A Talk With Dr. Spence - This paper was the result of an alert researcher picking up on an obscure finding and putting the pieces together. I was able to talk to Dr. Spence later. The founder of the MERGE research/advocacy group, he is an enormously engaging and enthusiastic researcher with a severe case of CFS. If my notes are correct, he believes that the circulatory problems seen in CFS – which MERGE has been studying for some time now – may originate in a dysfunction of the endothelial cells lining the blood vessels. These cells are not only involved in opening and closing the blood vessels but in the immune response as well, and they are often attacked by pathogens.

Funding, funding, funding - MERGE has been able to turn out several small studies a year and I asked him about his funding. He said it was all from CFS patients giving what they could. He noted that MERGE is trying to fund seed studies that major funders will pick up on and expand.

Funding is, of course, a big problem for CFS researchers. Dr. Evengaard several times during the conference noted the almost non-existent rate of governmental funding of non-behaviorally oriented CFS research in Europe. She said that (aside from Japan) the U.S. is the only country willing to fund biologically oriented research studies. I asked Dr. Hanna about the possibility of the NIH funding studies outside the U.S. and she said there was no problem with that, that she is simply looking for multidisciplinary studies that seek to explain, not simply characterize CFS. I asked both Dr. Spence and Dr. Kerr if they were considering attempting to secure funding through the NIH. They both were but the process is long and demanding and Dr. Spence, as mentioned earlier, has a severe case of CFS. These creative researchers desperately need more money. You can contribute to Vance Spence and MERGE by clicking here.

Elizabeth Maloney, DrPH, MS, James Jones, Chrisine Heim, Roumiana Boneva, William Reeves. CFS is associated with high allostatic load in Georgia.

This study extends the CDC work on allostatic stress in CFS. ‘Allostatic load’ is a measure of wear and tear on the body. The Wichita study showed that particularly with regard to cardiovascular factors CFS patients carry a high allostatic load (click here). In their Wichita studies the CDC took a broad brush approach to CFS research looking a wide variety of different factors. Intriguingly, given the recent findings from Vance Spence of MERGE and Dr. Cheney and others, cardiovascular factors jumped out.

This study, which extended the CDC’s look at these factors, found that both the CFS and CFS-like patients had significantly higher rates of allostatic load associated with the cardiovascular system than did the normal controls. My notes indicated Dr. Maloney found increased heart rate, SDB/DBP, and levels of albumin and, most importantly, c-reactive protein in CFS patients compared to age, sex and BMI matched controls.

(The CDC is careful to have body mass index matched CFS patients and controls in its research studies. Since both CFS and healthy controls were equally overweight it appears that something other that weight gain is causing the increased rates of metabolic syndrome in these patients. The higher waist/hip ratio’s in the CFS patients compared to the controls suggests they have a metabolic problem that causes greater fat deposition in the abdominal area. Fat in this area appears to be unusually active, pumping out increased pro-inflammatory cytokines such as Il-6.)

A key player in metabolic syndrome may be a pro-inflammatory cytokine called IL-6. Fortuitously a paper examining IL-6 levels in CFS was presented by another CDC researcher. This study was a highlighted not only because of its findings but because of its innovative approach to this issue.

Dr. Spence indicated that a logical outcome of increased arterial stiffness was diastolic dysfunction, a subject Dr. Cheney has focused on for the last three years.

Again (see Keynote Speech, Patient Conference) Dr. Cheney drew our attention to the fact that "preserved ejection fraction heart failure in women is epidemic, unexplained and deadly." Preserved ejection fraction heart failure refers to cases of heart failure in which the pumping action of the heart (systole) is preserved but the filling phase (diastole) is impaired. He believes that his scenario of impaired cellular energy production – which should, as he noted in the patient conference, affect diastolic functioning long before it affects systolic functioning – could explain the abrupt recent rise in diastolic heart failure.

He described a range of observed abnormalities in diastolic functioning found in his CFS patients during Tilt table tests. In a small study he found that echocardiography during Tilt best differentiates patients from controls. There is some disagreement about how well some of these measures reflect cardiac functioning but one of the measures Cheney presented called E/e’ ratio is well correlated with cardiac functioning. Dr. Cheney also found a high degree of atrial cavitation (50% of CFS patients), reversal of blood flow into the pulmonary vein, and abnormal E/A ratio’s.

