Dysfunctional low affinity antibodies leads to gut & immune problems in ME/CFS

Posted on 07/05/2016 by wames

Research abstract:

Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a heterogeneous illness characterized by a number of comorbid conditions; gastrointestinal (GI) dysregulation make up one subgroup of this disease.

IgA is the most abundant antibody isotype found in mucosal secretions including the gut. In a process of class switch recombination (CSR), that relies on the interaction of plasmacytoid dendritic cells (pDCs) with B cells, in a T cell independent (TI) manner, low-affinity IgA are produced that limit the adhesion of commensal bacteria to intestinal epithelia without neutralizing them. These low-affinity antibodies also limit bacterial overgrowth and potential bacterial translocation thus maintaining gut homeostasis. This process is known as “immune exclusion”.

Two ligands on the surface of pDCs that are obligatory for the process; the membrane bound form of APRIL and BAFF. The upregulation of APRIL and BAFF on the surface of pDCs is dependent on low-level expression of type I interferon (IFN) which is produced by intestinal stromal cells in response to Toll-like receptor (TLR) engagement.

Previous studies suggest that peripheral pDCs are significantly lower in subjects with ME/CFS when compared to controls and studies conducted by us further suggest these cells likely redistribute from the periphery to the gut. We have observed that, in contrast to controls, gut-associated pDCs in subjects with ME/CFS lack APRIL and BAFF expression.

These data support a model of gut pathology in ME/CFS whereby dysregulated pDCs fail to promote the production of low-affinity IgA through the process of TI activation of B cells, thereby leading to bacterial overgrowth, dysbiosis, bacterial translocation and systemic immune activation.

Failure of gut-associated pDCs to express membrane bound APRIL and BAFF prevents their ability to promote low-affinity IgA expression in ME/CFS by Vincent C Lombardi, Svetlana F Khaiboullina, Kenny L De Meirleir, Tanja Mijatovic and Jan Hulstaert in The Journal of Immunology, May 1, 2016, vol.196 (1 Supplement) 137.4

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Nausea and sickness: non-drug options

Posted on 07/04/2016 by wames

MEA blog post, 29 June 2016: Dr Charles Shepherd reports on two non-drug options for nausea and sickness in ME/CFS

New guidance from the Royal College of Obstetricians and Gynaecologists adds further weight to the fact that two non-drug options – ginger and acupressure bands – can be helpful in relieving nausea.

BBC report: Ginger and acupressure ‘options for morning sickness’

These are non-drug options which are also worth considering when nausea occurs in ME/CFS.

However, whilst nausea and sickness can be a symptom of ME/CFS, it is important to exclude other possible medical explanations before doctors or patients conclude that this is ‘just another ME/CFS symptom’.

Medical information on acupressure bands: Sea-bands

More information on ginger (from Cancer Research UK):

Some people find ginger very helpful when feeling sick. People say it is particularly good for motion sickness. You can use ginger any way you like, for example as crystallised stem ginger. Or you can add freshly ground ginger to your favourite dishes, or to hot water or tea to make a soothing drink. You can try sipping ginger ale. Fizzy drinks sometimes help to reduce nausea too.

Researchers have been looking at using ginger alongside anti sickness medicines during chemotherapy. But the results so far have been mixed. So more research is needed.

Drug treatment options for nausea and vomiting. Source: patient information UK

* Cinnarizine, cyclizine, promethazine – these medicines belong to a group of medicines called antihistamines. The exact way that they work is not fully understood. It is thought that antihistamines block histamine 1 (H1) receptors in the area of the brain which creates nausea in response to chemicals in the body. They are thought to work well for nausea caused by a number of conditions including ear problems and motion (travel) sickness.

* Hyoscine – this medicine works by blocking a chemical in the brain called acetylcholine. It is a type of medicine called an antimuscarinic (or anticholinergic). It works well for nausea caused by ear problems and motion sickness.

