New Exercise Study Brings Both Illumination and Questions

Simon submitted a new blog post:

New Exercise Study Brings Both Illumination and Questions

Simon McGrath looks at new objective evidence of abnormal response to exercise in ME/CFS patients, and the questions that researchers are still trying to answer ...


Exercise testing at Dr. Keller's lab

Given the doubt, scepticism and even denial of benefits that often confronts ME/CFS patients, it’s not surprising that many patients crave clear-cut, objective evidence of physiological problems in the illness. Preferably something that will explain at least some of the perplexing symptoms. Something that will say: “this is real”.

And finally it seems researchers might be closing in on this.

Two-day maximal exercise tests promise to provide objective evidence for the most striking and unusual feature of the illness, the exhaustion and flare of symptoms following exercise, called post-exertional malaise.

A couple of studies by researchers at Workwell showed distinctive abnormalities on these tests, and now another researcher Dr. Betsy Keller of Ithaca College has found them in an independent study.

But, as usual, science is messy, and these studies raise almost as many questions as they answer. While all three studies find substantial abnormalities, key details vary between them.

Furthermore, safety is a big unknown. These tests require patients to push well beyond normal limits twice in two days — exactly the kind of thing patients have found can cause lasting relapses. As yet, there is no hard safety data.

Even so, a little-noticed Social Security ruling in April states that while there is not yet a ‘definitive’ laboratory test, an abnormal exercise stress test, consistent with other evidence in the case record, proves a ‘medically determinable impairment’ in those with ME/CFS. And Keller reports that insurers increasingly accept her tests as evidence of incapacity. The two-day test could help secure a financial lifeline for patients.

Results from the latest exercise study

Keller used a similar two-day maximal exercise test at Workwell. ME/CFS patients exercised to complete exhaustion on a bicycle while their oxygen consumption, work output (pedal power), and numerous other measures were recorded. Then the 22 patients came back one day later to do it all again.


The most interesting measures were oxygen consumption and work output, a key measure of what people can actually do.

Work and oxygen consumption were measured at two key points: peak (usually just before people stopped from exhaustion), and at the anaerobic threshold.This is the point where normal aerobic (oxygen-burning) metabolism can't keep up, so the body has to draw more heavily on anaerobic metabolism to make up the shortfall, resulting in accumulation of lactate in the blood.

For healthy people at least, the anaerobic threshold is roughly the point where it’s still just possible to talk normally while exercising. (Strictly speaking, Keller used the "ventilatory threshold,” calculating it from the ratio of oxygen used to carbon dioxide exhaled, but that’s approximately the same as the anaerobic threshold.)

The patients showed an average fall in day-two oxygen consumption of 14% at their peak and 16% at their anaerobic threshold. Work output fell by similar amounts: patients could do less on day two.

There were no controls in this study, but there are well-established studies going back to the 1950s showing that healthy people can reliably reproduce their performance (within 7%) on two-day tests. Keller says the far greater drop in ME/CFS patients indicates an underlying physiological defect.

In fact, the results are even more striking for individual patients: while some show little to no change, some show very large drops, including one patient dropping 55% on day-two peak oxygen consumption. (It’s worth taking a look at the results diagram, Figure 3A in the paper, to see what’s really going on).

What’s more, those patients who didn’t show a clinically significant fall in peak oxygen consumption instead showed a significant fall oxygen consumption at anaerobic threshold: everyone showed abnormalities.


All patients showed a clinically significant drop on day-two, either for peak or anaerobic threshold oxygen consumption.


A one-day exercise test wouldn’t be enough to reliably show these patients’ true impairment. Using a standard measure of impairment developed for heart and lung patients based on a single exercise test, 13 of the 24 ME/CFS patients were classified as having little or no impairment. But while heart and lung patients can reproduce their exercise performance on day two, the ME/CFS patients could not.
The difference was big enough that half of the ME/CFS patients in this study would be classified as having lower functional ability on day-two results, and five of the thirteen that didn’t show any impairment on day one did on day two. This just highlights something very unusual going on with ME/CFS patients.

