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People with chronic fatigue syndrome (ME/CFS) have often said that they feel like they’ve run a marathon despite the fact that they haven’t done any exercise at all. That idea has never been put to the test in ME/CFS but it recently came close in long COVID.

Exhausted long COVID

The study compared circulation in long COVID at rest to runners after they’d exercised to exhaustion.

A recent Polish study “Chronic Fatigue Associated with Post-COVID Syndrome versus Transient Fatigue Caused by High-Intensity Exercise: Are They Comparable in Terms of Vascular Effects?” demonstrates two things: long COVID’s wide reach (it’s reached Poland) and the creative studies that it’s triggering.

The study used a technique called “flow-mediated skin fluorescence (FMSF) which the authors stated was “uniquely suitable” for assessing the microcirculation during periods of low blood flow (transient ischemia). A recent hypothesis proposed that people with long COVID or ME/CFS were in a chronic state of transient ischemia due to inadequate blood flows.

Ischemia-Reperfusion Hypothesis Opens New Treatment Options for Long COVID, Fibromyalgia and ME/CFS

Since the vascular system is put under great stress by exhausting exercise the authors did a rather daring experiment: they used an exercise stressor to determine if the microcirculatory systems of long COVID patients at rest were similar to those in seen in amateur athletes after they’d exercised to exhaustion.

It turns out that high-intensity exercise causes a great deal of stress to the circulatory system. For one, the massive amounts of energy produced come with an equally massive increase in oxidative stress (free radical production). Besides possibly whacking the mitochondria, that oxidative stress can decrease the bioavailability of the main vasodilator of the blood vessels – nitric oxide. The narrowed blood vessels that result would then reduce blood flows.

The non-invasive technique used measures blood flows in the skin. Since the epidermis or top layer of the skin, doesn’t contain any blood vessels oxygen and nutrients are transported to it via diffusion from the blood vessels. Due to this unusual arrangement, the authors reported that assessments of epidermal cell metabolism are “considered a unique and sensitive marker” of early vascular dysfunction and metabolic problems. The approach they used also enabled them to assess the macro (larger blood vessels)

The twist in this study came when the researchers compared the microcirculation of people with long COVID and the healthy controls at baseline to the runners before and immediately after an intense exercise session The runners who participated in this study were supremely healthy having participated in long-distance running, cross-country running, and marathons.

This study, then, compared the microcirculation of people with long COVID at baseline to the microcirculation of runners who’d just been pushed to exhaustion. If the long COVID patients’ microcirculation looked like it had been pushed to the limit without exercise, that would validate the experiences of people with long COVID.

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Two parameters were assessed: the NOI (Normoxia Oscillatory Index) and RHR (Reactive Hyperemia Response). The NOI parameter characterizes microcirculatory “oscillations” (a function of activity??) and is particularly sensitive to the effects of high-intensity exercise. The RHR parameter assesses blood vessel function as it relates to the production of nitric oxide (NO) – the main blood vessel vasodilator – in the larger blood vessels.

The authors didn’t employ people with ME/CFS in the study but highlighted the “broad overlap” between the two diseases and referring to Wirth and Scheibenbogen’s ME/CFS hypothesis proposed that both feature problems with calcium dysregulation that in turn affects the adrenergic and muscarinic receptors that regulate blood flows.

Results

Circulation long COVID

Note the high levels of NO in both the healthy controls and runners before exercise on the left side, and then compare that to the low NO levels in the long COVID patients at baseline and in the runners after exhaustive exercise on the right side.

Both the small and larger blood vessels in long COVID patients – at baseline – looked like they’d just exercised to exhaustion. The long COVID and exhausted runners had near identical microcirculation (NOI) and macrocirculation (RHR) test results. In other words, if you feel like you’ve just run a marathon they may have found a reason for it.

The authors proposed that problems with calcium homeostasis are producing endothelial or blood vessel dysfunction. An interesting study suggests that the opposite may be true as well; that blood vessel problems could be causing mitochondrial issues. The Sept, 2022 study “Flow pattern-dependent mitochondrial dynamics regulates the metabolic profile and inflammatory state of endothelial cells” found that disturbed blood flows increased a bunch of negative factors including mitochondrial free radicals production (mtROS), increased glycolysis (reducing ATP production), endothelial cell activation (inflammation), mitochondrial fragmentation and a hypoxia (low oxygen) factor ( hypoxia-inducible factor 1).

There were some provisos to this study. While the groups appeared to be age-matched they were not gender-matched. The long COVID group was 58% female, the healthy controls were 45% female, and the runners’ group was all male. Given what we’ve learned about gender differences that could make a difference and that needs to be cleared up.

The Gist

  • Polish researchers assessed both the micro and macro circulation in healthy controls, runners, and people with long COVID using something called “flow-mediated skin fluorescence (FMSF). 
  • The twist was that they compared the circulation in people with long COVID and the healthy controls at baseline to the circulation in the runners after they’d exercised to exhaustion
  • Exercising to exhaustion puts the circulatory system under high levels of stress. The increased levels of free radicals produced during energy production can make it difficult for nitric oxide to vasodilate the blood vessels – leaving them narrowed and impairing blood flows.
  • The results bore out the old canard in ME/CFS- that having these diseases feels like one has just run a marathon. The exhausted runners and long COVID patients’ at baseline produced near identical readings suggesting that both the macro and microcirculation have been dramatically affected in long COVID. 
  • The main proviso to this study concerned the all-male makeup of the runners and the 60% female makeup of the long COVID group. Since gender effects can be large, that issue must be dealt with in future studies.
  • This study adds another data point to the growing evidence of blood vessel dysfunction in long COVID. The RECOVER Initiative is assessing coagulation factors in its initial assessments.  It would be shocking if blood vessel issues weren’t a major emphasis as well. 

Conclusion

People with long COVID (or ME/CFS) may feel like they’ve have run a marathon because their blood vessels – both larger and smaller – may actually look like they’ve run a marathon. Rather remarkably, two measures of circulatory blood flows – both micro and macro – were nearly identical in long COVID patients at baseline and in runners after they’d run to exhaustion.

The authors proposed that problems with calcium metabolism aka Wirth and Scheibenbogen’s hypothesis are ultimately causing the blood vessel problems. A recent study, however, suggested that disturbed blood flows may, in turn, be causing mitochondrial problems by reducing ATP production and increasing oxidative stress. Etc.

This study was by no means definitive and seemed rather simple in that it assessed two aspects of a very complex system but it provides another data point suggesting that blood vessel problems play a major role in long COVID (and probably ME/CFS). Overall, while some controversy exists, the blood vessel findings seem to be adding up. The blood vessel research topic was present in ME/CFS but long COVID has really brought it to the fore.

A number of hypotheses have been put forward to try and explain them: damaged adrenergic/muscarinic receptors, shunts that bypass them, micro blood clots, damaged endothelial cells, broken ACE-2 receptors, deformed red blood cells, and probably others

What we really need are big, well-managed studies that can come to a conclusion regarding the blood vessel, and blood clotting issues in long COVID and ME/CFS. That’s where the RECOVER Initiative should theoretically shine at least with long COVID patients. Coagulation factors are part of the standard assessments being done. I’d be shocked if a major effort at understanding the role the blood vessels play in long COVID wasn’t underway.

 

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