* Chlorpromazine, haloperidol, perphenazine, prochlorperazine, levomepromazine– these medicines work by blocking a chemical in the brain called dopamine. They are useful for nausea that is caused by some cancers, radiation, and opiate medicines such as morphine and codeine. Prochlorperazine (or brand name Stemetil®) is one of the most used medicines for nausea. It works for many causes of nausea, including vertigo, ear problems and sickness in pregnancy.

* Metoclopramide – this medicine works directly on your gut. It eases the feelings of sickness by helping to empty the stomach and speed up how quickly food moves through the gut. It is often used for people with sickness due to gut problems or migraine. It is not usually used for more than a few days.

* Domperidone – this medicine works on the CTZ (an area of the brain known as the chemoreceptor trigger zone). It also speeds up the emptying of the gut. It is not usually used for more than a few days.

* Dexamethasone – this is a steroid medicine. It is a man-made version of a natural hormone produced by your own body. Dexamethasone has a wide range of actions on many parts of the body. The reason why it reduces nausea isn’t clear.

* Granisetron, ondansetron, and palonosetron – these medicines work by blocking a chemical called serotonin (5-HT) in the gut, and the brain. Serotonin (5-HT) has an action in the gut and the brain to cause nausea. These medicines are useful for controlling nausea and vomiting caused by chemotherapy.

* Aprepitant and fosaprepitant – these are newer medicines and work by blocking a chemical that acts on neurokinin receptors in the body to cause nausea. They are sometimes called neurokinin-1 receptor antagonists. They are usually given to people on a certain type of chemotherapy.

* Nabilone – it is still not clear how this medicine works to control nausea. It is normally prescribed for people who are having chemotherapy.

Medicines for nausea are available as tablets capsules, liquids, suppositories and skin patches. Some are given as injections into the muscle or directly into the vein.

Some of these medicines are also available as tablets that dissolve in the mouth against the gum. They are called buccal tablets. These medicines come in various different brand names.

Dr Charles Shepherd
Hon Medical Adviser, ME Association

 

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Dr Maureen Hanson radio interview about her gut research

Posted on 07/04/2016 by wames

Dr Maureen Hanson gives a radio interview about her recently published paper, “Reduced diversity and altered composition of the gut microbiome in individuals with myalgic encephalomyelitis/chronic fatigue syndrome“.

Maureen Hanson

It is an interview designed to explain the study to lay people.

WRFI Community Radio interview with Dr Maureen Hanson 28 June 2016

 

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Prof Ron Davis outlines key research needs for ME/CFS

Posted on 07/04/2016 by wames

OMF blog post, 1 July 2016: Open Medicine Ron Davis’ response to the NIH Request For Information (RFI): Input for New Research Strategies for ME/CFS.

We would like to share the information that Dr. Ron Davis sent in response to NIH’s Request for Input on new ME/CFS research strategies.

dr-ronald-davis-stanford

We are grateful for the opportunity to provide input to the Trans-National Institutes of Health (NIH) ME/CFS Working Group as they develop strategies to guide NIH’s research efforts and priority setting for research on ME/CFS. Our mission at the Stanford Chronic Fatigue Syndrome Research Center is to discover causes, a molecular diagnosis, and treatment options for ME/CFS. Through our research efforts, collaborations with the ME/CFS research and clinical community, and extensive engagement with patients, we have defined several elements of importance for future ME/CFS research programs.

Complex and multisystemic disease

A key consideration in ME/CFS research efforts is the complex and multisystemic nature of this disease, and we are happy to see the involvement of several NIH institutes in developing this plan. Because the causative factors driving the disease remain unknown, and because work from our team and others has indicated effects on neurology, metabolism, immunity, and more, it will be crucial that calls for proposals allow for open, unbiased, multifaceted, and systematic research.  Broadening the scope of ME/CFS research will create opportunities for engaging researchers in other disciplines.

Similarly, investigating numerous organ systems and biological pathways perturbed in ME/CFS may well reveal informative parallels to other diseases – for example, we and others have observed symptomatic, transcriptomic, and metabolic overlap between ME/CFS and neurodegenerative disorders like Parkinson’s Disease. It is important not to limit research to single organs like the brain, and to integrate results from many different organs and molecular processes so that they can be understood at the systems level. Big data approaches and high-throughput, large-scale molecular profiling should therefore be prioritized. Such efforts hold promise to identify key genes or pathways underlying ME/CFS. Similarly, large-scale in vitro drug screening efforts would help point to a variety of molecules and molecular processes as therapeutic targets.

