It’s always encouraging to see established researchers from outside the chronic fatigue syndrome (ME/CFS) and fibromyalgia fields converging on them. David Systrom, a pulmonologist at Brigham and Women’s hospital in Boston, has been interested in idiopathic or unexplained exercise intolerance for at least a decade.

He and Oldham recently published their magnus opus on exercise intolerance; a study employing over six hundred patients that stretches back nine years.

Unexplained exertional dyspnea caused by low ventricular filling pressures: results from clinical invasivecardiopulmonary exercise testing. William M. Oldham,1,2,3 Gregory D. Lewis,3,4 Alexander R. Opotowsky,2,3,5 Aaron B. Waxman,1,2,3 David M. Systrom1,2,3. Pulm Circ 2016;6(1):55-62. DOI: 10.1086/685054.

In it they proposed that a significant subset of patients with exercise intolerance and heart abnormalities have simply slipped through the cracks. No diagnosis has been able to explain their low energy production (VO2 max) during exercise; they don’t have heart failure or arrythmia or cystic fibrosis or known mitochondrial problems. Aside from telling them that they’re deconditioned or depressed the medical profession hasn’t known what to do with these patients.

How a field that gets over $2 billion in funding year in and year out could let any significant group “slip through” the cracks is unclear. Systrom’s use of invasive cardiopulmonary testing techniques apparently has given him a unique insight into these patients.

“In this study, we tested the hypothesis that failure of these mechanisms to increase cardiac preload during exercise….may be the primary limitation….in an undiagnosed population of patients with unexplained exercise intolerance.”

Some of them, perhaps many of them, have ME/CFS/FM or POTS (or would be diagnosed with it if anyone tried) and those that don’t must have something close. (At least three people with ME/CFS/FM have ended up in Systrom’s office, and probably many more were in the study.)

Systrom, though, is ignoring the ME/CFS/FM for the moment – and probably rightly so. He has bigger fish to fry; his goal right now is to enroll his colleagues in the idea that they haven’t been correctly diagnosing a significant subset of their patients.

If my reading of medical history (I highly recommend “The Biography of Cancer” and “The Death of Cancer”) is representative, that conclusion is probably not to going over well.

The Study

In this study Systrom evaluated people experiencing breathlessness (dyspnea) after exercise (or, as he put it later in the paper, simply exercise intolerance). First he worked his patients to exhaustion on a bicycle as he gathered every bit of information he could using a procedure called invasive Cardio Pulmonary Exercise Testing (iCPET). It’s clearly not a fun procedure but yields a ton of information.

Systrom placed catheters into the radial and pulmonary arteries of his patients, had them jump on a bike and exercise to exhaustion. Then he allowed them to rest for two minutes, then they cycled without load for three minutes, and then Systrom turned the screws on again by increasing the resistance of the pedals.

Systrom essentially did a quickie repeat exercise study that lasted less than an hour.

These exercise intolerant mysteries patients aren’t a small part of Systrom’s practice and this wasn’t a small study either. Systrom, a pulmonologist, reported that about eight percent of the people that have gotten Cardio Pulmonary Exercise Testing (CPET) testing done in his lab fit in this group. This study presented the results of no less than 619 iCPET tests done over a 9-year period at Brigham and Woman’s Hospital in Boston.

Results

Systrom found that these patients had low Qt and ventricular filling; i.e. their hearts were not filling enough with blood during diastole – the part of the heart cycle when the heart fills with blood. (We just saw a similar pattern in ME/CFS in “Chronic Fatigue Syndrome: A Small Heart Disease?” and “A Mestinon Miracle.”) A finding of reduced stroke volume augmentation indicated that the problem probably traced to low preload. Preload is defined by how much the heart muscle cells stretch as they expand to increase the volume of the ventricles during diastole.

(The end-diastolic ventricular pressure and volume measures both measure something similar; they all measure how large the heart gets as it contracts to fill with blood just before it pumps it out.)

A critical part of filling actually occurs outside the heart. As we begin to exercise our veins vasoconstrict or narrow and the muscle pump in our legs swings into action in order to push the blood upwards. After the blood takes a trip to the lungs to get rid of waste products and become oxygenated, it moves into both ventricles which expand like a balloon (diastole), and then in a rush pump the blood out (systole).

