(Dr. Newton’s studies suggest the muscles of people with ME/CFS are not efficiently removing the acids that build up during exercise. It’s possible this acid buildup is contributing to the hyperventilation, and, of course, the exercise problems in ME/CFS. Earlier she mentioned she was determining if drugs could reverse that acid buildup. That prompted this question:)
Can you say anything about the drugs you’re testing that you believe may help reverse the acidification in the muscles of people with ME/CFS?
The experiments that are going on in the laboratory at the moment are focused on drugs that couldn’t be used in humans to show whether the acidification is reversible.
It does appear to be reversible, and we are now working to tease out whether there are currently available drugs that could be repurposed for use in humans, and in the first instance, incorporated into clinical trials in patients with ME/CFS.
(CJ – Reversible! )
An abstract in a recent Autonomic Nervous System conference which found that hyperadrenergic POTS patients hyperventilate when they stand, which lowers their blood CO2 levels, causing the blood vessels in their brains to constrict and reduce blood flow to the brain seemed to follow almost word for word your findings in your recent paper.
You looked at ME/CFS patients, however, not hyperadrenergic POTS patients. What do you think is going on here? Were you looking at a hyperadrenergic subset of ME/CFS, or is the hyperventilation issue more widespread in chronic fatigue syndrome?
That’s a very interesting finding. The patients that we studied did not have POTS, but as you know we believe that there is considerable overlap between POTS and ME/CFS.
(CJ. This is an amazing finding! The huge increases in heart rates found in the subset of POTS patients mentioned occur when the blood vessels in their brain tighten up and reduce blood flows. The same process appears to be occurring in Newton’s patients except that the increased heart rate, which is believed to be adaptive in POTS, does not occur. Could this mean that Newton’s non-POTS patients are worse off than the POTS patients?
In any case, the similar findings in two groups, appearing at nearly the same time, was astonishing. The fact that two groups, one in the U.S. and one in the U.K. are looking at what a newly discovered abnormality in ME/CFS/POTS is encouraging. )
They also found that giving the POTS patients CO2 reversed their blood flow and heart rate problems upon tilting. They suggested an aberrant chemoreflex response could be responsible. Do you see this as a likely possibility?
Again, it is difficult for me to comment having not seen this abstract, but to me that would make physiological sense.
(CJ. Unfortunately I could not find the abstract again (lol). Two chemoreceptors control breathing in humans; one in the brain and one in the carotid artery. These receptors tell the brain to increase ventilation or breathing when excess carbon dioxide and H+ is present The hyperventilation seen in ME/CFS appears to lower CO2 levels too much, causing the blood vessels in the brain to tighten, reduced oxygen flows to the brain. This suggests, that malfunctioning chemoreceptors could start this whole process.)
(In Dr. Newton’s recent study she proposed that problems with vascular control could explain several problems in chronic fatigue syndrome. That prompted this question).
Could you briefly (or extensively if you wish) explain how problems with ‘vascular control’ could explain the central sensitization, HPA axis problems and cognitive problems?
In terms of how problems with vascular control and autonomic dysfunction could lead to problems with cognition: it is well recognized in the field of autonomic dysfunction that the lower your blood pressure is, the worse you perform on memory tests, and that if your blood pressure falls when you stand up, then the degree of that fall associates with cognitive decline over time.
Therefore, if we recognize that autonomic dysfunction is a common problem in patients with ME/CFS, it is not unreasonable to assume that the cognitive problems that occur in almost 90% of patients may well be related to the presence of autonomic dysfunction.
We have now shown that having a greater autonomic symptom burden, i.e., a score on the orthostatic grading scale associates statistically with scores on a symptomatic measure of cognitive function, the Cogfail Questionnaire.
We have also recently shown that performance on cognitive testing also associates with autonomic symptoms and objective autonomic function.