Molecular etiology of ME/CFS

Understanding the molecular etiology of ME/CFS is another important opportunity. A long-standing belief in the field is that an infectious agent causes the disease, and that the pathogenicity of the as-yet-undiscovered organism is responsible for the severity of the illness.

An equally plausible explanation is that a stressor such as trauma, infection, or genotoxic stress may trigger a series of events that lead to a hypometabolic state. This model is observed in children with congenital mitochondrial disorders, where the phenotype does not present itself until after a serious viral infection. This shift in thinking opens up the possibility that ME/CFS has strong genetic and environmental associations, which may also explain the extensive heterogeneity in its presentation, progression, and recovery across patients.

The search for novel infectious agents should continue, but research efforts should also focus on understanding individual host susceptibility and response to infection. For example, it may not be a particular infectious agent that results in the disease, but rather a particular host state as a function of numerous biological and external factors that governs an individual’s susceptibility.

This perspective mirrors the NIGMS-funded Glue Grant on Inflammation and Host Response to Injury, which used an integrated omics approach to define variable responses to infection and trauma. Characterizing host responses to infection and understanding the mechanisms of the long-term sequelae may reveal insights into ME/CFS that are relevant to numerous other diseases of infectious origin, such as Chronic Lyme Disease and Post-Ebola Syndrome (Mattia et al., 2016). Moreover, such precision medicine approaches would build a more comprehensive understanding of ME/CFS and offer richer opportunities for therapeutic intervention.

Prevalence and landscape
Another major challenge is our lack of understanding of the prevalence and landscape of ME/CFS, which is largely due to the difficulty in diagnosing the disease. The search for precise molecular biomarkers is a great opportunity afforded by this research program, which would be accelerated through multi-omics approaches in large patient cohorts.

Current estimates of the prevalence of ME/CFS vary widely (800,000 to 2.5 million cases in the US) due to varying diagnostic and data collection methods. There is an opportunity here to improve these estimates based on modernized methods and community-defined standards, including criteria specified in the 2015 Institute of Medicine Report, and by considering questionnaire-based responses like the Avon Longitudinal Study of Parents and Children (ALSPAC) birth cohort in the United Kingdom (Collin et al., 2016).

Novel methods & technologies

Because of these complex scientific challenges, ME/CFS research presents an excellent opportunity for developing and piloting novel methods and technologies in discovering biomarkers, elucidating disease mechanisms, and revealing therapeutic possiblities. The methods we need to understand this complex disease may very well not exist yet.

Engineering and technology development efforts towards highly sensitive, quantitative molecular profiling and/or measuring novel cellular properties, as well as novel computational analyses that integrate multiple datatypes to define disease mechanisms, should be encouraged. Again, it is highly likely that such efforts will prove useful in the study of other diseases, be they infectious, genetic, or complex in origin.

Long term studies
Beyond scientific considerations, we would like to note several programmatic considerations that we believe are key for rapid progress. Long-term studies of patients are absolutely essential. Such a mechanism has proven effective in the NIGMS Glue Grants described above. Moreover, maintaining an open structure in RFAs will allow scientists to develop and refine their hypotheses as research progresses, as appropriate for the unknown/uncertain nature of the field.

Collaboration & data sharing

As highlighted in several places above, the opportunities for collaborative efforts within and beyond the ME/CFS research community to understand and treat this disease are numerous. There are numerous experts spread across the world, each taking their own approaches based on their own expertise. We believe future funding programs should not only encourage, but establish frameworks for highly collaborative data sharing and strategizing that bring together researchers and clinicians.

All data should be made publicly available as early as possible (even before publication), in both raw and accessible formats. This will not only facilitate collaboration (for example by encouraging biocomputing experts to engage with the data) and integrative analyses, but also empower patients to understand more about their disease and what progress is being made. As we have all seen, the ME/CFS patient community is extremely active, engaged, and eager for actionable results.

