Researchers and doctors get interested in ME/CFS in different ways. Many have a personal connection, but for David Systrom, a pulmonologist, it was all about demand. He didn’t seek chronic fatigue syndrome patients out – quite the contrary. When Systrom was given control of a clinical cardiopulmonary lab, he started doing invasive cardiopulmonary exercise tests (iCPET’s) on people with exercise intolerance. Once word of that got out, chronic fatigue syndrome, fibromyalgia, POTS and other patients starting pouring in.

It wasn’t the patients seeking Systrom out – it was their doctors; they finally had a place to send their strange exercise intolerant patients to. Rheumatologists, cardiologists, neurologists, and infectious disease specialists have gladly sent their patients his way for years. It’s not a small number. Systrom suggests that 10 percent of people with exercise intolerance fit this profile. Those referrals have lead to 1,500 highly sophisticated exercise tests, about 700 of which were done on people with ME/CFS/FM/POTS.

Systrom’s had his eye on chronic fatigue syndrome (ME/CFS) for a while, but up until now he’s been looking at exercise intolerance in general. That’s why, despite the fact that he has one of the biggest, and certainly the most sophisticated, database of exercise results in ME/CFS, he’s mostly unknown to researchers and patients.

Armed with a grant from an anonymous donor to The Solve ME/CFS Initiative (SMCI) to support his work, Systrom, is for the first time focusing a study solely on ME/CFS.

Invasive Cardiopulmonary Exercise Testing (iCPET)

Systrom has taken exercise testing in ME/CFS to the next level with his invasive cardiopulmonary exercise testing (iCPET). Non-invasive cardiopulmonary exercise (CPET) testing can do a lot of things. It can demonstrate that exercise intolerance is present, define the aerobic and anaerobic contributions to exercise, determine if lung problems are present and others, but with an iCPET researchers can dig much deeper.

Systrom’s an acknowledged expert in the iCPET field; in 2013 he was the senior author of the first review paper on iCPET and in 2016 he co-wrote the first methodology paper explaining how to do it correctly.

Invasive CPET’s involve the insertion of catheters into the pulmonary artery and radial arteries that monitor blood flow, oxygen content and other factors. These catheters allow researchers to determine if the problems with oxygen are occurring in the lungs or in the muscles, where oxygen uptake is occurring and so on. Because iCPET can determine changes in venous blood O2 occurring with exercise, they’re able to determine how much oxygen the muscles are using. The technique can therefore be used to diagnose mitochondrial issues.

iCPET tests needed to identify three under-recognized causes of exercise intolerance, the third of which concerns ME/CFS: preload failure or the inability of the blood vessels to provide the heart with enough blood to pump effectively. Several studies suggest that preload failure is causing the small hearts in ME/CFS.

In the 2013 review article Systrom explained what happens (or should happen) when we exercise.

Muscles need oxygen to generate energy. During exercise, increased breathing (ventilation) in the lungs and increased gas exchange between the lungs and blood provides more oxygen to the blood. First the heart increases it’s stroke volume so that it can shoot more blood out to the muscles. Once the heart maximum stroke volume is reached, the heart rate begins to increase in order to pump out more and more blood. In order to provide the increased levels of blood to the heart, the veins leading to it enlarge so that they can accommodate more blood.

It’s All About Oxygen

First, aerobic (oxygen-oriented) energy production mostly prevails. When the limits of aerobic metabolism are reached, though, one’s “anaerobic threshold” is reached. At that point, a non-oxygen way of producing energy called anaerobic metabolism becomes prominent. Two toxic byproducts of anaerobic metabolism, lactate and CO2, build up and cause fatigue, pain, etc. (Anaerobic thresholds are identified during the CPET test by an abrupt increase in CO2 levels). Here’s the key part for ME/CFS, FM and POTS patients from Systrom’s 2013 paper:

“People with low anaerobic thresholds; that is, people who quickly exhaust their ability to generate energy aerobically and rapidly enter into anaerobic metabolism have one of two problems: either the oxygen isn’t getting to the mitochondria in their muscles or the mitochondria aren’t taking it up….