The results were so unusual, in fact, that it raised the possibility of faulty equipment. Though Keller didn’t run a control group, separate testing in her lab during the same period found normal results for healthy people, indicating equipment worked effectively.

Workwell included controls in their studies, and Chris Snell said this was mainly to prove the equipment was working (not to demonstrate that healthy controls can replicate performance on day two).


Science is messy

Perhaps these inconsistent results are not so surprising. A complex disease like ME/CFS is unlikely to yield its secrets so easily, and science is messy, especially in the early days.

A good example of messy findings came in the most important discovery in biology of the twentieth century: the structure of DNA.

X-ray diffraction images of DNA provided key evidence about its structure. Original images of DNA were clear in some parts but blurry in others, making them hard to interpret. This changed when X-ray expert Rosalind Franklin discovered DNA came in two types: A-DNA and B-DNA.

The original images turned out to be for a mixture of A and B DNA. Separate images for A and B revealed the extra information needed to solve the structure of DNA.

The different X-ray diffraction patterns of A and B DNA
Perhaps a similar scenario will play out in two-day testing, if studies are able to identify different subgroups, each with clear and distinct abnormalities - perhaps even a subgroup with none. Given that many researchers believe ME/CFS is likely to be more than one illness, it would almost be surprising if all patients did respond the same way to exercise.

Different differences

Unfortunately, when you compare the results of the various studies, as Keller did in her paper, the story becomes considerably murkier.

First, let’s look at oxygen consumption. Keller’s result, in summary, was that every one of her twenty-two patients had a drop in oxygen consumption either at peak or at anaerobic threshold, but not necessarily both.

The first wave-making 2007 Workwell study found drops in both for all six patients. A 2010 Dutch study found drops in both as well — but they were too small to be confident that they were meaningful.

Last year, a larger Workwell study (51 patients, 10 controls) found that the oxygen consumption at anaerobic threshold dropped significantly (by 11%), but the drop in peak oxygen consumption wasn’t big enough to be statistically or clinically significant (only 5%).

However, this last study also found a huge drop of 55% in work output on day two at the anaerobic threshold for patients.

This was especially surprising because the drop in oxygen consumption was far smaller at 11%, meaning that the patients produced much less work for each unit of oxygen. This inefficiency could point to some major metabolic change.

In contrast, Keller’s new study found a less dramatic drop of 21% in work. While that’s a clinically interesting result, it is broadly in line with the 16% drop in oxygen consumption at anaerobic threshold. It doesn’t suggest that the body is producing less work per unit of oxygen, the way the larger Workwell study did.

The Dutch study found a non-significant drop in work output of 7%, while work wasn’t measured in the first Workwell study.

So three of four published studies find substantial drops in day-two performance (the fourth Dutch study was on the margins of finding a difference), but no clear pattern has emerged as to which are the most important measures.

Is it peak oxygen consumption, anaerobic threshold oxygen consumption, or work output at anaerobic threshold?


Moving beyond messy science

Researchers have uncovered a very promising area for study. What’s needed to build on these findings and find out what’s really going on is further, more thorough investigation. Keller says we sorely need a much bigger study -- and by bigger she means involving hundreds of subjects, which will come with a hefty price tag.

The bigger study will help clarify exactly what changes in response to exercise and for whom. It could even establish thresholds for measures like peak oxygen consumption that could then be used by clinicians in diagnosis. Such guidelines will be crucial if more patients want to take advantage of the test to help with disability claims, as currently only three labs in the United States carry out this work.

Keller is clearly disappointed by the lack of interest in these extraordinary findings from exercise physiologists working outside ME/CFS. She’s not sure why but thinks it may go back to training.

As in so many medical fields, exercise physiology undergraduates learn next to nothing about ME/CFS, while young researchers are deterred by a lack of funding for this area. As things stand, moving the field forward will fall on the shoulders of the existing small group of researchers.

What could be going on physiologically?


Given the mixed findings, it’s hard to know what is driving the problem. The reduced oxygen consumption suggests two possibilities.

