Exercise Intolerance: Insights from Invasive Cardiopulmonary Exercise Testing of Patients with ME/CFS (Joseph et al., 2021)

[ChookityPop]

Autoantibodies that attack either peripheral or central nervous system. Seems like the peripheral nervous system autoimmunity has a lot less documentation. They know very little about this. These complex carbohydrate antibodies that can potentially damage nerve cells are just now being looked into. I believe they are still trying to confirm whether or not they're actually pathogenic. Which means they are very far away from determining their origin.

If thats the case would the answer be to eliminate carbs?

 

[livinglighter]

Is PEM happening as a result of having some form of exertion/exercise intolerance?

I've revisited my medical records and can see what basically reads as exertion intolerance related to a hyperimmune response recorded during wider communications with health professionals about the condition. The comments are made by the immunology team where I met the CFS/ME diagnosis. I wasn't told this in person though, PEM was the only part explained directly to me, so I'm currently connecting the dots.

I was told to monitor my heart rate and stay within my energy evelope as well to avoid triggering PEM.

 

[Pyrrhus]

If thats the case would the answer be to eliminate carbs?

No, there may be good reasons for limiting dietary carbohydrates, but this isn't one of them.

Is PEM happening as a result of having some form of exertion/exercise intolerance?

Great question. This study only looks at how dysautonomia results in exercise intolerance, and possibly SFN, but it does not address PEM. PEM may be an entirely separate phenomenon, or it may be related.

Here's a brief clarification:

• Exercise Intolerance is a medical term that refers to the inability to perform aerobic exercise. Even though the patient is trying their best to exercise aerobically, a physiological problem is depriving the exercising muscles of sufficient oxygen, resulting in rapid muscle weakness/soreness.
• Exertion Intolerance, on the other hand, is a general term that can refer to any bad reaction to any type of exertion.
• Post-Exertional Malaise (PEM), also known as Post-Exertional Symptom Exacerbation (PESE), is a type of exertion intolerance where there is an exacerbation of symptoms (and maybe some new symptoms) after minimal exertion.

 

[sometexan84]

If thats the case would the answer be to eliminate carbs?

It's a good question. I'm not going to pretend I know the answer.

I think calling them carbohydrate antibodies is oversimplifying a little. It's more like these saccharides, made up of sugars and sometimes acids, joining together via glycosylation. The end-product seems to usually involve glucose, fucose, galactose, etc.

From what I understand, you could cut carbs, but your body would still produce glucose, and other elements needed to join together and form these types of complex glycan-based antibodies.

You could check out this COVID study on self-carbohydrate antibodies for some specific auto-antibody examples.

Looks like in COVID patients, some of these glycan/carb auto-antibodies include IgG and IgM to....

• Gangliosides
• N-linked glycans like GlcNAcβ1-2(GlcNAcβ1-6)Manα1-6[GlcNAcβ1-2(GlcNAcβ1-4)Manα1-3]Manβ1-4GlcNAcβ
• LacNAc-containing glycans like Galβ1-4GlcNAcβ1-3Galβ1-4GlcNAcβ1-3Galβ1-4GlcNAcβ1-3Gal
• Blood group H
• Sialyl Lewis X [Neu5Acα2-3Galβ1-4[Fucα1-3)GlcNAc]
• BG-H1 (Fucα1-2Galβ1-3GlcNAcβ)

 

[wigglethemouse]

@Pyrrhus Full text journal pre-proof copy link on researchgate :
https://www.researchgate.net/public...gic_EncephalomyelitisChronic_Fatigue_Syndrome

https://twitter.com/i/web/status/1361237793171726339

 

[Pyrrhus]

In an attempt to further categorize the patients in this study, the authors somewhat arbitrarily divided the group of patients into those with relatively higher blood flow and those with relatively lower blood flow.

At peak exercise, the patients with relatively higher blood flow had significantly less peripheral oxygen extraction from the muscles. Perhaps their hearts tried to beat faster in order to provide more oxygen to the muscles, but the extra oxygen ended up simply bypassing the muscles.

The authors felt that this was a "major finding", and felt that the patients with relatively higher blood flow were more likely to have issues with peripheral oxygen extraction, such as arterio-venous shunting or mitochondrial energy problems.

