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Decreased Oxygen Extraction during Cardiopulmonary exercise test in patients with CFS

shannah

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http://www.translational-medicine.com/content/12/1/20/abstract

Decreased oxygen extraction during cardiopulmonary exercise test in patients with chronic fatigue syndrome

Ruud CW Vermeulen and Ineke WG Vermeulen van Eck



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Journal of Translational Medicine 2014, 12:20 doi:10.1186/1479-5876-12-20

Published: 23 January 2014
Abstract (provisional)
Background
The insufficient metabolic adaptation to exercise in Chronic Fatigue Syndrome (CFS) is still being debated and poorly understood.

Methods
We analysed the cardiopulmonary exercise tests of CFS patients, idiopathic chronic fatigue (CFI) patients and healthy visitors. Continuous non-invasive measurement of the cardiac output by Nexfin(R) (BMEYE B.V. Amsterdam, the Netherlands) was added to the cardiopulmonary exercise tests. The peak oxygen extraction by muscle cells and the increase of cardiac output relative to the increase of oxygen uptake (DeltaQ'/DeltaV'O2) were measured, calculated from the cardiac output and the oxygen uptake during incremental exercise.

Results
The peak oxygen extraction by muscle cells was 10.83 +/- 2.80 ml/100ml in 178 CFS women, 11.62 +/- 2.90 ml/100ml in 172 CFI, and 13.45 +/- 2.72 ml/100ml in 11 healthy women (ANOVA: P=0.001), 13.66 +/- 3.31ml/100ml in 25 CFS men, 14.63 +/- 4.38 ml/100ml in 51 CFI, and 19.52 +/- 6.53 ml/100ml in 7 healthy men (ANOVA: P=0.008).

The DeltaQ'/DeltaV'O2 was > 6 L/L (normal DeltaQ'/DeltaV'O2 [almost equal to] 5 L/L) in 70% of the patients and in 22% of the healthy group.

Conclusion
Low oxygen uptake by muscle cells causes exercise intolerance in a majority of CFS patients, indicating insufficient metabolic adaptation to incremental exercise. The high increase of the cardiac output relative to the increase of oxygen uptake argues against deconditioning as a cause for physical impairment in these patients.
 

alex3619

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This is finding problems in 70% of us without a 2 day testing I think. I do not know what a Nexfin is. I will have to look that up.

PS http://www.edwards.com/products/mininvasive/pages/ccnexfinsystem.aspx

The ccNexfin System A noninvasive hemodynamic monitor which provides real-time, beat-to-beat information on cardiac output (CO), blood pressure (BP), and other hemodynamic parameters. Backed by over 30 years of research and development on noninvasive cardiac output and hemodynamic monitoring technology, ccNexfin system has been validated in a number of studies.5,6,9,10 Delivering clarity in every moment.

 

biophile

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Vermeulen RC, Vermeulen van Eck IW. Decreased oxygen extraction during cardiopulmonary exercise test in patients with chronic fatigue syndrome. J Transl Med. 2014 Jan 23;12(1):20. [Epub ahead of print]

BACKGROUND: The insufficient metabolic adaptation to exercise in Chronic Fatigue Syndrome (CFS) is still being debated and poorly understood.

METHODS: We analysed the cardiopulmonary exercise tests of CFS patients, idiopathic chronic fatigue (CFI) patients and healthy visitors. Continuous non-invasive measurement of the cardiac output by Nexfin(R) (BMEYE B.V. Amsterdam, the Netherlands) was added to the cardiopulmonary exercise tests. The peak oxygen extraction by muscle cells and the increase of cardiac output relative to the increase of oxygen uptake (DeltaQ'/DeltaV'O2) were measured, calculated from the cardiac output and the oxygen uptake during incremental exercise.