Keller thinks that too little blood could be being delivered to the muscles, thus not supplying enough oxygen. There is some indirect evidence to support this, including a modestly reduced heart rate on day two in this study, indicating less blood is being pumped around the body.

Poor autonomic response, says Keller, could be behind reduced blood flow, and there is plenty of research showing autonomic problems in ME/CFS, at least for subgroups.

An alternative explanation is that muscles are simply unable to burn more oxygen, and a study by a Dutch group suggested muscle uptake of oxygen was the problem. The muscle problem in turn could be down to mitochondrial or other energy metabolism defects. Again, it may need careful identification of subgroups before researchers can really get a handle on what’s going wrong.

Is it unique?

We don’t know if these findings are unique to ME/CFS, though it’s certainly unusual. This kind of maximal testing has been used frequently in diseases affecting heart and lungs (where all published results indicate they can reproduce results the second day).

Yet no published data exists on other fatiguing illnesses such as multiple sclerosis, HIV and rheumatoid arthritis. In a pilot study, however, Workwell reported normal reproducibility for one MS and one HIV patient.

The safety question


There will inevitably be concerns from some patients about taking a test that by definition pushes them to their absolute limits, and then does it again twenty-four hours on in the midst of post-exertional malaise.

Pushing beyond normal limits has triggered many a relapse, and sometimes patients never bounce back. But how big are the actual risks for a two-day test?

Keller says that most people in their tests report recovering to baseline in seven to 21 days, though some take longer. She also points out there is a lack of published data on long-term effects even for a one-day test, let alone two-day tests.

What’s needed, she says, is long-term follow-up looking at both symptoms and activity levels, to establish how long it takes patients to recover to baseline symptoms and activity. And she wants to use actometers (activity sensing devices) to ensure objective measurements of patient activity. This would also allow researchers to see if changes in patient activity matched the physiological changes seen on day two.

If these tests do cause extended relapses in some patients, they may never be appropriate to use for all patients in the clinic, even if they fulfil their promise to unravel some of the mechanisms of the disease. And in that case, there’s a cruelty in the new disability ruling. The only way that patients can prove their disability might be by risking making it worse.

The promise of exercise stress tests

To me, these are extremely interesting findings, because they have found substantial effects linked to the central feature of ME/CFS, abnormal response to exertion. It’s not just these two-day tests either: in Utah, the Lights’ fascinating gene expression studies are particularly interesting as they only uses a single, moderate test to reveal differences between patients and controls.

This is closer to real-world exertion by patients, as well as probably carrying less risk of relapse. The Lights’ initial findings have apparently been replicated in a larger NIH-funded study, but have not yet been published.

Clearly this isn’t a done deal yet, but the biological response to exercise is becoming an important new front in helping to unravel ME/CFS.

Simon McGrath tweets on ME/CFS research:

Picture credits: Exercise testing photo courtesy of Dr Betsy Keller; Exhausted pose drawings by JoeyGates on deviantART, Creative Commons CC BY-NC-ND 3.0; X-ray photos By I.C. Baianu et al. [GFDL or Creative Commons CC-BY-SA-3.0], via Wikimedia Commons.



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Comments

I really salute your emphasis on the issue of safety … This test in my view ought to be a means for research alone, and not a means to prove disability to insurers. Have a few hundred courageous ME/CFS sufferers undergo the test for the sake of science, and for that sake alone. It would be terrible if insurers were one day to demand it systematically to thousands of sufferers... As you have pointed, the moderately ill run the risk of worsening their state, and the severely ill could not even perform the test in the first place. (If one is to prove that one has a heart condition, do you demand that he or she go through a near- heart attack experience?!...) That is why I find the merging of the two studies - the CPET and the Lights' on gene expression - so harmonious. The CPET provides "hard core" and damaging data, so to speak, that backs up the softer gene expression studies, which take the lead from there in direction of biomarkers. Let's just hope that some day soon with the latter we can prove the pathology underlying post-exertional exhaustion, without having to go through it to prove it...
 