THREE PATTERNS

In a June interview, Systrom stated that about half of his patients have POTS/ ME/CFS or FM. When he tests them, a couple of different patterns show up – a pattern of dysautonomia, which reflects problems with the blood vessels, and reduced oxygen uptake pattern reflecting other problems.

Dysautonomia – the primary problem is inadequate venoconstriction; i.e. the autonomic nerves are not constricting the veins enough to propel sufficient amounts of blood (i.e. oxygen) to the heart for exercise or other activities to take place. Damage to the nerves in the arteries may be present as well.

– the primary problem is inadequate venoconstriction; i.e. the autonomic nerves are not constricting the veins enough to propel sufficient amounts of blood (i.e. oxygen) to the heart for exercise or other activities to take place. Damage to the nerves in the arteries may be present as well. Reduced skeletal muscle oxygen uptake -the mitochondria are not taking in as much oxygen as they should.

-the mitochondria are not taking in as much oxygen as they should. Genetic issues – are not nearly as common as the other two, but Systrom can at times find genetic issues.

TWO MAJOR PROBLEMS

(1) Dysautonomia, Small Fiber Neuropathy and Autoimmunity

Systrom believes an autoimmune process that’s damaging autonomic nerves is probably running rampant in ME/CFS, FM and POTS patients. The skin is just the starting place; what’s happening in the skin is also happening in other places, including autonomic nerves that surround and regulate the activity of the veins and probably the arteries in our bodies. He’s currently working with Anne Oaklander (who basically discovered the small fiber neuropathy (SFN) present in FM) to investigate this hypothesis further.

A recent study suggests he may be right. That study found damage to the autonomic nerves regulating microcirculatory blood flow to the lungs in fibromyalgia. Every measure of lung functioning (carbon monoxide transfer factor, carbon monoxide diffusion capacity, alveolar capillary membrane volume and pulmonary capillary blood volume) was significantly reduced in fibromyalgia patients. Further analyses found that the reduction in lung diffusing capacity was probably due to a significant reduction in lung capillary volume; i.e. the microvascular volume of the FM patients’ lungs had declined.

The authors proposed that the receptors on the endothelial cells that cause FM patients’ blood vessels to dilate have been so overstimulated over time that they’re not responding to signals to dilate anymore. That leaves them constricted and results in reduced blood flow.

Systrom regularly does autonomic nervous system testing in his patients. Skin biopsies demonstrate autonomic nerve loss in approximately 70% of his ME/CFS/FM/POTS patients. (He’s apparently the first to start looking for SFN in ME/CFS). He uses classic rheumatologic serology to look for signs of an autoimmune disease such as Sjogren’s (lip biopsy) and Guillain-Barre Syndrome. He uses a paraneoplastic antibody panel from the Mayo Clinic to look for more esoteric autoantibodies. Autoantibodies to acetylcholine are showing up frequently. Acetylcholine is a neurotransmitter needed for muscle function and is the major neurotransmitter in both branches of the autonomic nervous system.

Ganglionopathy

When the skin biopsies turn up negative, Systrom turns to a ganglionpathy (damage to a nerve ganglia) that’s presenting an impediment to blood flow – to explain what’s going on. Nerve ganglia are structures that contain numerous nerve cell bodies. An active EBV or other infection (aka Van Elzakker’s vagus nerve infection hypothesis) or a hit and run infection that could be damaging these ganglia.

(2) Reduced Oxygen Uptake

Because Systrom has the ability to measure blood oxygen levels prior to and after the muscles have used it up, he can tell how much oxygen the lungs are taking in and how much is left over after the muscles have taken it. He’s finding that the blood oxygen levels in ME/CFS patients’ veins are simply too high; i.e. not enough oxygen is being taken up by their muscles when they exercise. The oxygen is in the arteries, but the muscles are not taking enough of it up. That’s a big clue.