RESULTS: The peak oxygen extraction by muscle cells was 10.83 +/- 2.80 ml/100ml in 178 CFS women, 11.62 +/- 2.90 ml/100ml in 172 CFI, and 13.45 +/- 2.72 ml/100ml in 11 healthy women (ANOVA: P=0.001), 13.66 +/- 3.31ml/100ml in 25 CFS men, 14.63 +/- 4.38 ml/100ml in 51 CFI, and 19.52 +/- 6.53 ml/100ml in 7 healthy men (ANOVA: P=0.008).The DeltaQ'/DeltaV'O2 was > 6 L/L (normal DeltaQ'/DeltaV'O2 [almost equal to] 5 L/L) in 70% of the patients and in 22% of the healthy group.

CONCLUSION: Low oxygen uptake by muscle cells causes exercise intolerance in a majority of CFS patients, indicating insufficient metabolic adaptation to incremental exercise. The high increase of the cardiac output relative to the increase of oxygen uptake argues against deconditioning as a cause for physical impairment in these patients.

PMID: 24456560 [PubMed - as supplied by publisher]

http://www.ncbi.nlm.nih.gov/pubmed/24456560

http://www.translational-medicine.com/content/pdf/1479-5876-12-20.pdf
 
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This is interesting because this is an objective marker of muscular fatigue that is apparently independent from deconditioning.

From the cited paper:
The spectrum of exercise tolerance in mitochondrial myopathies: a study of 40 patients
http://brain.oxfordjournals.org/content/126/2/413.long

. In healthy individuals, cardiac output increases ∼5 l for each litre of increase in oxygen consumption. Since arterial blood normally contains ∼200 ml O2/l, a ΔQ/ΔVO2 of 5 indicates a virtual 1:1 relationship between oxygen delivery and oxygen utilization during exercise. Oxidative limitation due to deconditioning maintains a ΔQ/ΔVO2 ≌ 5. In contrast, when VO2 is limited by impaired muscle oxidative phosphorylation, the normal coupling between O2 delivery and utilization is disrupted and ΔQ/ΔVO2 >> 5 (Haller and Bertocci, 1994). VE/VO2 is a more complex relationship, with VE linearly related to VO2 at moderate workloads but rising disproportionately to VO2 above the so‐called ‘anaerobic’ threshold (Wasserman, 1986).
 
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Also, the peak V’O2 in patients was similar or exceeded that of the sedentary controls (in another study).

Further, speculation by V & V as to the reason for this observation:

If the mitochondrial system is intact in CFS patients [4], the low oxygen extraction in a subgroup of CFS patients may indicate a downregulation of the activity in vivo. A downregulation by a factor that is involved in the activity of the immune system would explain the same phenomenon in SLE [23], different from damaged mitochondria in HIV [5,30]. The lower oxygen extraction and higher ΔQ’/ΔV’O2 however do not differentiate between down regulation of cell metabolism and congenital or acquired mitochondrial pathology in CFS patients. The abnormal results of the Shifting Attentional test visual of the ANT suggest that the impaired oxygen uptake is not limited to the muscle cells.
 
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Reading this study more and I'm less excited now, because the overall question still remains. (why is there a drop in V'O2 max?)

What they showed was the cardiac output was similar to matched sedentary controls, but the level of V'O2 max was significantly lower than the controls. It is not explained by a lack of effort as the anerobic threshold was also dropped by the expected amount.

The heart is is something that responds well to exercise conditioning, but this conditioning is also lost somewhat quickly (weeks to months after cessation). This suggests that patients had enough activity to maintain heart tone and the drop cannot simply be explained by deconditioning due to lack of activity.

But as I said, the question still remains - why is there a drop in V'O2 max?
 

MeSci

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Reading this study more and I'm less excited now, because the overall question still remains. (why is there a drop in V'O2 max?)

What they showed was the cardiac output was similar to matched sedentary controls, but the level of V'O2 max was significantly lower than the controls. It is not explained by a lack of effort as the anerobic threshold was also dropped by the expected amount.

The heart is is something that responds well to exercise conditioning, but this conditioning is also lost somewhat quickly (weeks to months after cessation). This suggests that patients had enough activity to maintain heart tone and the drop cannot simply be explained by deconditioning due to lack of activity.

But as I said, the question still remains - why is there a drop in V'O2 max?
One or more of the mitochondrial abnormalities that have been found/theorised?
 

A.B.