I also put a message on the Workwell Facebook page some time ago - the question I have in mind is whether or not severe ME patients are permanently in anaerobic metabolism, and whether this test would then be useful. I have had no reply to date.
Alex, there is an email address for Workwell listed on their Facebook page. I have emailed them previously and gotten a response from Jared Stevens within a couple of days
 
I am being treated for POTS, but first all the tests. Where do I begin. First I can only do a few tests at one time. So it's been three appointments and only once a month. It actually takes me longer to recover but I'm in this, really in this.

Tilt table test, blood volume test, hemodynamic test, autonomic reflex test, and my personal favorite the stress test on a treadmill that put me in bed for a week and got some abnormal results and mortality rates 5-10% in 5 years depending on which institution you are going by.

I know I'm a mess but now they know it. I will get the final results on 8/25 but they are wondering why I'm not doing the exercises with the heart rate gizmo. Well I haven't recovered from the tests yet and I won't do them until all results of tests are given to me and then a plan is made.

I must say I never thought my life would be this hard, not in a million years. (real tears).
@PNR2008 I am so sorry to hear all that you are going through and admire your strength and perseverance with all those tests. Hopefully your results on Mon will bring clarity and a solid plan. :hug:
 
Just a quick question. It is not 100% clear, but I'm guessing you consulted with Keller about her research while writing this article?
Thanks for raising that and I'm sorry it wasn't clear: yes, I did get in touch with Betsy Keller, who was very helpful.

One of the difficulties must be that each of us has a different mix of long and short fibre muscle, which (if I remember correctly) correlate to marathons versus sprints. The initial mix depends upon genetics, but the balance can be adjusted through training. What if (pure speculation here) some people with ME have a muscle balance that, after several years of the disease and careful "nudging the envelope" have increased their short fibre muscles? What effect would that have on measurements such as this?
It would have no effect on the main effect observed here, the drop off on day two. I think it could affect the basic day one level of the anaerobic threshold in particular, but I'm really not too sure.
 
Two O2 consumption test on a treadmill in two consecutive days (10 minutes with last 2 being uphill and fast) left me almost useless for a week. But something interesting: both test showed abnormally low anaerobic threshold and the second test showed lower oxygen consumption than the first, 24 hours later. It weas hard to get those tests done since I'm from Argentina and nobody here knows much about ME and let alone these scientific studies. What do you think?
 
I feel like a stranger in a strange land with all of this exercise testing. I had a mild case of ME/CFS for 10+ years prior to taking a cardiac stress test 9 years ago, which caused very severe disease progression and heart damage. I am now in Stage 2 diastolic heart dysfunction with Stage 4 heart failure symptoms as a result of this stress test. I also lost my ability to talk after the stress test. I had no heart problems or problems with my voice before the stress test. I am now almost entirely bed and wheelchair bound.

"Findings which suggest mitochondrial metabolic dysfunction similar to mitochondrial encephalomyopathy in CFS patients led CFS expert Professor Paul Cheney to comment. ‘The most important thing about exercise is not to have patients do aerobic exercise. I believe that even progressive aerobic exercise is counter-productive. If you have a defect in mitochondrial function and you push the mitochondria by exercise, you kill the DNA.’ Numerous heart, lung, brain and other abnormalities also show strong evidence that exercise can have extremely harmful effects on CFS patients in many different bodily systems, permanent damage may be caused, as well as disease progression." (Williams 2004, [online]).

"In CFS physical overexertion causes relapses of symptoms and continued physical overexertion can lead to disease progression - which may be irreversible." The Hummingbirds' Foundation for M.E.

"As well as long-term effects on disease progression, exertion can also have serious (and sometimes fatal) effects which are more immediate (cardiac complications for example)." The Hummingbirds' Foundation for M.E.

