Insights from Invasive Cardiopulmonary Exercise Testing of Patients with ME/CFS, 2021, Joseph et al

[John Mac]

ABSTRACT
Background
Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) affects tens of millions worldwide; the causes of exertional intolerance are poorly understood. The ME/CFS label overlaps with postural orthostatic tachycardia (POTS) and fibromyalgia, and objective evidence of small fiber neuropathy (SFN) is reported in ∼50% of POTS and fibromyalgia patients.
Research Question
Can invasive cardiopulmonary exercise testing (iCPET) and PGP9.5-immunolabeled lower-leg skin biopsies inform the pathophysiology of ME/CFS exertional intolerance and potential relationships with SFN?

Study Design and Methods
We analyzed 1516 upright invasive iCPETs performed to investigate exertional intolerance. After excluding patients with intrinsic heart or lung disease and selecting those with right atrial pressures (RAP) <6.5 mmHg, results from 160 patients meeting ME/CFS criteria who had skin-biopsy test results were compared to 36 controls.
Rest-to-peak changes in cardiac output (Qc) were compared to oxygen uptake (Qc/VO 2 slope) to identify participants with low, normal, or high pulmonary blood flow by Qc/VO 2 tertiles.

Results
During exercise, the 160 ME/CFS patients averaged lower RAP (1.9±2 vs. 8.3±1.5; P<0.0001) and peak VO 2 (80%±21 vs. 101.4%±17; P<0.0001) than controls.
The low-flow tertile had lower peak Qc than the normal and high-flow tertiles (88.4±19% vs. 99.5±23.8% vs. 99.9±19.5% predicted; P<0.01).
In contrast, systemic oxygen extraction was impaired in high-flow versus low and normal-flow participants (0.74±0.1% vs. 0.88±0.11 vs. 0.86±0.1; P<0.0001) in association with peripheral left-to-right shunting.
Among the 160 ME/CFS patient biopsies, 31% was consistent with SFN (epidermal innervation ≤5.0% of predicted; P < 0.0001). Denervation severity did not correlate with exertional measures.

Interpretation
These results identify two types of peripheral neurovascular dysregulation that are biologically plausible contributors to ME/CFS exertional intolerance–depressed Qc from impaired venous return, and impaired peripheral oxygen extraction. In patients with small-fiber pathology, neuropathic dysregulation causing microvascular dilation may limit exertion by shunting oxygenated blood from capillary beds and reducing cardiac return.

Abbreviation:
Ca-vO2/[Hb] ( Arterial–mixed venous oxygen content difference/hemoglobin concentration), iCPET ( Invasive cardiopulmonary exercise test), NAM ( National Academy of Medicine, formerly the Institute of Medicine), ME/CFS ( Myalgic encephalomyelitis/chronic fatigue syndrome), MM ( Mitochondrial myopathy), mPAP ( Mean pulmonary artery pressure), PAWP ( Pulmonary arterial wedge pressure), PLF ( Preload failure), POTS ( Postural orthostatic tachycardia syndrome), PVR ( Pulmonary vascular resistance), RAP ( Right atrial pressure), Qc ( Cardiac output), SFN ( Small fiber neuropathy), VO2 ( Oxygen uptake), vPO2 ( Venous oxygen tension)

https://journal.chestnet.org/article/S0012-3692(21)00256-7/fulltext


EDIT: also available here:
https://www.sciencedirect.com/science/article/abs/pii/S0012369221002567

 

[Hoopoe]

During exercise, the 160 ME/CFS patients averaged lower RAP (1.9±2 vs. 8.3±1.5; P<0.0001)

RAP is the blood pressure in the right atrium of the heart (one of the four chambers in the heart). I'm not sure how important a healthy blood pressure is in there but it seems like a disturbingly large difference between patients and controls. Something is very wrong.

I'm not sure I understand what peripheral left-to-right shunting is, as I'm only finding explanations for regular left-to-right shunting.

This seems like a potentially very important study.

 

[Snow Leopard]

I'm not convinced there are many insights to be gained by comparing patients to controls on a single CPET. Several of the observations could simply reflect the fact that the individuals have different activity (and fitness) patterns to controls. I'd be more excited about a low-flow scenario, rather than high-flow, since VO2Max is a measure of how much oxygen can be delivered to the muscle. The observation suggests these participants are not actually reaching a true VO2Max.

Instead, I'd propose some sort of self-controlled study where patients perform worse on a particular physiological threshold that would otherwise be replicated in healthy controls is necessary for insights to identify cause-effect relationships.

edit- merged posts

RAP is the blood pressure in the right atrium of the heart (one of the four chambers in the heart). I'm not sure how important a healthy blood pressure is in there but it seems like a disturbingly large difference between patients and controls. Something is very wrong.