We thank you once again for the opportunity to provide input on this matter, and look forward to the new strategies for ME/CFS research efforts put forth by this working group.

Yours sincerely,

Ronald W. Davis, Ph.D.
Professor of Biochemistry and Genetics, Stanford University Director, Stanford Chronic Fatigue Syndrome Research Center and Stanford Genome Technology Center Director, Scientific Advisory Board, Open Medicine Foundation[

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Eating difficulties in adolescents with CFS/ME

Posted on 07/01/2016 by wames

Research abstract:

BACKGROUND: An estimated 10% of children and adolescents with chronic fatigue syndrome/myalgic encephalomyelitis (CFS/ME) experience eating difficulties; however, little is known about why these difficulties develop, what the impact is or how to manage them.

METHODS: Semi-structured interviews were conducted with adolescents (aged 12-17 years) attending a specialist service who have a primary diagnosis of CFS/ME and experience nausea, abdominal pain and/or eating difficulties. A total of 11 adolescents were interviewed (eight female, mean age: 15 years). Transcripts were analysed thematically using techniques of constant comparison which commenced soon after data collection and informed further interview protocols.

RESULTS: Adolescents perceived their eating difficulties were caused by abdominal symptoms, being too fatigued to eat and changes to their senses of taste and smell. Some of the adolescents recognised how their eating difficulties were exacerbated and maintained by psychological factors of low mood and anxiety. The adolescents eating difficulties had a negative impact on their weight, fatigue, socialising and family life. They perceived helpful interventions to include modifying their diets, families adjusting and also medical interventions (e.g. medication). Adolescents identified that early education and support about diet and eating habits would have been helpful.

CONCLUSIONS: If adolescents diagnosed with CFS/ME develop eating difficulties, this has a significant impact on their quality of life, illness and on their families. Not eating increases fatigue, low mood and anxiety which further exacerbates the eating difficulties. Clinicians should screen for eating difficulties in those with symptoms of nausea and abdominal pain, warn adolescents and their families of the risk of developing eating difficulties and provide interventions and support as early as possible.

Source: Harris S, Gilbert M, Beasant L, Linney C, Broughton J, Crawley E. A qualitative investigation of eating difficulties in adolescents with chronic fatigue syndrome/myalgic encephalomyelitis, by Sarah Harris, Matthew Gilbert, Lucy Beasant, Catherine Linney, Jessica Broughton and Esther Crawley in Clin Child Psychol Psychiatry. 2016 May 23. [Epub ahead of print]

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The crucial role CoQ10 plays in FM & ME/CFS

Posted on 07/01/2016 by wames

Prohealth blog post by Karen Lee Richards, 27 June 2016: The crucial role CoQ10 plays in Fibromyalgia and ME/CFS

No two fibromyalgia or ME/CFS patients are exactly alike. Each has a unique set of symptoms with varying degrees of severity. There is, however, one common denominator for the vast majority – a serious, sometimes even profound, lack of energy.

What could possibly cause that kind of fatigue?

Multiple studies have suggested that mitochondrial dysfunction may play a significant role in both fibromyalgia and ME/CFS, which would explain much of the energy deficit experienced by patients.

Mitochondria are the engines – or energy producers – that power every cell in the body. It is the job of the mitochondria to take in nutrients, break them down and use them to create energy for the cells. The more energy a cell needs, the more mitochondria it contains. Cells that require a lot of energy – like the heart, brain and other vital organs – may have thousands of mitochondria.

How do the mitochondria produce energy? This is where CoQ10 (coenzyme Q10) comes in. CoQ10 is the catalyst that makes it possible for the mitochondria to produce ATP (adenosine triphosphate), the molecule upon which all cellular functions in the body depend. In fact, 95% of all cellular energy production depends on CoQ10.

