural NO boosters but several natural substances (L-Citrulline, L-arginine, niacin) are reportedly able to increase nitric oxide levels. I have no idea if they would work in ME/CFS or not but at least with me, niacin (Vit B-3) can temporarily provide small boosts to cognition and oddly enough, given its rather stimulating properties, be relaxing.

Lastly, the EndoPat is typically used to assess the risk of cardiovascular disease. The study results suggested that half the study group might be at increased risk.  While no studies have verified that this is so, the combination of arterial stiffness, low grade inflammation, and high levels of oxidative stress has been hypothesized to put people with ME/CFS at increased risk of cardiovascular diseases. 

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