He believes the striking similarities in diastolic dysfunction in CFS patients and young men exposed to low oxygen environments indicates that CFS patients exist in a state of ‘functional hypoxia’.

Paul Cheney and L. Nucki. Evidence of increased frequency of patent foramen ovale (PFO) in the Chronic Fatigue Syndrome and enriched oxygen modulation of the PFO (poster)

We noted that Dr. Cheney believes that CFS patients exist in a state of ‘functional hypoxia’ or low oxygen levels relative to their needs (see Keynote Address, Patient Conference). He believes that a left-shift on the oxy-hemoglobin dissociation curve should raise pulmonary artery pressure and that this, in combination with the low blood pressures often found in CFS, would result in increased rates of the patent foramen ovale. Poor diastolic functioning would then increase the severity of the PFO.

Looking at 41 consecutive CFS patients he found 81% of them had PVO – the highest percentage yet reported in a disease. Two thirds required a Valsalva maneuver to open them and one third exhibited it without doing the maneuver. The Valsalva maneuver consists of blowing hard with the mouth and nose closed. This raises venous pressure and is used to investigate some aspects of cardiac functioning including decreased filling, i.e. diastolic dysfunction. Some PFOs only open during strain such as lifting, during sex, etc. That most PFO’s opened only during the Valsalva maneuver would appear to suggest that they are usually closed in 2/3rds of CFS patients (?). Dr. Cheney graded the PFOs in severity – most were of low to intermediate severity. This finding appears to be very similar to that of diastolic dysfunction in CFS – it is very common in CFS but is usually of a mild to intermediate level of severity. Giving oxygen to these patients closed the PFO in about a third of them.

Dr. Cheney believes that these PFOs are the source of the ‘unidentified bright objects’ seen on MRI scans.

A Summary - Cardiovascular/Vascular Implications in CFS - What does all this mean? Are the increased rates of abdominal fat, elastase, arterial stiffness, IL-6, c-reactive protein, metabolic syndrome and diastolic dysfunction in CFS related? Are these researchers converging on each other from different directions? At least at this point it does appear so. High Il-6 levels, c-reactive protein levels and arterial stiffness are found in metabolic syndrome and all three may be risk factors for diastolic dysfunction. This is a complex subject, one that Phoenix Rising will be covering in more detail as these studies are published.

I loved the understatement made by the Snell group in one of their abstracts "For many patients these problems are exacerbated following physical activity and adversely affect their work, social and even family lives. For such a prominent symptom of CFS research in this area has been limited. . . "

Yes, it is amazing how little research has been done on what many CFS patients consider their most unique symptom – the crushing fatigue and/or pain and cognitive dysfunction, etc. that occurs after (too much) exercise. If someone had asked me what to study in CFS 20 years ago I would have said whatever you do find out what happens to me in the hours and days after I exercise. Give me an exercise test and start taking blood, start scanning my brain, etc.

There are some things we do know. One study suggested immune activation (complement system) occurs after exercise and a gene expression study found evidence of altered ion channel transport activity. Please note that nothing in this section implies that CFS patients should not exercise to the extent that they can without relapsing.

A. Garcia Quintana, A. Garcia-Burillo, J. Alegre-Martin, I Mena, J. Garcia-Quintana. Brain SPET quantification in Chronic Fatigue Syndrome: comparison of basal and post-stress studies.

The enterprising Garcia Quintana group from Spain used a SPET scan to examine brain activity before and after an exercise session. This is the first time, to my knowledge, that this has been done. It found that one area in particular, the Wernicke area, showed evidence of reduced activity after exercise. This area, which is found in the cerebral cortex, is thought to be ‘essential for understanding and formulating coherent . . . speech.’ Other areas in the temporal lobe were affected. Interestingly it was difficult to tell if the anterior cingulate region – a region we will see mentioned time and time again with regard to CFS – was affected, because the activity in this region was too low to begin with.