Given that statistic, it’s not surprising to learn that, according to several different studies, people with FM and/or ME/CFS generally have very low levels of CoQ10. As we, therefore, might expect, many of the symptoms of a CoQ10 deficiency are remarkably similar to symptoms of FM and ME/CFS, such as:
• Fatigue
• Pain
• Headaches
• Exercise intolerance • Generalized weakness
• Memory loss
• Difficulty concentrating
• Depression
• Vision problems
• Seizures
• Heart failure

Because CoQ10 is essential to every cell in the body, a severe CoQ10 deficiency can cause mitochondrial dysfunction, which in turn has a serious negative impact on multiple organs and body systems.

Fibromyalgia and CoQ10

Since 2009, a team of Spanish researchers has led the way in conducting studies that link CoQ10, mitochondrial dysfunction and fibromyalgia. They have consistently found that FM patients are deficient in CoQ10 – often with a 40-50% reduction in CoQ10 levels compared to healthy controls.

Following are some of their significant findings:

  • The distribution of CoQ10 in the blood was altered in FM patients.(1)
  • A CoQ10 deficiency alters mitochondrial function, leading to increased oxidative stress in FM.(2)
  • FM patients tested had low CoQ10 levels; after supplementation, both CoQ10 levels and symptoms improved.(3)
  • Results suggest a role for mitochondrial dysfunction and oxidative stress in the headache symptoms associated with FM; oral CoQ10 supplementation restored biochemical parameters and induced a significant improvement in clinical and headache symptoms.(4)
  • This study suggests that mitochondrial dysfunction may be driving an inflammatory process in FM; oral supplementation restored biochemical parameters and induced a significant improvement in clinical symptoms.(5)
  • FM patients had a CoQ10 deficiency, mitochondrial dysfunction and increased expression of a particular inflammasome (an immune system sensor that can induce inflammation); oral supplementation reduced the inflammasome activation.(6)
  • FM patients had low levels of both CoQ10 and serotonin; following CoQ10 supplementation, CoQ10 and serotonin levels were restored and symptoms of depression were measurably improved.(7)

Many well-known FM/ME/CFS physicians, like Dr. Mark Pellegrino, Dr. Charles Lapp and Dr. Jacob Teitelbaum, have been recommending CoQ10 for their patients for years. In fact, CoQ10 is one nutritional supplement that is almost universally endorsed by traditional and alternative FM/ME/CFS practitioners alike.

ME/CFS and CoQ10

As with fibromyalgia, ME/CFS patients have also been found to be deficient in CoQ10. In a 2009 study, plasma CoQ10 was analyzed in 58 ME/CFS patients and 22 normal controls. Researchers found that CoQ10 levels were significantly lower in the ME/CFS patients than in the normal controls. Additionally, they demonstrated a relationship between low CoQ10 levels and increased fatigue, autonomic and neurocognitive symptoms. The researchers went on to note that low CoQ10 levels are a predictor of chronic heart failure and may explain the early mortality rates of ME/CFS patients due to heart failure.(8)

A 2016 article in the journal BioFactors reported on two studies using oral ubiquinol-10 (an advanced form of CoQ10) supplementation on ME/CFS patients. The first was an open label trial with 20 patients and the second a double-blinded, placebo controlled trial with 43 ME/CFS patients. Both trials found that ubiquinol-10 supplementation was effective in improving autonomic nervous function and cognitive function in ME/CFS.(9)

In her paper, “Chronic Fatigue Syndrome and Mitochondrial Dysfunction,” Dr. Sarah Myhill, MD, a UK-based ME/CFS researcher and clinician, makes the case that ME/CFS is actually a symptom of mitochondrial failure.(10) Dr. Myhill recommends that ME/CFS patients have their CoQ10 levels checked and begin taking CoQ10 supplements if they are low. She also notes that CoQ10 will work best in conjunction with acetyl L-carnitine, magnesium, D-ribose and Vitamin B3 (niacinamide).(11)

Medications That Deplete CoQ10

There are numerous prescription and over-the-counter medications that can deplete the body of CoQ10. Unfortunately several of them are frequently prescribed for FM and ME/CFS, including many antidepressants, anticonvulsants and analgesic/anti-inflammatory medications.