The Gist Systrom has built an extensive database of exercise results in ME/CFS/FM and POTS using invasive cardiopulmonary exercise tests Systrom’s studies indicate two main problems are present. Autonomic nerve problems are impeding blood flows in the veins and probably the arteries and reduced oxygen uptake at the mitochondria is present. The autonomic nerve problems in the endothelial cells lining the veins is probably responsible for the reduced preload and small hearts found in several ME/CFS studies. The autonomic nerve problems are likely related to and a continuation of the small fiber neuropathy found in FM. Systrom has found evidence of extensive SFN in ME/CFS and POTS patients as well. Systrom is working with Anne Oaklander to investigate the SFN in these diseases. Systrom believes the autonomic nerve problems are probably caused by an autoimmune process. Antibodies to acetylcholine are showing up in his tests. Reduced oxygen uptake at the mitochondria is reducing energy levels and causing toxic byproducts to accumulate during exercise. The reduced oxygen uptake is probably due either to damage to the autonomic nerves lining the arteries, to a shunt that is depriving the slow-twitch muscles of blood or problems with mitochondrial energy production. Reduced oxygen uptake is found in about 80% of his ME/CFS/FM/POTS patients. Most people with these diseases hyperventilate during exercise resulting in increased CO2 levels, fatigue and other symptoms. Systrom believes the hyperventilation is probably due to small fiber neuropathy and problems with the metaboreflex. Systrom has found Mestinon (pyridostigmine bromide) very helpful in his exercise intolerant patients. Systrom’s new study funded by an anonymous donor will attempt to get at the molecular heart of the exercise intolerance occurring by measuring metabolites three times at two different parts of the body during exercise.

For one, it means the problems are not limited to the veins. Problems with the veins do appear to be reducing blood flow to the heart, but in many, many people, problems are also occurring after the blood leaves the heart. Oxygen consumption, as noted, is down. Either the oxygen in the arteries is not getting to the mitochondria in the muscles or it’s getting there and the mitochondria are not using it up; i.e. either we have a circulatory problem or a cellular energy production problem (or who knows, perhaps both…)

Systrom suggested that damage to the adrenergic nerve fibers resulting in problems in the arteries (similar to that occurring in the veins) could be hampering blood flow to the muscles. Failure to divert enough blood to the slow twitch muscle fibers could also be resulting in a “de facto microcirculatory L-R shunt” which causes blood pooling and reduces blood flow to the mitochondria. Mitochondrial problems all by themselves are another possibility.

This isn’t the first time low oxygen uptake to the muscles has been found in ME/CFS. Natelson and McCully found the same way back in 1999 and in 2003. They attributed the low oxygen delivery and alterations in blood flow to autonomic nervous system issues. Low oxygen uptake also fits well with metabolomic and exercise study findings suggesting that low energy production is present. Systrom finds low oxygen uptake in about 80% of his ME/CFS, FM and POTS patients.

Hyperventilation, Exercise and Dysautonomia – When I asked him about exercise, he noted the huge interplay between dysautonomia and the hyperventilation he commonly finds during exercise in many ME/CFS/FM/POTS patients. Systrom finds that the overwhelming majority of patients hyperventilate during exercise.

That hyperventilation is probably being caused by a dysfunction of the small nerves that regulate the metaboreflex. The metaboreflex increases blood flow during times of low oxygen by increasing heart rate and heart contractility. (Perhaps an over-reaction to low oxygen environments occurring during exercise cause increased heart and breathing rates; i.e. hyperventilation?) However it happens, rapid breathing or hyperventilation increases CO2 loss through the breath and lowers blood CO2 levels during exercise, causing pins and needles, brain fog, fatigue and other problems.

How CO2 is being regulated in ME/CFS/FM/POTS patients is another subject of key interest to Systrom and his team.

Treatment

Mestinon

An old and not much used drug called Mestinon (pyridostigmine bromide) has, surprisingly, turned out to be Systrom’s ace in the hole regarding treatment. He’s treated hundreds of patients with it over the past three years. Some people find that the drug has given their life back.