These studies found that the majority of the CFS patients had increased rates of RNase L activity (83%), RNase L fragmentation (88%) and a whopping 95% had increased elastase levels. They also have decreased ‘functional reserve’ and peak aerobic power. The high elastase readings were, of course, intriguing given Dr. Spence’s supposition that elastase was driving the high levels of arterial stiffness he found. These researchers suggested that the RNase L abnormalities could contribute to the muscle symptoms found.

The study that employed an exercise period found that RNase L activity in CFS was correlated with lactate concentrations, an intriguing finding given the increased lactate levels in the brain found earlier. Blood lactate research in CFS has, however, had a decidedly mixed history with some studies showing elevated lactates and others not. This could suggest that a subset of CFS patients have elevated lactate levels.

This is a preliminary report from a large study focusing on immune markers and gene expression before and after exercise in GWI, CFS patients and healthy controls. It found that NK cell counts went way up following the exercise period but that T-cell counts remained the same. Unfortunately they don’t tell us if this pattern was different in the controls versus the CFS or GWI illness subjects but this study does show that NK cells are sent into a tizzy after exercise and given the NK cell abnormalities found in CFS this is an interesting finding.

This Dutch group carried the exercise testing regime one step or rather one day further by having CFS patients and healthy controls exercise three times over four days. It found that all the healthy controls and half the CFS patients improved their aerobic functioning in the second exercise trial. This would be enough for some CBT practitioners to say I told you so – that group is not sick! – and then instruct them to exercise their hearts out (perhaps literally). When these researchers extended the exercise test one day further, the test scores (VO2 max) of a big chunk of the CFS patients (25% more) declined - now 75% of the CFS patients were hurting. If they kept giving this test day after day they would surely find that all the CFS patients started falling apart.

This suggests what seems to be a rather obvious idea in retrospect, that one way to differentiate people with CFS from people with something else is through multiple day exercise testing. If post-exertional fatigue is a true marker of CFS and that fatigue is reflected by measures of aerobic output, then this test should differentiate ‘true’ CFS patients from others, or at least from any subgroup of CFS patients who do not exhibit post-exertional fatigue. Of course this test would have to be limited to people who are not completely disabled by CFS.

The SNELL EXERCISE STUDIES - The Snell group, which is associated with the Pacific Fatigue Lab in the University of the Pacific in California, has focused closely on the post-exercise period. They are sponsored by the CFIDS Association of America.

So far we’ve found that if you test CFS patients after an exercise challenge, they exhibit declines in aerobic functioning and their NK cells proliferate wildly. Now the Snell group looks at cognition: CFS patients often complain that they have more trouble thinking after exertion. This study put that idea to the test; they measured a very simple measure of cognition – reaction time to both simple and complex stimuli - before and after an exercise test. It found that while CFS patients were slower, the results were not statistically significant. When they looked at all the test results together, however, there was a statistically significant difference. They also noted that variability within the CFS group was high while it was not in the control group. This suggests that some CFS patients did fairly well on these tests while others did not.

This was not an earth shattering study but it demonstrated very starkly how severely exercise affects CFS patients. After sedentary healthy controls and CFS patients exercised to capacity they were given SF-36 tests that characterize functioning in eight different areas: physical functioning, reduced activity levels because of physical problems, emotional problems, bodily pain, perception of general health, vitality (energy), social functioning and mental health. This study found that CFS patients reported significantly more problems in all eight areas compared to the flabby but still healthy controls. Only one of the 21 CFS subjects had recovered to baseline within 48 hours while all the healthy controls had. This, of course, indicates that the exercise problems in CFS are not due to simple inactivity – the healthy controls were sedentary as well - but are an integral problem of the disease itself.

This was an attempt to examine immune, metabolic (blood glucose, lactate) and sympathetic nervous system (nasal rhinometry) functioning during exercise and, with regard to the immune measures (RNase L fragmentation, elastase), after the exercise period in CFS patients and controls.

In contrast to the others this study failed. While CFS patients had significantly lower cardiopulmonary scores (VO2 max, etc.), rates of RNase L fragmentation and elastase activity were not increased after the exercise test. Nor were the measures of sympathetic nervous system functioning or metabolism different.