However, I'm not sure their logic really supports that conclusion. It might simply be that the patients with relatively higher blood flow just happened to have an autonomic response that increased their heart rate in order to compensate for the lower blood pressure in the veins.

For example, we know that many ME patients have orthostatic intolerance, where blood flow to the brain drops. But some of those patients happen to have an autonomic response that increases their heart rate in order to compensate for the lack of blood flow to the brain:

 

[Pyrrhus]

As some other studies have found, the ME patients could not reach the same level of oxygen consumption during exercise that healthy people could. (lower peak VO2) Whereas most other studies that showed this difference did not achieve statistical significance for the finding, this study found the difference clearly statistically significant.

Why does this study clearly achieve statistical significance for the observation of a lower peak oxygen consumption (VO2) on day 1, while other studies could not demonstrate statistical significance on day 1?

At first I thought it was because iCPET must have better data than regular CPET, but then I remembered that when it comes to calculating peak oxygen consumption (VO2), both iCPET and CPET use the same technology. Then I noticed that other studies generally compared weight-adjusted values of peak VO2, but this study compared age-weight-and-gender-adjusted values of peak VO2.

Specifically, this study reported peak VO2 as a percentage of the predicted peak VO2 for a healthy person of their age, weight, and gender, using the following "Wasserman-Hansen equation" for predicted peak VO2:

Could the difference in statistical significance simply come down to using the correct equation? If previous studies had used this equation, would they even have needed 2 days of CPET or would just 1 day have been enough?

We should note that other exercise studies used a 2-day CPET because the data collected on day 1 was insufficient to detect a significantly lower peak oxygen consumption. Therefore, they focused on demonstrating the difference between performance on day 1 and performance on day 2. This was notably documented in this classic paper from 2007:

Diminished Cardiopulmonary Capacity During Post-Exertional Malaise (VanNess, Snell, & Stevens. 2007)
https://forums.phoenixrising.me/thr...monary-capacity-during-post-exertional.10414/
(only accessible to Phoenix Rising members with more than 100 posts)
Excerpt:

Purpose:
To compare results from repeated exercise tests as indicators of post-exertional malaise in CFS.

Results:
Multivariate analysis showed no significant differences between control and CFS, respectively, for test [on day] 1.
[...]
However, for test [on day] 2 the CFS patients achieved significantly lower values for both [peak oxygen consumption] and [anaerobic threshold].

 

[roller]

with the muscles, it is million times better since im taking VASTAREL
also much improvement on breathing, dizziness, pains and more.. huge change!
endurance-wise.

e.g. long stairs
before: at the half of it, a break, gasping for air. when up there, very heavy/loud breathing, exhausted totally
after: i walk up the stairs and further.
gross...

 

[lenora]

A new publication by the team of Phillip Joseph, Anne Oaklander, and David Systrom, which I personally find exciting.

Insights from Invasive Cardiopulmonary Exercise Testing of Patients with Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (Joseph et al., 2021)
https://journal.chestnet.org/article/S0012-3692(21)00256-7/fulltext

Main points:

• 160 ME patients were subjected to both an exercise test (iCPET) and a skin biopsy of the lower leg.
• Results were compared to 36 healthy people.
• As many other studies have shown, the ME patients could not reach the same level of oxygen consumption during exercise that healthy people could. (lower peak VO2)
• During exercise, ME patients had lower blood pressure in the veins transporting blood from the legs to the heart. (lower right atrial pressure)
• 31% of ME patients showed Small Fiber Neuropathy (SFN) in the lower leg.
• The authors interpret the findings as possible clinical evidence for dysautonomia of the small nerves that control constriction of the small veins in the legs, which means that:
  1. The small veins in the legs remain abnormally dilated while standing,
  2. which means insufficient blood pressure to return the blood from the legs to the heart,
  3. which means the muscles in the legs have impaired circulation (blood pooling) and possibly insufficient oxygen,
  4. which may mean that the insufficient oxygen in the legs leads to death of the small nerve fibers in the legs. (Small Fiber Neuropathy)
  5. ...Which is exactly what many people have suspected for a while, and is the same mechanism behind dysautonomic orthostatic intolerance!