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I found the best way to describe my health problem is not in terms of fatigue, but in terms of energy production/consumption:

It's as if the body can produce 10 units of energy a day, but would require 20 to for normal daily activities. I feel unwell, but can spend more than 10 per day, however the resulting debt eventually becomes impossible to ignore. This energy debt takes disproportionally long to pay back.

It's not only an accurate description of the core problem (the other symptoms are not as important), but also an explanation that other people can understand. They can then also make sense of my energy conservation behaviour.

The study here suggests that something similar is going on at metabolic level. It may not be a problem of energy production, but the dynamics are similar enough.

I should mention that I do not (yet) have a CFS diagnosis.
 

anciendaze

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There are several problems with this study which bother me.

One is validation of cardiac output as measured by the Nexfin device. I strongly suspect there are untested assumptions in inferences from BP pulse shape to CO which devalue the effect of diastolic dysfunction, since this has been underrated by most cardiologists during the last 30 years when the research behind it was said to be done. Problems in systolic function will show up, but during diastole there is nothing happening to pressure to measure. Inadequate LV filling would not be detected if time allowed is adequate in other cases where heart muscle is better able to relax. This leads to undetected reduced stroke volume.

I would be more interested in direct measures of stroke volume via echocardiogram in validating the technique. Even in that case we would need to watch out for confirmation bias driven by commercial interest. The device could be useful in many conditions, yet fail in this particular condition. Evidence for impairment in CFS from impedance cardiography, used to validate the device, is less dramatic.

A second problem turns up in measures of hemoglobin. These are expressed in terms of mMols/L. This is a concentration, assuming patients are not suffering from hypovolemia. If hypovolemia is present total RBC mass will be reduced, which will result in decreased O2 supply, even if CO is normal.

A third problem is the increased recovery time both reported by patients and measured by Workwell foundation and others in 2-day CPET. There is a reference to work by van Ness, et al. on exercise testing and Jones, et al. on failure to recover from acidosis, and even prior work by Vermeulen, but this does not seem to have influenced the design of this study.

This fits with the complete omission of references to the CCC or ICC, though you will find a reference to translation of the CDC CFS symptom checklist. (Anyone remember Jason's study on these?) This is where the CDC has been getting recent ideas about CPET and diagnostic criteria, ignoring research they don't want to acknowledge.

They are moving somewhat, in admitting there might be a real problem with cellular hypoxia, but they are very slow in accepting this as a real disease. (Anyone remember what Pall and Bell published, and when? The authors don't.) Comparison with idiopathic fatigue indicates yet another attempt to merge categories and submerge this troublesome group of patients in a larger group with even less well-defined pathology.
 

bertiedog

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I was wondering if this study in any way ties in with Julia Newton's studies?

I have had definite evidence of low oxygen in my cells with the Breakspear Autonomic testing and I benefit hugely from using an oxygen concentrator every day. However this is only if I am exercising. Last week I had a terrible bout of Novovirus which wiped me out and I got no benefit from breathing oxygen. Same as when I was just resting for 3 days after but now I am back to normal and doing a lot more physically then I need and get benefits from the oxygen. (I can feel the energy running out of the muscles in my legs when walking and especially going up steps I end up with muscles that are dead and heavy).

Pam
 

anciendaze

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@Pam, they reference some of Sarah Myhill's research on mitochondrial dysfunction in the bibliography, which might tie in.

In reference to the Nexfin device, I think this might do very well in measuring relative cardiac output, which is handy for exercise testing. What I do not trust is the idea of inferring absolute cardiac output from measurements of peripheral circulation. I would like at least one real direct measurement of actual stroke volume per patient to calibrate the Nexfin measurements. It would also be a good idea to see how this measurement behaves in cases with dysautonomia and endothelial dysfunction. What happens near the heart may not be what you see in the fingers.

While I welcome the recognition that exercise intolerance may not be due to deconditioning, I am less impressed by continued failure to distinguish this condition from persistent fatigue of any other nature, especially psychological fatigue. (Recall Jason's study showing that 38% of carefully-diagnosed major depressive patients immediately met CDC criteria for CFS. Because depression is widespread, this strongly suggests that any cohort assembled using these criteria would be dominated by patients with major depression -- and no detected physical condition.)