As often happens, a single patient helped produce a major treatment breakthrough for him. It has, Systrom said, “really helped many people”. The Mestinon saga started with one of his most difficult POTS patients – a man with known mitochondrial myopathy and extensive dysautonomia. He’d been in and out of the hospitals, but his million dollar workup had availed him and his doctors little: he was just the kind of patient that Systrom typically sees:

After comparing notes with a Toledo neurologist, Systrom tried Mestinon and couldn’t believe how much better the patient got. After that, Mestinon’s become a cornerstone of his treatment plan for exercise resistant patients with autonomic nervous system problems. He can chart the results – an increase in aerobic functioning – in followup iCPET tests. (Mestinon might conceivably be helpful with small fiber neuropathy, as well.)

Mestinon doesn’t do anything for the mitochondria, but by promoting better nerve firing it increases blood (and oxygen) flow to the mitochondria in muscles. It also increases blood volume. It may even be healing small fiber neuropathies.

He occasionally finds treatment-resistant Mestinon patients, but not often. Side effects can include gastrointestinal issues and diarrhea and twitching muscles….If these happen he suggests that patients take a drug holiday and start again. I asked him about someone I knew who experienced severe exhaustion on Mestinon – he indicated that that was very rare.

While on Mestinon, he has his patients slowly build up their exercise regimen. Using a recumbent bicycle is best. Short-term, high intensity training might be helpful as well, but he doesn’t have enough data on that.

Other second-tier treatments include

Florineff – See Florinef for Chronic Fatigue Syndrome Midrodrine – see Midodrine for Chronic Fatigue Syndrome SSRI’s Atriatide – redistributes blood flows away from the gut Intravenous IgG / Rituximab – (requires solid evidence of SFN)



Systrom’s First ME/CFS Focused Study

Funded by a (really smart!) donor, Systrom’s ME/CFS study is being run through The Solve ME/CFS Initiative (SMCI). Using the invasive CPET Systrom, Systrom will be able to sample the blood in two body locations at three time points. He’ll be trying to get at the molecular basis of the problem for the first time.

Not only will Systrom be getting information on exercise (heart rate, anaerobic threshold, ventilation, etc.) but he’ll be directly measuring the metabolic changes occurring during exercise as well. Unusual metabolites showing up during aerobic respiration could provide clues, for instance, that could indicate how aerobic energy production is broken in ME/CFS. He’ll also be looking for protein biomarkers using proteomics. He hopes the plasma signatures he finds will help uncover the underlying pathogenesis behind chronic fatigue syndrome (ME/CFS). He’s also hoping to identify which patients benefit from IVIG.

It’s encouraging how many researchers are beginning to circle around the blood vessels. Fluge and Mella are testing endothelial cell (the cells that open and close blood vessels) functioning in both the large and small blood vessels in their Rituximab study. They believe blood vessel problems are preventing sufficient amounts of blood getting to the muscles.

Their endothelial cell Rituximab substudy will determine if endothelial cell functioning – necessary for proper blood flow through the muscles – is associated with severity and if Rituximab enhances it. If Rituximab does improve blood vessel functioning, it may be killing the B-cells that are producing autoantibodies that are whacking the blood vessels. A cardiovascular study is also reportedly underway at Stanford.

As we’ve seen, Systrom also believes an autoimmune process attacking the blood vessels is underway. The finding last year that autoantibodies to the adrenergic receptors on endothelial cells are present in postural orthostatic tachycardia syndrome (POTS) suggests a similar process is occurring in POTS patients.

Nobody can yet prove that ME/CFS is, at least in a part, an autoimmune disorder, but we seem to be hearing the word autoimmunity with increased frequency these days. Recently Dr. Mark Davis reported that everything he’s seen immunologically suggests ME/CFS is an autoimmune disorder. Ron Davis reported that his filtering experiments suggest that the problematic factor in the blood that appears to be messing with energy production in his tests is an autoantibody.

Systrom considered applying for the NIH Research Centers grant but decided that the small amount of money the NIH provided wasn’t enough to justify creating a research center; he believes applying for single ROI grants will be more cost-effective.

With his extensive database on exercise results, his interest in exercise intolerance and now his grant from an anonymous donor, Systrom is like a gift that is falling into our laps. Hopefully, with this grant to the SolveME/CFS Initiative (SMCI), Systrom will edge himself more and more into the ME/CFS/FM research community and we’ll see much more of him in the future.

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