Excerpt:

Earth to Pyrrhus: Once again thanks for looking up all of the research that you and so many others have done. It's most appreciated.

Also, did you notice that some alien changed your photo? Nice to actually meet you. Yours, Lenora.

 

[Pyrrhus]

Important question:

Were the authors trying to imply that the observed Small Fiber Neuropathy (SFN) was a cause or a result of the underlying dysautonomia?

Insights from another discussion:

I understand the proposed mechanisms of impaired aerobic capacity in the "Low, Low-Normal, and High-flow" groups and I don't doubt that dysautonomia plays a role in compromised blood flow in ME/CFS, but it seems the authors were more broadly applying proposed small-fiber neuropathy mechanisms than warranted by the 31% who had it.

Yes, in my opinion the article is poorly written and appears to implicate the small fiber neuropathy as the CAUSE of the dysautonomia, which, while plausible, is speculative.

It seems much more likely to me that the small fiber neuropathy is a RESULT of the dysautonomia, not a cause. That is, the loss of blood flow to the capillary beds leads to the death of the small nerve fibers. This interpretation would be better supported by their skin biopsy findings.

I'm also not clear how they ruled out mitochondrial dysfunction as a possible mechanism for the low oxygen extraction (@Pyrrhus do you understand this).

I'm not sure that they ruled it out. From my reading, they acknowledged mitochondrial dysfunction as a possible contributing factor to the impaired oxygen extraction. They simply said that their methodology could not support or rule out this possibility.

One of the big problems in their methodology is their use of a convenience sample in the patient selection process, which probably lead to a selection bias or two.

So perhaps the "Low and Low-Normal Flow Groups" also have difficulty extracting oxygen, but visibility to this is occluded by the greater oxygen extraction due to lower perfusion and slower flow of blood through the capillaries?

I think that could well be accurate.

 

[Pyrrhus]

Prior discussion:

Also eminently plausible. But note that any dysautonomic peripheral arterio-venous shunting is presumed to be primarily modulated by impaired constriction of veins, not by impaired arteriolar control. The walls of these veins are much more compliant than the walls of similarly-sized arteries, and therefore contribute much more to any A-V shunting.

I understand the proposed mechanisms of impaired aerobic capacity in the "Low, Low-Normal, and High-flow" groups and I don't doubt that dysautonomia plays a role in compromised blood flow in ME/CFS, but it seems the authors were more broadly applying proposed small-fiber neuropathy mechanisms than warranted by the 31% who had it. Also, there was an assumption that ME/CFS patients will have the same abnormal innervation to arterio-venous shunts found in some fibro patients (18 out of 24 according to the study cited). In my mind dysautonomia is part of the picture, but may not be exactly as described by the authors. I also wonder if low RBC deformability could also significantly contribute to low oxygen extraction and high SvO2. ( I think hypercoagulation would be more likely to lead to low SvO2).

I'm also not clear how they ruled out mitochondrial dysfunction as a possible mechanism for the low oxygen extraction (@Pyrrhus do you understand this). The authors state:

It has been hypothesized that MM underlies exercise intolerance in a subset of patients with ME/CFS, whose hallmark during incremental exercise is an increased Qc/VO2 slope. Possibly the inclusion criteria of PLF undermined our ability to detect patients with MM and an increased Qc/VO2 slope. There was no evidence of intracardiac left-to-right shunting at the time of the resting right heart catheterization. Together these exclusions leave systemic microcirculatory dysfunction (impaired oxygen delivery to muscles) as the presumptive mechanism.

But didn't the "High Flow Group" have an increased Qc/VO2 slope?

I was also mulling over why only the High-Flow group showed statistically significant low oxygen extraction (seems the other groups were trending that way). Do you think it is possible that in the Low-Flow and Low-Normal Flow groups: Lower venous return --> lower cardiac output would result in lower tissue perfusion and lower SvO2. So perhaps the "Low and Low-Normal Flow Groups" also have difficulty extracting oxygen, but visibility to this is occluded by the greater oxygen extraction due to lower perfusion and slower flow of blood through the capillaries?

