Earlier, Klaus Wirth and Carmen Scheibenbogen found a way to explain the brain issues in chronic fatigue syndrome (ME/CFS) without resorting to neuroinflammation. Their multipart series of ME/CFS hypotheses brought the most thorough potential explanation of what’s happening in this complex disease yet.

Hypothesis Predicts Major Failure Point in Chronic Fatigue Syndrome (ME/CFS)

Now Wirth, working with Mathias Lohn, has found a way to explain the orthostatic intolerance in long COVID and chronic fatigue syndrome (ME/CFS) without resorting to autonomic nervous system dysfunction.

These researchers demonstrate how important it is to have as many eyes on ME/CFS and related diseases as possible. A pharmacological researcher at the University of Frankfurt, Wirth has focused on things like cardiovascular pharmacology, the pharmacology of bradykinin antagonisms, and cerebral blood flows; i.e. he brings a skill set to ME/CFS that we haven’t seen before – and that has brought a new way to look at this disease to the table.

In “Orthostatic Intolerance after COVID-19 Infection: Is Disturbed Microcirculation of the Vasa Vasorum of Capacitance Vessels the Primary Defect?”, Wirth and another cardiovascular specialist, Matthias Lohn, take on orthostatic intolerance – the inability to remain upright without experiencing symptoms.

Most people equate the orthostatic intolerance in ME/CFS, POTS, etc, with autonomic nervous system (ANS) problems and stop there – but not Wirth and Lohn. They agree that the ANS is disturbed but don’t believe it’s necessarily dysfunctional. Instead, it’s doing its best to respond to a deeper problem in the blood vessels. In doing so, they’ve given us, in this hypothesis paper, a deeper cut into the vascular (blood vessel) system in ME/CFS than we’ve seen before.

The Blood Vessels…Again

It seems there’s no getting away from the blood vessels – especially for humans. Because we stand on two feet – leaving our head above our heart – we’ve evolved ways to keep the blood flowing to the all-important brain even as gravity is trying to pull our blood down to our toes. The blood vessels below the heart, for instance, contract when we stand to in order to keep the blood from puddling in our feet. (The blood vessels found above the heart contract in order to squeeze what blood is available up into our brain).

The authors note this vital need – to respond to standing and exercise with a coordinated system of blood vessel contractions – can be impaired in a number of ways:.

  • An inability to contract the blood vessels – the smooth muscles that line the blood vessels can fail to contract them – leaving them flaccid and dilated – and allowing blood to flow to settle in the lower part of the body.
  • Rigid blood vessels – overly rigid blood vessels that may have shrunken cannot contract and relax properly – and thus don’t provide the room for the blood volume needed to support standing and exercise.
  • Hypovolemia (low blood volume) – in what is called the “renin paradox”,  the RAAS system in ME/CFS and POTS patients does not produce enough blood to support standing and exercise.
  • Problems with autonomic regulation (baroreflex, volume regulation, volume- and barosensors, and vagal and sympathetic activity) – can throw blood flows off as well. For instance, exaggerated sympathetic activity is believed to cause vasoconstriction, or narrowing of the blood vessels. in the brain.
  • Hyperventilation, which is also reported to occur in ME/CFS and long COVID, may contribute to cerebral vasoconstriction.

Could the Microcirculation be THE Underlying Problem in ME/CFS and Long COVID?

While all these may have a place in ME/CFS, POTS, and long COVID, the authors believe one major factor – in fact, THE major factor is missing – damage to the microcirculation; i.e. the very smallest blood vessels that feed our tissues.

Several factors able to disturb the functioning of the small blood vessels (endothelial cell dysfunction, hypercoagulation, and altered red blood cells) have been found in long COVID (as well as ME/CFS). No one, though, has looked at the blood vessels that feed the blood vessels – the “vasa vasorum”.

The Vasa Vasorum and the Veins

vasa vasorum

Could the vasa vasorum – the small blood vessels (in dark) that feed the big blood vessels be a problem in ME/CFS and long COVID?

