Unexplained exertional intolerance associated with impaired systemic oxygen extraction. (Melamed, Systrom, et al. 2019)

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Eur J Appl Physiol. 2019 Sep 6. doi: 10.1007/s00421-019-04222-6. [Epub ahead of print]
Unexplained exertional intolerance associated with impaired systemic oxygen extraction.
Melamed KH1, Santos M2,3, Oliveira RKF4, Urbina MF2,3, Felsenstein D5, Opotowsky AR6,3, Waxman AB2, Systrom DM2,3.
6Boston Adult Congenital Heart Service, Harvard Medical School, Boston Children's Hospital, Boston, MA, USA.
Abstract

PURPOSE:
The clinical investigation of exertional intolerance generally focuses on cardiopulmonary diseases, while peripheral factors are often overlooked. We hypothesize that a subset of patients exists whose predominant exercise limitation is due to abnormal systemic oxygen extraction (SOE).

METHODS:
We reviewed invasive cardiopulmonary exercise test (iCPET) results of 313 consecutive patients presenting with unexplained exertional intolerance. An exercise limit due to poor SOE was defined as peak exercise (Ca-vO2)/[Hb] ≤ 0.8 and VO2max < 80% predicted in the absence of a cardiac or pulmonary mechanical limit. Those with peak (Ca-vO2)/[Hb] > 0.8, VO2max ≥ 80%, and no cardiac or pulmonary limit were considered otherwise normal. The otherwise normal group was divided into hyperventilators (HV) and normals (NL). Hyperventilation was defined as peak PaCO2 < [1.5 × HCO3 + 6].

RESULTS:
Prevalence of impaired SOE as the sole cause of exertional intolerance was 12.5% (32/257). At peak exercise, poor SOE and HV had less acidemic arterial blood compared to NL (pHa = 7.39 ± 0.05 vs. 7.38 ± 0.05 vs. 7.32 ± 0.02, p < 0.001), which was explained by relative hypocapnia (PaCO2 = 29.9 ± 5.4 mmHg vs. 31.6 ± 5.4 vs. 37.5 ± 3.4, p < 0.001). For a subset of poor SOE, this relative alkalemia, also seen in mixed venous blood, was associated with a normal PvO2 nadir (28 ± 2 mmHg vs. 26 ± 4, p = 0.627) but increased SvO2 at peak exercise (44.1 ± 5.2% vs. 31.4 ± 7.0, p < 0.001).

CONCLUSIONS:
We identified a cohort of patients whose exercise limitation is due only to systemic oxygen extraction, due to either an intrinsic abnormality of skeletal muscle mitochondrion, limb muscle microcirculatory dysregulation, or hyperventilation and left shift the oxyhemoglobin dissociation curve.

KEYWORDS:
Cardiopulmonary exercise testing; Chronic fatigue syndrome; Exertional intolerance; Hyperventilation; Poor systemic oxygen extraction
PMID: 31493035 DOI: 10.1007/s00421-019-04222-6
 
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This paper doesn't mention ME/CFS directly (edit: yes it does, although not in the abstract!) but it is by David Systrom, who is interviewed here:


I rather suspect he is thinking some of the 12.5% of people whose exercise intolerance is defined by problems using oxygen might be similar to the me/cfs people, especially those with bad mitochondria or bad microcirculation. Anyone else have thoughts on that?
 
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ryan31337

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EDIT: Fixed a misunderstanding.
The patient cohort for this study all Those found to have oxygen extraction issues also had an ME/CFS diagnosis. This looks to be a retrospective finding, probably added because it was funded by an ME/CFS charity...

To me it seemed like the authors were looking past the ME/CFS label to identify what is actually going on for these patients physiologically. They ignored ME/CFS diagnosis and categorised the vast majority of the patients into 3x groups: Mitochondrial Myopathy, Dysautonomia, Connective Tissue Disease.

They posit that the exercise intolerance comes from 3x overlapping and self-driving components: Mitochondrial issues in the muscle, which can be genetic or acquired due to infection/autoimmunity; hyperventilation, which is not necessarily psychosomatic due to the effects of mito issues & dysautonomia; microcirculation changes due to neuropathy.

I think this sort of explanation would cover off quite a large sub-group of ME/CFS. Certainly those with SFN/POTS as a result of inflammation/autoimmunity, which seems to fit for me at least and is probably vastly under recognised in many of the syndromic patients (ME/CFS/Fibro/POTS etc.) as Systrom has talked about previously.
 
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lauluce

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This paper doesn't mention ME/CFS directly but it is by David Systrom, who is interviewed here:


I rather suspect he is thinking some of the 12.5% of people whose exercise intolerance is defined by problems using oxygen might be similar to the me/cfs people, especially those with bad mitochondria or bad microcirculation. Anyone else have thoughts on that?
or maybe, they are indeed suffering from ME/CFS and they are a subgroup whose disease only manifest as PEM
 

Wishful

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I believe that many common ME symptoms are downstream of the actual cause. The changes from ME in the immune system and mitochondria and hormones and autonomic responses, and whatever else can cause dysfunction in various parts of the body. If ME is, for example, due to a single protein not being produced properly, that would cause some people to have immune system malfunctions, and cause other people to have muscle mitochondrial malfunctions, and maybe another group has microbiome problems or circulatory problems. Some may have several of these.