Systrom found, though, that hearts of the exercise intolerant patients are not expanding normally when they exercised. This inability to fill with more blood during exercise was why they exhibited low energy production (VO2 max).

Low Blood Volume Not the Primary Problem

When Systrom gave them IV saline to boost their blood volume most improved their Qt max. That suggested that low blood volumes did indeed contribute but here’s the kicker; even with the increased fluid intake, the exercise intolerant patients still had a reduced response to exercise.

That suggested that reduced blood volume was not the entire problem. Instead, as with Newton, Systrom’s evidence points to problems with what he called impaired “capacitance”, which refers to reduced constriction of the veins during exercise. As noted earlier, once exercise starts the veins should narrow in order to propel blood back up to the heart where it can be cleansed, oxygenated and sent off to the muscles again. That apparently was not happening normally in these patients.

What appeared at first to be a heart problem was actually a circulatory problem. We recently saw that Newton and Miwa found that blood flows to the heart in chronic fatigue syndrome (ME/CFS) are so reduced as to cause a substantial reduction in the size of ME/CFS patients hearts. This wasn’t because the hearts of ME/CFS patients were diseased (in heart failure the size of the heart actually expands) but because, like any muscle, the size of their heart muscle shrank when it wasn’t being worked enough.

Systrom didn’t diagnose any of the people in the study with chronic fatigue syndrome, but he did note that patients with POTS, autonomic neuropathy and adrenal insufficiency were part of the study. Any of these diseases could cause problems with constriction of the veins, and he noted that reduced heart size has also been found in POTS. POTS, of course, appears to be common in ME/CFS.

A recent study suggesting that autonomic nerve damage may be causing the reduced lung microcirculation in fibromyalgia suggested a similar process may be playing out in FM. Given the low cortisol findings in ME/CFS adrenal insufficiency – probably caused by problems with the HPA axis (not the adrenal gland itself) – is a possibility as well.

Systrom’s catalogue of possible issues in POTS; inadequate vasoconstriction, sympathetic dysautonomia, and damage to the autonomic nerves by autoimmune processes makes sense given what we know about ME/CFS and FM as well. Fluge and Mella are exploring the role autoimmune processes may play in effecting blood flows in ME/CFS. Small nerve fiber issues are well known in FM and the reduced lung microcirculation findings in fibromyalgia may be caused by autonomic nerve damage.

Missing the Muscles?

Yet another clue from this complex study came from the decreased oxygen utilization Systrom found. This could be caused by blood flows that get shunted past the capillaries in the muscle fibers to pool in other less metabolically active areas such as the abdominal region. (Increased blood flows to the abdominal region have been found in POTS/ME/CFS). Alternatively, they could be caused by mitochondrial issues.

Not Deconditioning

The study also indicated that neither deconditioning or a reduced maximal effort – both of which have been suspected in ME/CFS – play a role in the exercise intolerance found. In fact, deconditioned people, ironically, exhibit an opposite finding (increased as opposed to decreased filling pressures) to that found in this study.

Systrom’s anecdotal report that a severe illness often predated onset of the exercise intolerance presented another possible link to ME/CFS. He suggested that infection/inflammation probably played a major role in the development of the issues he’s found.

Systrom noted how different the people with idiopathic exercise intolerance are than people with heart failure and other problems, and emphasized that this is not a small group. As noted earlier, almost 10% of the patients he’s done CPET testing on have this problem. (It’s possible, in fact, that this is the first time this group has been characterized in the scientific literature.) Despite the lack of attention given to them, Systrom found that their problems were as limiting as those associated with heart failure and pulmonary disease. While their activity was not noted, this was clearly a very functionally limited group.

Treatment

Systrom also pointed to some possible help for people with POTS. Four POTS patients in the small second half of his study improved using B-adrenergic antagonists which reduced sympathetic nervous system functioning and one improved with midrodrine. All of them also increased their fluid intake, used compression stocking and engaged in exercise training.

Systrom found that increasing blood volume in his patients resulted in a smaller than expected improvement in their VO2 max. He believed this was probably due to the effects of “dilutional anemia” which make it more difficult for the red blood cells to pass oxygen to the tissues. This suggested that attempts to increase blood volume may be less effective than therapies that increase vascular tone; i.e. that support blood vessel health.