"Not only is it inappropriate for CFS patients to undergo a treadmill stress test or be pushed toward age-predicted target heart rates, but this is potentially dangerous." Philipa Corning, Ph D, Vice President Quest 61, 2003

So I am totally shocked by the growth of these exercise studies, and PWCs standing in line. Unless I have a different disease, or there is a difference between ME and CFS, or most of the PWCs taking these tests have been misdiagnosed, then I don't understand why PWCs taking these exercise tests aren't having the same horrific results that I've had. So I would warn all PWCs that taking a stress or exercise test could destroy your life and possibly lead to severe permanent disease progression and death from heart failure.

Furthermore, I don't understand why there are no mainstream research studies going on today reg. the effects that ME/CFS has on the heart, i.e. this is one of the main causes of death from ME/CFS.
 
I would be interested to see how results for patients with dysautonomia (including POTS) respond to this excerise test and how the results compare with ME patients. Once of most infuriating things I've found about ME and CFS is how quickly doctors are to slap a CFS diagnosis on patients (my daughter in our case), which means it's unlikely they'll investigate further, and getting any sort of treatment, other than seeing a psychologist is nearly impossible. But many patients orginally diagnosed with CFS have POTS or another form of dysautonomia, amongst other conditions, either alongside their ME or CFS or instead of, but this is rarely investigated, despite there being treatment that can significantly improve their quality of life and functionality.

Patients with POTS (just POTS with no ME) also complain of post exertional malaise and payback for pushing beyond their limits, so it would be interesting to find out if one of the subsets relates to autonomic dysfunction (rather than ME) and if another was specific to ME (and not to patients with 'just' autonomic problems).

At the moment, I suspect the exercise tests also pull patients with dysautonomia, and not necessarily ME, into the pot and also includes people with ME, who do not have dysautonomia. This begs the question, what other conditions would also show these sorts of results.
 
So I am totally shocked by the growth of these exercise studies, and PWCs standing in line. Unless I have a different disease, or there is a difference between ME and CFS, or most of the PWCs taking these tests have been misdiagnosed, then I don't understand why PWCs taking these exercise tests aren't having the same horrific results that I've had. So I would warn all PWCs that taking a stress or exercise test could destroy your life and possibly lead to severe permanent disease progression and death from heart failure.
For many patients a 2-day CPET result can make the difference between getting government or insurance benefits, versus being homeless, unable to feed themselves, and/or shunned by family, friends and doctors.

We know it's a risk, which is why we want it to be a central aspect of research looking for additional biomarkers which won't risk maiming or killing us in the process of collecting them :p
 
Patients with POTS (just POTS with no ME) also complain of post exertional malaise and payback for pushing beyond their limits, so it would be interesting to find out if one of the subsets relates to autonomic dysfunction (rather than ME) and if another was specific to ME (and not to patients with 'just' autonomic problems).
Exercise intolerance is what hits OI patients during and immediately after exertion. PEM has a substantial delay and exacerbation of the ME symptoms. I think you might be assuming that Exercise Intolerance and PEM are the same - they aren't.

ME patients often have both OI and PEM, so will get hit twice: once during or immediately after exertion, and then a day or two later. If an OI patient has ME symptoms and PEM, they probably need a new diagnosis (or not, if it means an end to helpful treatment).

An OI patient should be able to exercise lying down without problems, and can often build up muscles to help with OI and resulting exercise intolerance. That doesn't work at all for ME patients.
 
In 1992 I had a spect scan through Jay Goldstein which showed " diminished perfusion in the right frontotemporal lobes and incomplete response of regional cerebral blood flow to exercise". As far as he was concerned the first day of exercise and the spect scan showed the abnormality and said the second day was up to me but it could provoke an exacerbation of symptoms which wasn't necessary. I did not do the second day testing. I really miss that man and this was in 1992!

Now in 2014 I'm in worse shape than ever but being put to tests that may pinpoint problems with POTS and hopefully make my later years of life better or not? That is if I have enough time to get over the PEM these tests caused. This is a double-edged sword which just might pierce my heart literally.
 