In terms of how this relates to HPA axis, the hormones involved in the HPA axis in part control the autonomic nervous system, particularly blood pressure. Also, the areas of the brain that are around the HPA axis, i.e., the brain stem, are the areas of the brain that are also thought to control the autonomic nervous system.
(CJ. HPA axis findings suggest low cortisol levels are common in ME/CFS. Several studies suggest that both cognitive and sleep problems in ME/CFS are associated with reduced heart rate variability, which is regulated by the autonomic nervous system. Neither fatigue, effort or distress were associated with cognitive declines in one study, but reduced HRV was. The autonomic nervous system appears to affect many factors in ME/CFS. In a recent talk, an MRC official put the ANS at the top of the list of research topics.)
It appears that many of the autonomic nervous system problems overlap in ME/CFS and PBC, both of which are characterized by severe fatigue and other issues. Can you say what you think is happening to disrupt the ANS in both disorders?
You are right, there are considerable overlaps between the autonomic nervous system problems and the findings on MRI between patients with ME/CFS and PBC, which you are quite correct is often characterized by severe fatigue.
As you will know, primary biliary cirrhosis (PBC) is an autoimmune problem and there may be some suggestion that this plays a part also in the etiology of ME/CFS.
Equally, PBC is increasingly recognized as a systemic disease in patients who have a disorder of the liver. In animal experiments the liver and spleen have been shown to be major capacitant vessels in terms of blood pressure homeostasis.
Interestingly, similar experiments have never been performed in humans and it is unclear what the role of the liver is in blood pressure maintenance in patients with PBC (i.e., with an abnormal liver), or patients with ME/CFS.
Our current MRC grant application is looking at the role of the liver in blood pressure control using novel MRI techniques, so hopefully we will be able to begin to answer some of these questions when our MRC grant comes to an end, and we begin to finally analyze the data.
(CJ – An earlier study suggested that blood vessel issues in the hands, which contain a large volume of blood, could be affecting blood flows, but Dr. Newton suspects that the largest organ in the body, the liver, could be affecting blood flows, as well. The major detoxifying organ in the body, the liver receives enormous flows of blood. Fully thirty percent of our resting cardiac output goes directly to the liver, and like the hands, the liver is considered a ‘blood storage organ’ which contains capacity far beyond its needs. )
Several of your studies suggest that muscle membrane issues that interfere with pH handling could play a big role in ME/CFS. What could be causing muscle membrane dysfunction?
We have suggested from our MRI studies that the high levels of acid that accumulate in the muscles of patients with ME/CFS could be because they are having difficulty removing acid via specific transporters, or because there is lack of runoff of acid from the muscles, as they exercise, into the vascular system.
So it may be that there is a specific membrane abnormality of these specific transporters, or alternatively it could be entirely related to the caliber of the blood vessels.
(Caliber refers to the diameter of the blood vessels, which is controlled, I believe, by the autonomic nervous nervous. Blood vessels that are too constricted may not be delivering enough blood to remove the acid the muscles have produced during exercise. Interestingly, given the female predominance in ME/CFS, microvascular or small blood vessel disease is more common in women.)
Chronotropic incompetence — the inability get the heart rate and cardiovascular functioning up to speed during exercise — is sometimes found in ME/CFS. This inability to get our cardiovascular system up to speed is a strange partner with the increased heart rates during rest found in chronic fatigue syndrome. Do you find much chronotropic incompetence in your patients and, if so, what would explain this weird dichotomy: inhibited activity during stress, and increased activity during rest?
To me chronotropic incompetence is simply an inability of the heart to function properly in response to stressors such as standing. That would be completely in keeping with findings of tachycardia in response to the stress of standing, i.e., there is an inappropriate response to the stress of standing by the autonomic nervous system.
(CJ – It turns out that at least three abnormal heart rate responses can be found in ME/CFS; the higher than normal heart rates during rest, the very high heart rates that sometimes occur during standing, and the reduced heart rates in response to exercise.)