While problems with the microcirculation mainly affect blood flows in small vessels and capillaries, the authors point out that the large and medium-sized blood vessels are dependent on the small blood vessels that feed them to operate properly. Poor microcirculation in the blood vessels  – called the vasa vasorum (“the vessels of the vessels”) – which feed the larger blood vessels could therefore impact them.

Of all the larger blood vessels in the body, the veins stand out. The veins are not just passive vessels that deliver blood to the heart; they need to actively contract to push blood back up to the heart. Contraction requires energy – which requires oxygen – which requires that vasa vasorum be feeding the veins lots of oxygen-rich blood.

Because the veins – in their role of delivering “used up and oxygen-poor” blood to the heart – transmit less oxygen-rich blood, anyway, they might be particularly disturbed by an inability of the “vasa vasorum” to supply them with oxygen and nutrients. That could prevent them from filling the heart with sufficient amounts of blood – and cause the preload failure that David Systrom’s invasive exercise tests have repeatedly found in ME/CFS.

Preload failure occurs when the heart receives less than normal amounts of blood from the veins – which, in turn, impairs its ability to send blood to the tissues – particularly during times of increased stress like standing and exercise. Systrom has called preload failure “the elephant in the room” for ME/CFS and has found it in 90% of his patients.

Systrom’s Keynote Address Kicks off IACFS/ME ME/CFS and Long-COVID Conference

The low “preload” (i.e. the low blood volume presented to the heart) in people with ME/CFS could also be causing the smaller than normal hearts found in ME/CFS.

Flaccid Tubes

Blood vessels – particularly the veins – that have become unable to contract enough to force blood upwards (or towards the muscles) present another possibility. We’re going to hear a lot about the role that connective tissue problems may play in these diseases as time goes on. Suffice it to say, though, that Wirth believes that problems with the connective tissues lining the blood vessels and/or the high histamine release found in conditions like mast cell activation syndrome could be producing “flaccid tubes”; i.e. overly dilated and limp blood vessels that simply cannot move the blood along.

blood vessels

Over-dilated or flaccid blood vessels can’t produce enough pressure to get the blood to the tissues.

Lacking the nice taut tubes needed to squeeze blood out to the tissues, the body compensates by trying to squeeze those tubes down, telling the sympathetic nervous system (norepinephrine) to activate the alpha-adrenergic receptors that tell the smooth muscles lining the blood vessels to contract. That often not-so-successful attempt has consequences of its own.

Receptors that are chronically activated can, at some point, simply stop responding. Given what we know about the problems being upright in ME/CFS and similar diseases, chronic receptor activation could be common in ME/CFS. Being upright does not just refer to standing. Studies indicate that cerebral blood flows can be reduced in some people with ME/CFS even while they’re sitting, and in people with severe ME/CFS if they’re lying at a slight angle.

The authors believe that makes orthostatic stress an almost unavoidable chronic state for many and suggests that desensitized β 2-adrenergic and alpha2-adrenergic receptors could be producing an ongoing case of sympathetic and adrenergic hyperactivity and hypervigilance. (Autoantibodies that target those same receptors, as well as other factors (MAS-receptors, angiotensin-II-type-1 receptor) could produce a similar situation).

In all these cases, though, note that once again, it comes down to blood vessels that have lost the ability to respond properly to the stress of being upright, or to exercise.

Notice what’s missing in this picture? Any need for autonomic nervous system dysregulation. In this paradigm, the ANS is simply trying to compensate for problems caused in the blood vessels.

Rigid Blood Vessels

A different blood vessel could be in play as well. A rigid, and perhaps shrunken, blood vessel system that simply doesn’t have the capacity to store normal amounts of blood could be causing similar problems. Large blood vessels that are chronically squeezed down and unable to carry a normal amount of blood could also result in the presence of small hearts that lack the capacity to pump normal amounts of blood to the muscles and brain.

Either way – it all potentially originates in the blood vessels. (Earlier, Wirth and Scheibenbogen proposed that a similar process is occurring in the brain).