Statins, prescribed for lowering cholesterol, are particularly notorious for hindering the body’s production of CoQ10. More and more doctors are strongly recommending CoQ10 for their patients who are taking statins.

All CoQ10 Is Not Created Equal

The form of CoQ10 found in most supplements is called ubiquinone. In order to produce cellular energy, the body must convert the ubiquinone to ubiquinol. It is the ubiquinol that carries electrons through the mitochondria and produces energy.

Young healthy people (under 25) can easily convert CoQ10 to ubiquinol. But as we age or when we have a chronic illnesses, our ability to convert CoQ10 to ubiquinol diminishes. Therefore, it is particularly important for people with FM or ME/CFS to take the ubiquinol form of CoQ10 so they’re not expending precious energy converting ubiquinone to its usable form.

A 2007 study compared how well humans absorbed ubiquinone and ubiquinol. The results showed that it takes eight times as much ubiquinone to equal the blood plasma concentrations of ubiquinol. More specifically, 150 mg. of ubiquinol was equal to 1200 mg. of standard CoQ10.(12)

Additionally, in an unpublished study with aged rats, blood concentrations were sustained longer with ubiquinol. After eight hours, the concentration of ubiquinol CoQ10 was 3.75 times greater than standard CoQ10.(13)

How to Take Ubiquinol CoQ10

The suggested dosage of Ubiquinol CoQ10 for FM and ME/CFS patients varies, but most experts start at around 150-200 mg./day. One FM/ME/CFS physician told me that many of his patients take 600 mg. or more each day. Check with your physician to determine the best starting dosage for you.

It’s important to note that Ubiquinol CoQ10 is not a quick fix that will give you an immediate energy boost. Each individual is different, but it generally takes two to three weeks to restore optimal CoQ10 levels in blood plasma and tissues. You may, however, begin to notice a difference as your plasma levels start to increase around the fifth day. If you don’t notice any difference after three weeks, you may want to discuss increasing the dosage with your doctor.

References

More info: Ubiquinol-10 supplementation improves autonomic nervous function and cognitive function in chronic fatigue syndrome by S. Fukuda et al., 10 May 2016

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Dr Myhill video – Biological basis & treatment of CFS/ME

Posted on 07/01/2016 by wames

Dr Myhill gave a talk to the AGM of OMEGA on Sat 5 March 2016.

Dr Sarah Myhill

This talk covered:

  • The Biological Basis of CFS/ME – the “theory”
  • The Treatment of CFS/ME – the “treatment”

You can access the full PowerPoint slide show at this new webpage:

Watch the video

 

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Cardiac abnormality and low blood volume confirmed in CFS

Posted on 06/30/2016 by wames

Research abstract:

Objectives:

To explore potential mechanisms that underpin the cardiac abnormalities seen in chronic fatigue syndrome (CFS) using non-invasive cardiac impedance, red cell mass and plasma volume measurements.

Methods

Crdiac MR (MR) examinations were performed using 3 T Philips Intera Achieva scanner (Best, NL) in participants with CFS (Fukuda; n=47) and matched case-by-case controls. Total volume (TV), red cell volume (RCV) and plasma volume (PV) measurements were performed (41 CFS and 10 controls) using the indicator dilution technique using simultaneous 51-chromium labelling of red blood cells and 125-iodine labelling of serum albumin.

Results

Te CFS group length of history (mean±SD) was 14±10 years. Patients with CFS had significantly reduced end-systolic and end-diastolic volumes together with reduced end-diastolic wall masses (all p<0.0001). Mean±SD RCV was 1565±443 mL with 26/41 (63%) having values below 95% of expected. PV was 2659±529 mL with 13/41 (32%) <95% expected. There were strong positive correlations between TV, RCV and PV and cardiac end-diastolic wall mass (all p<0.0001; r2=0.5). Increasing fatigue severity correlated negatively with lower PV (p=0.04; r2=0.2). There were no relationships between any MR or volume measurements and length of history, suggesting that deconditioning was unlikely to be the cause of these abnormalities.