Note that VO2Max is always achieved at high blood pressures - especially in trained athletes. This is more evidence (besides the very low peak heart rates) that these patients didn't actually achieve a true VO2Max.

I'm not sure I understand what peripheral left-to-right shunting is, as I'm only finding explanations for regular left-to-right shunting.

They're suggesting that the veins and arteries are dilating too much, so that the blood is simply shunting through the capillaries with no resistance. I am not convinced by this argument, though if there is a loss of blood volume being circulated due to blood pooling elsewhere in the periphery, then this can limit performance. Note that unlike the veins/arteries which are regulated by the autonomic nervous system, capillaries regulate their own dilation locally to maintain flow.

 

[Trish]

RAP is the blood pressure in the right atrium of the heart (one of the four chambers in the heart). I'm not sure how important a healthy blood pressure is in there but it seems like a disturbingly large difference between patients and controls. Something is very wrong.

They selected the small subset with lower RAP to include in this study, so it doesn't necessarily indicate that this is the key problem for most pwME. It's hard to tell because the abstract doesn't give the data for the rest of the pwME.

 

[butter.]

Again, most likely this is a mitochondrial issue.

 

[Marky]

Full text anyone?

 

[wigglethemouse]

Full text anyone?

The Journal pre-proof is available

Unformatted full text appeared on researchgate.
https://www.researchgate.net/public...gic_EncephalomyelitisChronic_Fatigue_Syndrome

 

[Marky]

The Journal pre-proof is available

Thanks

 

[Grigor]

Thanks for sharing. I'm not really sure what they're trying to say. Too brainfogged to properly read and understand it. Is it that ME has many exercise intolerance phenotypes. Are they considering POTS, SFN and fibro similar or even the same? In what way would ME differ from these other conditions?

 

[Snow Leopard]

Thanks for sharing. I'm not really sure what they're trying to say. Too brainfogged to properly read and understand it. Is it that ME has many exercise intolerance phenotypes. Are they considering POTS, SFN and fibro similar or even the same? In what way would ME differ from these other conditions?

Those would be good questions for the authors!

In the manuscript they claim overlap between the conditions:

ME/CFS has significant overlap with the POTS and fibromyalgia syndrome labels2-4 where skin biopsy and other biomarker studies report high prevalence of abnormalities consistent with SFN.5-7,9 SFN is a common disorder caused by excess firing and/or axonal degeneration in the thinly myelinated and unmyelinated sensory/trophic/autonomic peripheral neurons. Common symptoms include distal-predominant sensory disturbances including pain, exertional intolerance, nausea, postural orthostatic tachycardia, and hypotension.21 The SFN diagnosis is confirmed by abnormally low densities of PGP9.5-immunolabelled epidermal neurites in lowerleg skin biopsies (≤5% of predicted), which is recommended for research inclusion.27

4 In exercising muscles, such blood shunting and impaired exercise-associated vasodilation can cause premature anaerobic metabolism with lactic acidosis, premature muscle fatigue, and exertional intolerance. Neurogenic AV shunting in splanchnic microvessels is proposed to also contribute to SFN’s characteristic postprandial abdominal discomfort, dysmotility, and nausea in addition to denervation of enteric smooth muscles.21

But SFN was only found in 1/3 of patients (which is why they claim there may be more than one 'flow' profile):

ME/CFS patients, slightly lower than the ~50% prevalences reported in fibromyalgia and POTS.5,9,36 Our iCPET data associate SFN with both low-flow and high-flow ME/CFS profiles. Immunohistochemical studies show that small fibers regulate microvascular tone, primarily by sympathetic and parasympathetic cholinergic synapses on perivascular myocytes.37 Distal degeneration (axonopathy) can impair venoconstriction with resultant peripheral blood pooling decreasing cardiac return, consistent with the “low-flow preload failure” we identified.

The suggestion of perivascular myocyte dysfunction is interesting, the citation is 37:
Quantitative assessment and correlation of sympathetic, parasympathetic, and afferent small fiber function in peripheral neuropathy.
https://pubmed.ncbi.nlm.nih.gov/10836618/

But that manuscript doesn't really explain it at all.

Use of the word perivascular reminded me of the pericytes too, though their role in microcirculation is controversial.

 

[Grigor]

Those would be good questions for the authors!