I would be interested to see how results for patients with dysautonomia (including POTS) respond to this excerise test and how the results compare with ME patients. Once of most infuriating things I've found about ME and CFS is how quickly doctors are to slap a CFS diagnosis on patients (my daughter in our case), which means it's unlikely they'll investigate further, and getting any sort of treatment, other than seeing a psychologist is nearly impossible. But many patients orginally diagnosed with CFS have POTS or another form of dysautonomia, amongst other conditions, either alongside their ME or CFS or instead of, but this is rarely investigated, despite there being treatment that can significantly improve their quality of life and functionality.

Patients with POTS (just POTS with no ME) also complain of post exertional malaise and payback for pushing beyond their limits, so it would be interesting to find out if one of the subsets relates to autonomic dysfunction (rather than ME) and if another was specific to ME (and not to patients with 'just' autonomic problems).

At the moment, I suspect the exercise tests also pull patients with dysautonomia, and not necessarily ME, into the pot and also includes people with ME, who do not have dysautonomia. This begs the question, what other conditions would also show these sorts of results.
CaronR,

Well said.

One research group who is starting to delineate subgroups are the Lights and Dr. Bateman. They delineated a unique group that had ME/CFS, fibromyalgia and "Orthostatic intolerance" and had a unique gene expression following a single exertion test.

Here is a summary from Kathleen Light:

α-2A Decrease Subgroup....Forty-eight CFS patients were studied and two distinct subgroups were identified on the basis of changes to the α-2A receptor, a key regulator of neurotransmitters in the central nervous system. The larger group of CFS subjects (71%) could be identified with a combination of four biomarkers (P2XR, α-2A, β-2 and IL10) at any time point within 48 hours following the exercise challenge with high specificity and sensitivity. The smaller group showed a large decrease in α-2A, opposite of the larger group. Most of the members of this subgroup had a clinical history of orthostatic intolerance. 18 subjects with fibromyalgia were also evaluated and a baseline marker combining 3 genes was identified. All subjects in the study (CFS and FM) exhibited post-exertional relapse of symptoms for at least 48 hours following the exercise task, but 49 healthy controls did not.
There used to be a good summary of this research over at the CFIDS (now Solve ME/CFS initiative) website, but I can no longer find it. I wrote a rambling blog about the study over at Cort Johnson site, focusing on the subgroup. (http://www.cortjohnson.org/blog/201...yndrome-subset-if-doctors-will-just-look-for/). As Simon has said, the Drs. Lights and Dr. Bateman have embarked on a much larger study that was supposed to be published somewhere around this time frame this year. So, hopefully they'll publish soon and There will be more detailed information about Gene expressions, sub-groupings and???
 
Kathleen Light said:
α-2A Decrease Subgroup....Forty-eight CFS patients were studied and two distinct subgroups were identified on the basis of changes to the α-2A receptor, a key regulator of neurotransmitters in the central nervous system. The larger group of CFS subjects (71%) could be identified with a combination of four biomarkers (P2XR, α-2A, β-2 and IL10) at any time point within 48 hours following the exercise challenge with high specificity and sensitivity. The smaller group showed a large decrease in α-2A, opposite of the larger group. Most of the members of this subgroup had a clinical history of orthostatic intolerance. 18 subjects with fibromyalgia were also evaluated and a baseline marker combining 3 genes was identified. All subjects in the study (CFS and FM) exhibited post-exertional relapse of symptoms for at least 48 hours following the exercise task, but 49 healthy controls did not.
α-2A is ADRA2A (Adrenergic Receptor Alpha 2A), which can cause low norepinephrine when over-expressed, and thereby low blood pressure and/or low pulse pressure. I've tested low in blood norepinephrine, and have very good results with a low dose of Yohimbe, an ADRA2A antagonist. I think someone else here is on it as well, and mentioned good results.

But the smaller group has a large decrease in ADRA2A, which might explain the rarer hyperadrenergic POTS patients with orthostatic hypertension which we have here. I know @taniaaust1 has that issue, and tests high in norepinephrine, rather than low. I've seen someone else mention that problem recently as well in a thread.
 