 

[Learner1]

Reading through all this with interest, once again, as my biggest symptomatic issue these days is aerobic exercise intolerance - crashing after as little as 2 minutes of high intensity exercise or after 20-30 minutes of sustained exercise. This is consistently repeatable with different forms of activity. By crashing, I mean:

• Drained feeling in arms and legs, worse in whatever muscles were working most (upper body or lower body activity)
• Dizziness and instinctively wanting to curl up in fetal position and sleep
• If only slightly over this threshold, lying still with eyes closed helps me recover to function at 75% of normal level within 20 minutes
• If I really overdid it, I feel the same symptoms as long as 5 days later.
• I am never out of breath and heart rate never exceeds 105bpm (on metoprolol for hyper POTS)

Testing has shown:

• I'm at 80% VO2max for typical women in late 50s
• No SFN
• Pyruvate and lactate have been consistently below range since my illness - they were normal 8 years ago prior to illness
• Mitochondria predominantly do glycolysis, and not fatty acid oxidation, which is very abnormal - they suggested that I burn up muscle glycogen faster than I can replace it.
• Huperzine A helps control my hyper POTS
• Metoprolol helps control my high blood pressure

The discussed theory doesn't seem to fit. What other explanations are there?

 

[RYO]

Glad to see that Dr Systrom’s research published. His work is gratifying because it utilizes existing methods of studying potential physiological abnormalities in MECFS patients. Over 1500 patients subjected themselves to invasive CPET. The study participants should be commended because a CPET itself takes a toll even without having a central swan ganz catheter floated in the proper position along with an arterial line in the radial artery.

Also, future studies will have to go beyond looking at the blood, urine, fecal and CSF samples. The NIH study took skin biopsies from near lower ankle and lateral upper tibial area. John Hopkins did not find evidence lower nerve fiber density in NIH patients. It was a small group of 17 patients and I agree that there is a possibility that they may have missed patients with SFN.

I hope Dr Systrom and his research group gets additional funding and it would be nice if the scope of his research got expanded to perform seahorse mitochondrial analysis on his patient cohort as well as additional muscle tissue studies. I wish there was a way to continuously monitor muscle function with minimally invasive techniques. I wonder if invasive CPET has been used to evaluate long covid patients. In general, as a theme perhaps new technologies that allow functional studies of MECFS patients before and after exercise will yield better insights into disease pathophysiology.

My guess is that his findings of autonomic disruption and poor oxygen extraction is just an important piece of the puzzle. There are an abundance of questions about the interplay between the brain, immune system and end organs that still remain. Correcting fluid status and treating SFN does not cure patients.

 

[Pyrrhus]

It is also important to note one of the potential limitations of this study: the use of a convenience sample in patient selection.

This is how patients were selected for this study:

1. Data from 1516 iCPETs performed between 2011 to 2018 at the Brigham and Women’s Hospital Dyspnea Clinic (Boston, MA, USA) were analyzed.
2. If the iCPET data for a person indicated either heart or lung disease, that patient was excluded.
3. If the iCPET data was not accompanied by a test for small fiber neuropathy (SFN), that patient was excluded.
4. If the iCPET data did not show an abnormally low blood pressure in the veins returning blood from the legs to the heart, that patient was excluded. (RAP >= 6.5 mmHg)
5. For the remaining 223 patients, the IOM criteria for Systemic Exertion Intolerance Disease (SEID) were applied: "additional medical record review to confirm presence of ME/CFS using the NAM requirement of documentation of 3 major criteria (i.e. chronic fatigue for ≥ 6 months, post-exertional malaise, unrefreshing sleep) plus 1 minor criteria (i.e. either cognitive impairment, orthostatic intolerance)"
6. The 160 patients who met the IOM criteria were then included in the study.
7. 36 patients who had undergone iCPET for exertional intolerance, but who had normal results, were used as controls.

 

[bread.]

@Pyrrhus

I am sure you will find a good thread where this paper fits best.

I think, what we are dealing with here is very similar to what happens in post-polio syndrome.

https://pubmed.ncbi.nlm.nih.gov/2711135/

 

[Pyrrhus]

I think, what we are dealing with here is very similar to what happens in post-polio syndrome.