Conclusions

This study confirms an association between reduced cardiac volumes and blood volume in CFS. Lack of relationship between length of disease, cardiac and plasma volumes suggests findings are not secondary to deconditioning. The relationship between plasma volume and severity of fatigue symptoms suggests a potential therapeutic target in CFS.

Key questions

What is already known about this subject?

  • Chronic fatigue syndrome (CFS) has been shown to be associated with a range of cardiac abnormalities.
  • Studies, to date, have suggested that these abnormalities probably arise because of deconditioning.

What does this study add?

  • This study has confirmed in a large cohort that there are reductions in cardiac volume in CFS measured using cardiac MRI.
  • The degree of these end-diastolic and end-systolic volume abnormalities associates with blood volume.
  • The abnormalities seen are not arising secondary to deconditioning.
  • Reductions in plasma volume associate with fatigue severity.

How might this impact on clinical practice?

  • This study reinforces, using state-of-the art MRI, previous findings that there is a cardiac abnormality in those with CFS.
  • The finding of hypovolaemia in association with cardiac structural abnormalities and fatigue severity represents a potential therapeutic target.

Reduced cardiac volumes in chronic fatigue syndrome associate with plasma volume but not length of disease: a cohort study, by Julia L Newton, Andreas Finkelmeyer, George Petrides, James Frith, Tim Hodgson, Laura Maclachlan, Guy MacGowan and Andrew M Blamire in Open Heart Vol 3, Issue 1 2016

Funded by the (UK) Medical Research Council & ME Research UK

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ME/CFS: the small heart disease

Posted on 06/30/2016 by wames

Health rising blog post, by Cort Johnson, 27 Jun 27 2016: Chronic Fatigue Syndrome: the small heart disease

Did you know that you probably have a smaller heart than normal? Four studies suggest that if you have chronic fatigue syndrome (ME/CFS) you probably do.  The word on the small hearts for years has been that they’re probably caused by inactivity or deconditioning. This study suggested that they probably are indeed caused by inactivity – but not by deconditioning at all.

Small hearts appear to be common on ME/CFS – but not in the way the medical community has thought.

Newton’s earlier small study had found reduced heart mass and significantly reduced blood pumping by the heart, and Miwa in Japan has produced three studies showing that smaller hearts are present in people with chronic fatigue syndrome (ME/CFS).

Mirroring Dr. Cheney’s unpublished findings, both Newton and Miwa have also found reduced diastolic volume (30%).  The diastolic phase of the heart cycle is the filling phase. During diastole, the ventricles relax and then, in an energy intensive process, expand so that they can fill with oxygen enriched blood. Reduced diastolic volume or preload indicates that  the heart is not being filled as much as normal.

Both Newton’s and Miwa’s study published last year found significantly reduced diastolic volume and mass, stroke volume index and cardiac output.  (Miwa targeted and consistently found reduced left ventricular volume and density. He did not measure right ventricular functioning. He or she also appears to be the first Japanese researcher to drop the term CFS and use myalgic encephalomyelitis exclusively throughout the latest paper. )

The Study

Now Newton is back doing more tests with a much larger and better defined cohort (n=41 ME/CFS patients / 10 healthy controls).

Newton measured how much blood entered the heart during the diastolic phase (end-diastolic volume) and systolic phases (end-systolic volume) then how much it spate out (stroke volume). She also assessed the size or mass of the heart.

This time, suspecting that reduced blood volume played a role in the poor cardiac performances, she analyzed blood volume three ways: total blood volume (TV), red blood cell volume (RCV) and plasma volume (PV).

As before, Newton found reduced blood volume during both the diastolic and systolic phases of the heart cycle and not just minor reductions either; ME/CFS patients had a whopping 25% less blood entering their hearts than the healthy controls. They also had about 25% less stroke volume and index and almost 30% smaller heart mass.  These appear to be very large reductions in both heart mass and heart functioning in ME/CFS patients.