This is why I object to too many resources going to study symptoms that not everyone shares. It's not completely wasted research, but it's at the cost of research into the root cause. Finding and treating the root cause would also treat the downstream symptoms.
 
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The patient cohort for this study all had an ME/CFS diagnosis, it was funded by an ME/CFS charity.
Is that true? I downloaded the paper and it specifies that all the subjects who turned out to have poor oxygen extraction had an ME/CFS diagnosis, but doesn't say whether the others had it:


All of our cohort with poor SOE (systemic oxygen extraction) carried a clinical diagnosis of myalgic encephalo- myelitis/chronic fatigue syndrome (Bested and Marshall 2015). We were additionally able to identify three general disease categories: MM, dysautonomia, and connective tis- sue disease. Although about two-thirds were referred with suspected MM, most did not hold a confirmed diagnosis by muscle biopsy or blood mutation screens at the time of iCPET (invasive cardiopulmonary execise testing). MM is a difficult diagnosis to make, and many patients with MM (mitochondrial mutation) have negative DNA mutation screens in blood and muscle biopsies (Taivassalo et al. 2003; Tarnop- olski 2004), as was the case here. Concordant increases in peak PvO2 and SvO2 observed in a subset of our poor SOE are typical of primary mitochondrial defects in skeletal muscle (Taivassalo et al. 2002). Our results suggest a sub- set of patients with unexplained exercise intolerance share an iCPET phenotype similar to those with a well-defined skeletal muscle mitochondrial mutation. Moving forward, as we accumulate a larger database of patients, we will be able to subdivide and describe this group further with num- bers large enough to perform statistical analysis among sub- groups. Currently, we have a descriptive analysis of patients who share a common cause or phenotype of their exertional intolerance.


My suspicion is not all patients were ME/CFS patients had it, as the patient cohort is 313 consecutive people who showed up to Brigham hospital between 2011 and 2013.


313 consecutive patients presenting with unexplained exertional intolerance

185 of these people were diagnosed with pulmonary hypertension and/or heart failure. They ended up with 32 who had systemic oxygen extraction problems (around 10% of patients) and my read is that it's only after they located the 32 that they looked back at their clinical notes and were able to say: these ones turned out to be patients with me/cfs. The paper says many of the patients were sent in with suspected mitochondrial disease.


EDITORIALISING:

This is a big paper that provides substantial real evidence of major problems in the way our bodies work. It's consistent with either mitochondrial failure or autonomic failure. It's real science, and it's well progressed. It deserves more focus and attention.
 
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ryan31337

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Is that true? I downloaded the paper and it specifies that all the subjects who turned out to have poor oxygen extraction had an ME/CFS diagnosis, but doesn't say whether the others had it
Well caught. Sorry, I took for granted something said on an ME/CFS news site and didn't read the paper carefully enough and repeated the mistake. That makes a lot more sense given how many were excluded for actual heart and lung issues.

Its a shame they don't mention how many patients in the non-SOE group also had an ME/CFS diagnosis, you'd think this would be important if trying to establish relevance... The way I read it was that they established the ME/CFS diagnosis themselves retrospectively: reference to ME/CFS clinical diagnostic guidelines & use of 'we were additionally able' in following sentence, but hard to say.

Perhaps i'm being a bit cynical because of the funding source, but it seems a little convenient to leave out numbers of CFS patients that did not exhibit abnormal SOE.
 
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ryan31337

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I believe that many common ME symptoms are downstream of the actual cause. The changes from ME in the immune system and mitochondria and hormones and autonomic responses, and whatever else can cause dysfunction in various parts of the body. If ME is, for example, due to a single protein not being produced properly, that would cause some people to have immune system malfunctions, and cause other people to have muscle mitochondrial malfunctions, and maybe another group has microbiome problems or circulatory problems. Some may have several of these.

This is why I object to too many resources going to study symptoms that not everyone shares. It's not completely wasted research, but it's at the cost of research into the root cause. Finding and treating the root cause would also treat the downstream symptoms.
Personally I don't expect there will ever be a single disease process that is understood and named "ME/CFS".

Our understanding of each ME/CFS sub-group will improve to the point that they become distinct, well understood disease entities, given a more accurate name and obviously excluded from the ME/CFS syndrome. They just happen to create similar, downstream dysfunction as you rightly say that makes them look similar.

The work by these authors and the overlapping research into 'apparent autoimmune' SFN/dysautonomia will probably be one of the first major sub-groups to break away. Divide and conquer until nothing is left.
 
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