Let me review the evidence which has been disregarded in the past: cluster outbreaks, sudden onset with flu-like symptoms in previously healthy individuals, post-exertional malaise which is not the same as ordinary fatigue, orthostatic intolerance, dysautonomia, episodic cognitive impairment. (Others I have missed?) This is not to say that individuals without all these characteristics may not be suffering from similar or related conditions, just that there has been clear evidence of a large subset of patients with these characteristics in which it might well be easier to discover etiology.

This is apparently not the game plan.

As for the official misdirection of research, how could you parody setting up studies in Wichita KS and Bibb county GA, for a disease reported in Incline Village NV (and Yerrington NV, which has no yuppies) or Lyndonville NY? For that matter, what about follow up on the patients involved in earlier outbreaks like the Punta Gorda outbreak investigated long ago by researchers from CDC and written up in NEJM? Did they ever recover?
 

Marco

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While I welcome the recognition that exercise intolerance may not be due to deconditioning, I am less impressed by continued failure to distinguish this condition from persistent fatigue of any other nature, especially psychological fatigue. (Recall Jason's study showing that 38% of carefully-diagnosed major depressive patients immediately met CDC criteria for CFS. Because depression is widespread, this strongly suggests that any cohort assembled using these criteria would be dominated by patients with major depression -- and no detected physical condition.)

Let me review the evidence which has been disregarded in the past: cluster outbreaks, sudden onset with flu-like symptoms in previously healthy individuals, post-exertional malaise which is not the same as ordinary fatigue, orthostatic intolerance, dysautonomia, episodic cognitive impairment. (Others I have missed?) This is not to say that individuals without all these characteristics may not be suffering from similar or related conditions, just that there has been clear evidence of a large subset of patients with these characteristics in which it might well be easier to discover etiology.
Well this is certainly a debate worth having.

We also need to remember that Jason's team recently found that the CCC and ICC criteria - which do require many of these characteristics - found higher levels of disability but also greater rates of 'psychiatric co-morbidity' using these supposedly 'better' criteria.

I also doubt any assumptions that most patients report a sudden onset with flu-like symptoms. Even if this were the case no causality can be inferred - it could just be assigning significance to a temporally related event as with 'stressful life events' or a sudden health improvement following a particular treatment.

There may well be a substantial sub-set associated with a viral onset but this doesn't necessarily mean that the condition they are suffering from is qualitatively or even quantitatively different from those triggered by other factors. We just don't know enough to make this distinction.

I'm also constantly at a loss to understand why 'psychiatric' or mood disorders are assumed to 'contaminate' a cohort in a condition which we like to argue is neurological. Try to find a neurological condition that doesn't have these 'co-morbidities'.
 

SOC

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I'm also constantly at a loss to understand why 'psychiatric' or mood disorders are assumed to 'contaminate' a cohort in a condition which we like to argue is neurological. Try to find a neurological condition that doesn't have these 'co-morbidities'.
I believe the concern about psych diagnoses is not with comorbid conditions, but with including psych patients without ME symptoms such as PENE or immune dysfunction.

At this point it is far from clear that psych issues are an organic part of ME-- there are plenty of patients without them. That doesn't mean that a number of patients don't have them, whether endogenous or reactive.

A clear ME research cohort would include only patients with clear organic illness and not patients with only idiopathic fatigue and clear psych issues. That's the point, I believe.
 

anciendaze

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@Marco,

Sudden onset is a standard criterion for epidemiological investigation, even if there are cases without such evidence. There is no question we have patients available who really went from bouncing back from common viral infections to remaining in post-viral fatigue for an indefinite period. What changes in these cases?

The problem is not "contamination" of a cohort, it is dilution of any evidence which might make it possible to isolate causes. Remember that the number of cases of major depression is much larger than those meeting criteria based on more specific definitions of ME/CFS. For comparison, consider how little research on "cancer" was able to do when all cases were lumped together. For purposes of determining disability, you may not care about these distinctions, only the endpoint of the pathology. For research on etiology, the distinctions are literally vital.