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I feel like a stranger in a strange land with all of this exercise testing. I had a mild case of ME/CFS for 10+ years prior to taking a cardiac stress test 9 years ago, which caused very severe disease progression and heart damage. I am now in Stage 2 diastolic heart dysfunction with Stage 4 heart failure symptoms as a result of this stress test. I also lost my ability to talk after the stress test. I had no heart problems or problems with my voice before the stress test. I am now almost entirely bed and wheelchair bound.
@JKN I am so sorry you had that experience and was wondering if the doctor ever explained to you how the exercise stress test (I am assuming it was on a treadmill?) led to heart failure and losing your voice. I believe you and am only asking b/c I just did the exercise echo (treadmill test) a few days ago myself and curious to learn more from your experience. Have you found any treatments that brought you any improvement and did your doctors offer any suggestions? Again, I am so sorry to hear how much you have suffered with this and wish you peace moving forward.
 
α-2A is ADRA2A (Adrenergic Receptor Alpha 2A), which can cause low norepinephrine when over-expressed, and thereby low blood pressure and/or low pulse pressure. I've tested low in blood norepinephrine, and have very good results with a low dose of Yohimbe, an ADRA2A antagonist. I think someone else here is on it as well, and mentioned good results.

But the smaller group has a large decrease in ADRA2A, which might explain the rarer hyperadrenergic POTS patients with orthostatic hypertension which we have here. I know @taniaaust1 has that issue, and tests high in norepinephrine, rather than low. I've seen someone else mention that problem recently as well in a thread.
@Valentijn,

So, The smaller group (the one with the large decrease) might be affected by mechanisms described in this paper,

http://atvb.ahajournals.org/content/32/8/1910.long

Where they find:

.....The expression of norepinephrine transporter was lower in POTS patients compared with healthy volunteers. In the absence of altered SLC6A2 gene sequence or promoter methylation, this reduced expression was directly correlated with chromatin modifications......
Or am I confused?
 
So, The smaller group (the one with the large decrease) might be affected by mechanisms described in this paper....
I think it would be a different pathway into the same (or similar) symptoms. Unless the way that ADRA2A reduces norepinephrine is by reducing SLC6A2, in which case it could be the same problem. I need to read more about the mechanism for how ADRA2A is impacting norepinephrine!
 
Nice reporting but I feel the researchers are barking up the wrong tree... .

If the purpose of exercise testing results in help PWMEs get financial help then more power to the researchers for correlating the subject findings . However, wouldn't similar respiratory-exertion findings be common to any serious long term sickness?
Assuming that's the case then these experiments might prove embarrassing, like publishing results tantamount to 'when it rains things get wet!'

I am under the impression that adrenaline rising (rushing) is a shared, sic felt, causative symptom from physical OR mental effort (exertion) and that it ultimately leads to malaise, even perhaps severity of the malaise (>adrenaline production) is directly correlated to a measure of that exertion?

If this is the case then wouldn't measuring epinephrine and its analogs before and during exertion yield more significance, in that an autonomic immune system dysfunction is a resultant of ME (albeit likely initiated from variant causes)? I'm not aware of the HEPA axis dynamics having been ruled out as causative of the kind of malaise we all suffer.
 
Nice reporting but I feel the researchers are barking up the wrong tree... .

If the purpose of exercise testing results in help PWMEs get financial help then more power to the researchers for correlating the subject findings . However, wouldn't similar respiratory-exertion findings be common to any serious long term sickness?

Dr. Alan Light, et. al., have done these gene expression studies on patients with ME/CFS, ME/CFS with fms, patients with only fibromyalgia, prostrate cancer, and patients with multiple sclerosis only. The patient subsets with ME/CFS, and ME/CFS with fibromyalgia each have unique signatures.

If you type this into the pub med search engine, you can see a listing of their publications, and are well worth perusing:

(Chronic fatigue syndrome) AND Light ar[Author]

Their color-coded gene expression graphs are pretty spectacular.
 