Thank you for digging a bit more into the paper. What is also not clear to me if they feel exercise intolerance is the same as PEM seen in ME. It's an interesting paper but confusing.

 

[Snow Leopard]

What is also not clear to me if they feel exercise intolerance is the same as PEM seen in ME.

It definitely isn't the same thing. They only mention PEM with regards to the case definition.

 

[Grigor]

A short email exchange with dr. David Systrom:

Anil:

Dear mister Systrom,

My name is Anil van der Zee. I'm a former professional ballet dancer from Amsterdam, the Netherlands and currently a bedbound ME patient. I've been following your work with great interest as I feel that I might have SFN as well.

I just read through your new paper about the connection with ME and SFN but I had a few questions about it.

https://www.researchgate.net/publication/349183533_Insights_from_Invasive_Cardiopulmonary_Exercise_Testing_of_Patients_with_Myalgic_EncephalomyelitisChronic_Fatigue_Syndrome?s=09

What I've understood is that ME has different exercise intolerance phenotypes. Since there is an overlap between ME, POTS and SFN, do you considering POTS, SFN and fibro similar or even the same? In what way would ME differ from these other conditions? Especially in regards to PEM as you refer to exercise intolerance in the paper. By some, PEM is considered the "hallmark" symptom.

Thank you for all your amazing work. As an athlete it has been frustrating not being believed that I became ill when I "over exerted" myself. Glad to see top researchers from Harvard digging into this.

Kind regards,

Anil van der Zee

Systrom:

Thank you for your email. Yes we believe there is substantial overlap among ME, pots, FM and SFN. Some of our emerging work may link pro inflammatory cytokines elicited by exercise as a reason for PEM. Thank you for your interest.

Anil:

Dear mister Systrom,

Thank you for answering. That there is a substantial overlap is what I understood from the paper but do you feel they are different conditions. Or is that something you simply do not know?

Kind regards,

Anil van der Zee

Systrom:

similar diseases w/ nuances

Anil:

Ok thank you. That was what I was wondering.

Kind regards,

Anil van der Zee

 

[jaded]

What I don’t understand is in the table of baseline characteristics they say out of 160 ME/CFS patients, 31% had SFN, 33% had POTS and 22% had fibromyalgia.

They then state that between 32-50% of all patients with fibromyalgia have SFN and a similar figure is also found in POTS (they report 38%).

So how do we know that the SFN found in 33% of their patients with ME isn’t due to them also having either a diagnosed or undiagnosed comorbidity of POTS and FM?

Am I missing something? I guess I’d like to see the breakdown of SFN stats in the ME patients who definitely didn’t have a co-morbidity of POTS or FM.

I have all three diagnoses so what’s my risk of SFN? It’s too much for my brain fogged brain.

 

[jaded]

@Grigor - many thanks for contacting Dr Systrom and sharing his email with us.

It kind of make sense now that he views the diseases and maybe the underlying pathology as overlapping but with nuances, whatever that means.

He said somewhere that he’s mainly treating ME patients with a dysautonomia pattern. So I wonder if he’s just homing in on a subset of us?

Or maybe the SFN is just a secondary consequence of the underlying disease process as seen in diabetes, but it’s not present in everyone. It still doesn’t address the root cause though. Only offers potential symptomatic management for those affected.

 

[Mij]

"similar diseases w/ nuances"?

I've known a few people with FM irl, and not one of them experienced PEM or anything close to what I have.

Hasn't exercise been shown as an effective therapy for pwPOTS?

 

[Ryan31337]

Hasn't exercise been shown as an effective therapy for pwPOTS?

POTS has been understood & described as the "final common pathway for a number of overlapping pathophysiologies".

In the context of simple, isolated deconditioning as a cause of POTS its not unreasonable to assume exercise therapy will be effective. But this isn't the case for people like us, deconditioning will be a very small factor, if at all.

 

[Ryan31337]

Systrom:

Thank you for your email. Yes we believe there is substantial overlap among ME, pots, FM and SFN. Some of our emerging work may link pro inflammatory cytokines elicited by exercise as a reason for PEM. Thank you for your interest.

I imagine that's related to this work:
https://www.s4me.info/threads/infla...utoantibodies-2021-gunning-grubb-et-al.19055/

 

[Mij]

I returned to running again after 6 years of PVFS and felt very much improved. I wasn't deconditioned at all and picked up right where I left off and felt great. . . except I had delayed PEM ever time.

 

[Mij]

PEM is a pathophysiology with symptoms that ebb and flow, but it’s not "gone" just because you don’t have bad symptoms one day. You don’t have "a diabetes." or "a migraine".