Second, consider the terrible record of research on "depression" with regard to etiology and actual cures. Except for some symptomatic relief, which clearly fails in an important subset of cases, labeled treatment-resistant or treatment-intolerant, there have been no actual cures, except for chance treatment of some cases for organic illness like mononucleosis or leukemia.

Added: from years of reading literature on depression defined by psychological criteria I can confidently assert that the best predictor of future depression is a history of past depressive episodes. Patients who are not currently depressed are still considered to be depressive.
 
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Valentijn

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We also need to remember that Jason's team recently found that the CCC and ICC criteria - which do require many of these characteristics - found higher levels of disability but also greater rates of 'psychiatric co-morbidity' using these supposedly 'better' criteria.
They were assessed using the DSM, by professionals who were either not aware of their ME/CFS diagnosis or not taking it into account. By that process, physical symptoms are used to arrive at a psychiatric diagnosis. And since CCC/ICC patients will have more physical symptoms and disability than Fukuda patients, using the DSM would result in more psychiatric diagnosis for the CCC/ICC patients.

This is a flaw with the DSM as a diagnostic tool, and that study is not a reliable indication of increased actual psychiatric co-morbidity in CCC/ICC patients.
 
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Marco

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I believe the concern about psych diagnoses is not with comorbid conditions, but with including psych patients without ME symptoms such as PENE or immune dysfunction.

At this point it is far from clear that psych issues are an organic part of ME-- there are plenty of patients without them. That doesn't mean that a number of patients don't have them, whether endogenous or reactive.

A clear ME research cohort would include only patients with clear organic illness and not patients with only idiopathic fatigue and clear psych issues. That's the point, I believe.

Where to start?

As far as I'm aware I don't have immune dysfunction or at least no-one has ever shown me objective evidence that I do. Depending on how the questions are asked and interpreted I could easily meet both the CCC and ICC criteria but not Fukuda. Let's just say if I was asked the simple question - particularly in the early years - have you suffered from fatigue over the last 6 months - I'd have answered no - although I did have exercise intolerance and POTS plus other symptoms required by the 'better' criteria.

Its also not clear at this point that pysch issues are not an organic part of ME (emotional lability as per Ramsey ME anyone). I accept that some and even many may not have them. I wouldn't expect everyone to be affected in the same way even if the problem is primarily neurological. I don't and never have had tender lymph nodes but I don't deny that others might.

What exactly is 'clear organic illness'. Isn't it 'the point' that we don't have any objective markers of organic disease and what exactly is PEM or PENE and how is it measured?

Making a distinction between 'idiopathic' fatigue and ME, ME/CFS or CFS is an entirely arbitrary one at present as is a 'psychiatric' diagnosis. Let's face it MS used to be considered a 'clear psych issue'.

If you wish to make a distinction between 'CFS' and Myalgic Encephalomyelitis (which I do have listed on my medical records BTW) then I'm afraid the only cohort who could logically qualify for a diagnosis of Ramsey ME are those who were hospitalised at the Royal Free at the time. Extending this diagnosis to anyone else is pure conjecture.
 

MeSci

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I believe the concern about psych diagnoses is not with comorbid conditions, but with including psych patients without ME symptoms such as PENE or immune dysfunction.

At this point it is far from clear that psych issues are an organic part of ME-- there are plenty of patients without them. That doesn't mean that a number of patients don't have them, whether endogenous or reactive.

A clear ME research cohort would include only patients with clear organic illness and not patients with only idiopathic fatigue and clear psych issues. That's the point, I believe.
It might be useful to compare the percentage of people with ME/CFS who have depression with the percentage in the general population. I think I saw a paper that reported that depression was not higher in people with ME/CFS than in the general population, but I have a feeling it was research done by Wessely et al. There are studies that report ways to differentiate CFS from depression, using patient self-reports, biochemical tests and imaging. But clearly some people with ME/CFS are depressed as well as having ME/CFS. Like most health issues, it's not clear-cut.