No Neuroinflammation Needed? An Epic ME/CFS Hypothesis Series Winds Up


  • Klaus Wirth and Mathias Lohn’s new hypothesis demonstrates once again how important it is to have as many eyes as possible on these diseases. These cardiovascular and pulmonary specialists bring a different skill set to these diseases – and it shows!
  • They don’t believe that the autonomic nervous system is behaving poorly in ME/CFS and long COVID at all; instead, they believe its simply trying to compensate for problems in the small blood vessels that feed our tissues.
  • In particular, they propose that damage to the small blood vessels (called the vasa vasorum) that feed the larger blood vessels (the arteries and veins) may play a critical role in these disorders.
  • Each of the blood vessel problems they tick off – narrowed, rigid blood vessels, flaccid blood vessels – could be caused by an inability of the vasa vasorum to feed them the oxygen and nutrients they need.
  • Because the veins already receive deoxygenated blood, and because they need to contract – an energy-intensive process – to push blood up to the heart, they may be impacted most of all. That makes sense given David Systrom’s finding of “low preload” – low blood flows to the heart – in many of his ME/CFS patients.
  • The chronic stress imposed by standing in ME/CFS and long COVID could also desensitize the receptors responsible for contracting the blood vessels and maintaining blood flows.
  • The microcirculatory hypothesis could explain why the current treatment approach – focusing largely on manipulating the autonomic nervous system – has been of limited help. We might get further along, the authors believe, by focusing on the root of the problem – damaged small blood vessels. That would lead, they believe, to “more specific treatment options” and improved outcomes.
  • Klaus Wirth believes he’s found a drug (unnamed) that he thinks can help in ME/CFS. He formed a company called Mitodicure which is currently looking for funding.


Next, the authors ask whether the same factors are causing orthostatic intolerance in ME/CFS and long COVID? The answer is: possibly. Studies indicate the vasa vasorum – the small blood vessels that feed the big vessels – can be damaged by the coronavirus. The inability of those blood vessels to contract could result in a state of chronic sympathetic nervous system activation; i.e. the same autonomic nervous system dysregulation that is seen in ME/CFS.

A More Focused Treatment Approach

The microcirculatory hypothesis could explain why the current treatment approach – focusing largely on manipulating the autonomic nervous system – has been of limited help. We might get further along, the authors believe, by focusing on the root of the problem – damaged small blood vessels. That would lead, they believe, to “more specific treatment options” and improved outcomes.

One way to assess whether their thesis is correct would be to compare the diameter or volume of the large blood vessels in both the supine and upright positions in long COVID and ME/CFS patients versus healthy controls. An inability of the large blood vessels to adjust to an upright position would put a focus on blood vessel functioning.

The Big Picture

Wirth wrote that both precapillary cardiovascular problems (low blood volume, low cardiac filling, vasoconstriction issues) and capillary disturbances (microclots, large monocytes, damaged red blood cells, sticky red blood cells) are present in ME/CFS and allied diseases. Both work together to make it more difficult to maintain good blood flows in ME/CFS and allied diseases. He and Lohn are writing a paper on the “catastrophic interaction” they believe these factors produce in diseases like ME/CFS.

Earlier, Wirth wrote he and his partners have “derived pharmacological mechanisms necessary to address the core of the pathophysiological mechanisms, the vicious circles, that keep the disease process running. Key disturbances are the ionic disturbances in skeletal muscle and disturbed skeletal muscle and cerebral blood flow. To realize this drug project, a company has been recently founded and is looking for seed funding to finance the project.”

ME/CFS Muscle Study Results in Drug Company Startup

That company is called Mitodicure and the drug it’s focused on could help with the blood flows as well as other issues. Right now, Mitodicure is in the phase of gathering financial support in what is currently a difficult market situation (high-interest rates restrict flows into venture capital companies) for a rather controversial disease; in other words, it’s not a piece of cake. Let’s hope they succeed.

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