Yes, thanks, post-polio syndrome (PPS) is very similar to ME, so the results here may be applicable to some people with post-polio syndrome.

Although the exercise intolerance in PPS may have a component of motor neuron neuropathy, in addition to or rather than autonomic neuron neuropathy:
https://journal.chestnet.org/article/S0012-3692(16)33157-9/pdf

 

[Inara]

• 31% of ME patients showed Small Fiber Neuropathy (SFN) in the lower leg.
• The authors interpret the findings as possible clinical evidence for dysautonomia of the small nerves that control constriction of the small veins in the legs, which means that:
  1. The small veins in the legs remain abnormally dilated while standing,
  2. which means insufficient blood pressure to return the blood from the legs to the heart,
  3. which means the muscles in the legs have impaired circulation (blood pooling) and possibly insufficient oxygen,
  4. which may mean that the insufficient oxygen in the legs leads to death of the small nerve fibers in the legs. (Small Fiber Neuropathy)
  5. ...Which is exactly what many people have suspected for a while, and is the same mechanism behind dysautonomic orthostatic intolerance!

For those with SFN...Does this mean...exercise accelerates destruction of small fibers? Does being upright?
For those with POTS or anything else that leads to this oxygen problem... Does this lead to the onset of SFN? (But not everyone with POTS, e.g., has SFN...)

Since being upright and exercise/using muscles have certain positive effects - and being only supine as well as sedentary has well-known negative consequences (which can't always be avoided as it is known) - where's the balance??

 

[bread.]

Yes, thanks, post-polio syndrome (PPS) is very similar to ME, so the results here may be applicable to some people with post-polio syndrome.

Although the exercise intolerance in PPS may have a component of motor neuron neuropathy, in addition to or rather than autonomic neuron neuropathy:
https://journal.chestnet.org/article/S0012-3692(16)33157-9/pdf

I am not sure motor neuron neuropathy is a non-issue in myself, and therfore maybe others with me/cfs? But I definitely agree it will be to a lesser degree than in pps.

 

[lenora]

I actually lived with a family where the mother had polio. We stayed in close contact over many years and she developed post-polio syndrome.

She liked talking to me (& the reverse was true) b/c our symptoms were incredibly similar. I often wondered about any connection between the two viruses at that time even. She lived to be 95....imagine that one, and had two knee replacements at the same time when she in her late 80's. Even today, I look to her with great respect and admiration. Her family (and I loved these people) thought the answer lay in more exercise for her, were extremely kind and thought they were being helpful BUT these conditions do exist and the polio virus that later came back to haunt its victims, was one of them.

One question: I read some of the papers, but I wondering if it was mentioned anywhere as to what percentage of the recovered victims went on to the develop post-polio syndrome? It seems that major viruses do carry something that adds additional stress to the body. It's possible that something as simple as an extended recovery period is the answer.....but then Long Haul Syndrome seems to belie that question.

I can distinctly remember the relief that the polio vaccine was met with, how we lined up around and around the community center it was being given at.....and the immense relief of parents. I also remember quarantines and being quarantined ourselves for red measles, I believe....can't remember details. Maybe those old-fashioned methods really did work and we should consider going back to them. The world has been without a major outbreak of anything except AIDS and now COVID for so long that we don't know how to deal with these matters. Maybe it takes resurrecting health officials and the sign, "Quarantine." Yours, Lenora.

 

[Pyrrhus]

For those with SFN...Does this mean...exercise accelerates destruction of small fibers? Does being upright?

For those with POTS or anything else that leads to this oxygen problem... Does this lead to the onset of SFN?

Possibly yes, if you remain upright for long periods of time. (The issue of exercise is more complicated.)
But more research is needed.

Personally, if I have to be upright for extended periods of time, I regularly contract my feet and calf muscles to keep the blood moving. Contracting the calf muscles especially helps to push blood back up to the heart.

Since being upright and exercise/using muscles have certain positive effects - and being only supine as well as sedentary has well-known negative consequences (which can't always be avoided as it is known) - where's the balance??

Excellent question. Perhaps try slow, supine exercise instead of fast, upright exercise?

I am not sure motor neuron neuropathy is a non-issue in myself, and therfore maybe others with me/cfs?

Yes, I think you may be right here.