If the purpose of exercise testing results in help PWMEs get financial help then more power to the researchers for correlating the subject findings . However, wouldn't similar respiratory-exertion findings be common to any serious long term sickness?
The answer appears to be no. Its certainly not the case for cardiac or respiratory patients that I am aware of, nor MS patients. One patient with HIV does test this way though, but I suspect this person is unfortunate enough to have both HIV and ME. Its also not seen in deconditioning. There is some question of whether or not its seen in things like POTS or post-cancer fatigue however. We do not know yet.

The results re so unique to ME (so far) that two separate research teams were at first convinced their machine was broken or needed calibration.

There are three benefits to the 2 day CPET:

1. As a research finding it gives us another direction and clearly shows severe pathophysiology in many patients, and so is a biomarker for ME even if its not diagnostic. It currently is best thought of as an outcome marker in my opinion, and indeed it has been used this way I think.

2. It can assist patients obtaining disability or insurance payouts. Its hard for anyone to dispute this finding, at least at present.

3. It can provide information on a patient's anaerobic threshold and current recovery status ... whether or not their treatment is working. This can help plan treatment changes.

However, it may also have the following issues.

A. Insurance companies may decide to mandate testing. I wonder if they will accept responsibility if this forces a crash.

B. Most patients do somewhat to a lot worse after testing. Some go into serious crashes. I would not recommend this for anyone as a routine test, its something that should be up to the individual, their doctor, and their current needs.

C. More severe patients cannot do this kind of testing. Its limited to mild to perhaps the low end of severe (depending on what you mean by severe), and the more severe the patient the less desirable this testing might be.

I think this kind of technology will be necessary for a while for some patients, but I also suspect it will be superseded. However even the Light's testing requires one bout of exercise, though perhaps at lower intensity. Its also the case that lower intensity testing might suffice for determining anaerobic threshold, and even that gas analysis for metabolic rate testing is all that is needed in some cases, particularly severe cases.

Despite this technology being around since at least 1949, and docs using it for ME since the 80s at least, its still very early in the research for us to have a good grip on what this tech should be used for.
 
Nice reporting but I feel the researchers are barking up the wrong tree...

If the purpose of exercise testing results in help PWMEs get financial help then more power to the researchers for correlating the subject findings .

However, wouldn't similar respiratory-exertion findings be common to any serious long term sickness?
Assuming that's the case then these experiments might prove embarrassing, like publishing results tantamount to 'when it rains things get wet!'
Glad you liked the article :)

As the article mentions, a lot of testing has been done on on patients with heart and lung diseases - that's been the main medical use of these exercise tests (CPET - cardiopulmonary exercise testing in the jargon). For example, angina patients were found to be able to repeat the test reliably three times in 3 days. There's a lack of data other fatiguing illnesses, though Workwell have set the ball rolling with tests on one MS & one HIV patients - more data is needed, though the fact that people with serious heart and lung disorders can repeat the test strongly suggests to me this isn't a generic feature of chronic illness. Though to be honest, before I'd seen the data for other illnesses I'd assumed, like you, that it would be.
 
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One of the difficulties must be that each of us has a different mix of long and short fibre muscle, which (if I remember correctly) correlate to marathons versus sprints. The initial mix depends upon genetics, but the balance can be adjusted through training. What if (pure speculation here) some people with ME have a muscle balance that, after several years of the disease and careful "nudging the envelope" have increased their short fibre muscles? What effect would that have on measurements such as this?

I ask because I have "classic" ME, and sit somewhere in the middle severity range. I used to cycle a lot (it is very hilly here), but was useless at sprints. A little while ago I was sent to have my heart irregularity checked on a treadmill (on the understanding that I could stop at any time), but I actually managed a fast uphill walk without more than a day's payback (of course, in my pre-ME days I would have laughed at how trivial the test was).

I appreciate that this comment is muddled, but it does puzzle me that I seem to get less payback problems these days for going a little over the physical limits than for going over the concentration limits, something that just wasn't true for the first ten years or so of the illness.
Try this thread. Title "Functional characterization of muscle fibres from patients with CFS" :)