Systrom believes that circulatory problems, not blood volume, are the biggest issue facing these patients. He suggests that drugs like pyridostigmine (Mestinon) and midodrine (ProAmatine) will be most helpful, in particular, in people with viral onset or autoimmune issues.

This is not to say that increasing blood volume is not helpful; Systrom has his patients increase blood volume but he believes that other therapies will be more effective in this type of patient. See the story of one of his ME/CFS patients who has done very well on Mestinon.

Characterization – Not Cause

If Systrom’s, Newton’s and Miwa’s findings hold sway in ME/CFS then Dr. Cheney must get credit for uncovering the diastolic issues in ME/CFS as well.

We should be clear that Systrom is not getting to heart of ME/CFS or FM; instead he’s characterizing an important facet of what may have gone wrong. If problems with diastolic functioning are a key issue in ME/CFS the next question becomes what’s causing it? In the case of his POTS patients, Systrom suggested that an infectious or otherwise significant event tripped off an inflammatory autoimmune response, which, in turn caused the blood flow problems.

That’s very similar to Fluge and Mella’s proposal that autoimmune issues are causing blood flow and other problems in their ME/CFS patients. They believe that Rituximab’s success may be due to its ability to reduce the levels of autoantibodies present. POTS is more and more being considered an autoimmune disease as well.

Convergence

It’s very good to see a well published researcher from outside the field converging on it, and coming to similar conclusions as our researchers.

It’s good as well to see the exercise intolerance found in ME/CFS showing up in so many different ways. The Workwell Group and Dr. Keeler have used a repeat, two day exercise test to demonstrate that energy production is reduced in at least a significant subset of people with ME/CFS. Systrom used a one-day repeat exercise test to demonstrate that exercise intolerance is a significant problem for an important subset of his patients – some of whom must have had ME/CFS (or would meet the criteria for it). Peckerman used (unpublished) a one day test to show that exercise quickly reduces heart blood flows in people with ME/CFS.

The data from these groups suggests that problems with the blood vessels or mitochondrial issues or both may be the key to these finding. Systrom didn’t get into mitochondrial problems much but he stated mitochondrial problems could also be in play.

Addendum – A Postural Orthostatic Tachycardia Syndrome (POTS) Slant

Postural Tachycardia Syndrome (POTS) Is Not Caused by Deconditioning. Svetlana Blitshteyn1, MD and David Fries2, MD

Systrom and Oldham’s study prompted a rather long letter titled “Postural Tachycardia Syndrome (POTS) Is Not Caused by Deconditioning” to the editor by Svetlana Blitshteyn, MD of the Dysautonomia Clinic at the University at Buffalo School of Medicine and David Fries, MD of the Sands-Constellation Heart Institute at Rochester General Hospital.

They believe that Systrom’s finding are probably applicable to the majority of POTS patients.

The extensive, non-invasive cardiac testing most POTS patients undergo at some point leave them being told that their symptoms are caused by deconditioning. Indeed exercise studies showing that they exhibit low stroke volume and reduced heart mass have attributed both to deconditioning.

Systrom and Oldham’s study was the first to show that the hearts in POTS patients don’t appear to be deconditioned at all; in fact, the low ventricular filling pressures found are opposite to the high ventricular filling pressures found in people who are deconditioned.

This is not to say that deconditioning does not occur in POTS. Anyone who undergoes long periods of bed rest will become deconditioned, but the study indicates deconditioning is at most a secondary factor in POTS. The authors also applauded Systrom and Oldham for showing that reduced effort is not contributing to POTS patient’s exercise intolerance.

The authors hoped this study will provide some relief to POTS patients who, despite the fact that they do exercise and are not bedridden, still get blamed by their doctors who believe inactivity is causing their problems.

Key Points

Idiopathic Exercise Intolerance is not rare in doctors offices but has rarely been diagnosed correctly

Neither deconditioning nor lack of effort is to blame; in fact, people with unexplained exercise intolerance have the opposite findings to those in deconditioned people

Low blood volume contributes to, but is probably not the main cause, of unexplained exercise intolerance

Blood vessel or mitochondrial problems (or both), that prevent sufficient amounts of blood getting to the heart during exercise are probably the main cause of unexplained exercise intolerance

Treatments that emphasize blood vessel health may be more effective than blood volume enhancers

The immune system may ultimately be the culprit