If I remember correctly you first came to ME/CFS when you found that seniors with dizzy/fainting spells experienced enormous fatigue as well. My understanding is that cardiovascular issues and increased rates of oxidative stress play an important role in ageing. Both, of course, are also found in ME/CFS. Might research on ageing provide some clues to ME/CFS at some point.
You will know that I am a member of the Institute for Ageing & Health and actually my Chair is Professor of Ageing and Medicine and I am a geriatrician by background, so of course I would believe there are lessons to be learned from ageing in terms of clues as to the etiology of ME/CFS.
In fact, in terms of primary biliary cirrhosis we have often described this disease as a disease of premature ageing because some of the symptoms and signs that we find in PBC would be consistent with an ageing phenotype.
(CJ – An early study from Dr. Newton suggested that some aspects of the hearts of PBC patients looked like they came from people who were16 years older. The abstract wrapped up with“ Hence the hearts of fatigued PBC patients may be subject to processes of accelerated aging.”)
There seem to be a lot cardiovascular issues in ME/CFS. Do you see any signs or are you worried that these cardiovascular issues could turn into significant health problems as people with ME/CFS age?
Certainly, some of the cardiovascular issues that we find in patients with ME/CFS on tilt testing or cardiac MRI represent real abnormalities and as a result it is important we look longitudinally in people with ME/CFS to see whether having these problems in the long term creates significant health problems.
I think it is really important that we begin to set up large cohorts of patients that are properly and appropriately characterized so that we can look at the natural history of ME/CFS over time.
What do you suggest doing to increase fitness in ME/CFS?
That is a very difficult question and until we have evidence as to the muscle bio-energetic abnormalities in patients ME/CFS it is difficult to be sure what the most appropriate mechanisms by which individuals affected by this disease should increase their fitness.
Certainly when you talk to patients they will sometimes describe things like graded exercise therapy are of no benefit to them or in fact make them worse, so I don’t think it is one size fits all and therefore I believe an individualized approach is the most important thing when managing activity levels in ME/CFS.
Of course, increasing your cardiorespiratory fitness is something that should be encouraged in anyone, but how we actually achieve that in patients with ME/CFS is still something that needs to be addressed with appropriate research.
What studies are you doing right now?
At the moment we are in the middle of the MRC-funded projects. There is the one that I am the principal investigator for which is looking at autonomic dysfunction in ME/CFS and its consequences, and the second one which has Fai Ng as PI, which is looking at identifying a fatigue biomarker.
We are looking at red cell mass and plasma volume as part of the current MRC-funded study which is looking at whether or not the autonomic dysfunction that is so commonly seen in patients with ME/CFS could be related to changes in blood volume as has been shown in previous studies.
Both are going very well and we hope to be at the point of analyzing data in the next few months.
We have just finished off a study that was funded by Action for ME looking at sleep in ME/CFS, and the ME Association have very kindly funded a pilot study to look at intervention for sleep abnormalities which will happen in the next few months.
Ongoing at the minute is Gina’s Action for ME PhD Studentship, and Gina is developing the muscle exercise in the laboratory system further and looking at teasing out particular drugs that might impact upon the acid that is accumulating in the muscles of ME/CFS patients that we have detected on MRI.
We have a number of other projects going on at the moment which are funded from a variety of different sources: we are looking at mitochondrial DNA, have a PhD student looking at temporomandibular joint dysfunction in ME/CFS, and are always collecting data on the patients that we see in the clinic which gives medical students and biomed science students the opportunity to get involved by helping us analyze data.
We have also recently launched a new clinic at the Campus for Ageing and Vitality in Newcastle which is a fatigue clinic which aims to address the generic symptom of fatigue in patients, and that is also a great opportunity for us to begin exploring how common fatigue is and the impact that it has for individuals.
There are too many questions and not enough pairs of hands to help, but our group here in the North East is expanding and we regularly have meetings that pull together the researchers and clinicians interested in the symptom of fatigue, which are very well attended.
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