Blood pressure was affected as well; ME/CFS patients had significantly lower systolic (125-109) and diastolic (76-70) blood pressures than the healthy controls.  The reduced blood pressure and stroke volumes could result from the poor heart functioning or they could produce the poor heart functioning by not pushing the heart to work harder.

Dr. Cheney appears to believe that reduced heart energetics are interfering with the hearts ability to contract enough to accommodate the blood entering it.  Another possibility is that reductions in blood pressure have resulted in smaller hearts.

Another possibility is that there’s  something wrong with the vascular system leading to the heart which is reducing blood flows to the heart. Reduced blood flows would result in a smaller heart. That’s the option Dr. Newton appears to be most interested in.

Non Compliant Veins?

Dr. Newton questioned whether a problem with “venous compliance” was present.  Since 2/3rd’s of our blood is locked up in our veins the reduced diastolic volume or preload found in ME/CFS could reflect large amounts of blood that has somehow gotten stuck in our veins.

Venous compliance refers to the ability of veins to “push back” once they get extended with fluid. The more full of fluid they are, the more the veins should – like a rubber band that has been stretched – exert pressure on the fluid to  move. If ME/CFS patients veins are non-compliant; that is, if they’re kind of flaccid in response to filling they may not be moving the blood along as they should.

That could lead to reduced preload (reduced diastolic volume).
Venous compliance can be affected by a number of factors including vasodilators and vasoconstrictors, the muscle tone of the smooth muscle tissue, and the renin–angiotensin system. One wonders if connective tissue problems (eg Ehlers Danlos Syndrome) could come into play as well.

Blood Volume

The blood volume results were assessed according to the norms expected. Blood volume was lower in the ME/CFS patients, but perhaps not to the extent that might have been expected.  About half the ME/CFS patients had normal red blood cell volume and about half fell below the 95th percentile expected. About a third of ME/CFS patients had plasma volumes below the 95th percentile.

On the other hand, statistical analyses suggested that the reduced red blood volumes were strongly associated with reduced ventricular mass in ME/CFS.  That suggests the ventricles may be smaller they’re not getting as much blood as usual.

There’s quite a bit of increased interest in blood volume right now.  Medow’s study on the effects of saline solution on ME/CFS should be published soon. He is currently examining whether the World Health Organization’s oral rehydration formula could be helpful in ME/CFS. His ability to use phenylephrine to increase blood flows to the brain and completely knock out POTS during a tilt test was astonishing.

Dr. Newton proposes to increase the blood volumes of ME/CFS patients and see if the size of their heart’s increase to normal size.

Is Arnold Peckerman Smiling Somewhere?

Arnold Peckerman apparently passed away a couple of years ago but one wonders what he would be thinking of all this.  Peckerman, LeManca and others working at Dr.  Ben Natelson’s NIAID funded ME/CFS research center were hot on the trail of cardiovascular issues when NIAID pulled the plug on its ME/CFS research.

The group had produced some interesting results. The first heart study in 1999 showed increased heart rates and reduced blood flows during a tilt test and presaged the attention on orthostatic intolerance and POTS.  The declines in heart rates and blood pressure during a stressful cognitive test they found may have been the first indication that the autonomic nervous system was prone to poop out under stress.

In 2003 their finding that people with ME/CFS were trying as hard as healthy controls knocked the legs out from under a prominent psychological interpretation. Next, Peckerman showed that people with severe ME/CFS (but not moderate ME/CFS) had a significantly lower stroke volume than healthy controls. Then he showed that the blood pressure responses of ME/CFS patients were off during exercise.

Could reduced heart blood flows after exercise help explain post-exertional malaise?
These results were positive but it was the last study, whose results were never published, which was a potential game-changer.

An MD, Peckerman, had seen post exertional malaise in some of his heart patients after the blood flows through their hearts had been stunted. Peckerman, therefore, decided to measured heart functioning before and after exercise in ME/CFS.

It was a small study – just 16 ME/CFS patients and four healthy controls but the results were astounding, and if they had been published and held up could have produced a simple and effective exercise test. Peckerman didn’t measure VO2 max – he measured blood flows – and it didn’t take him two exhausting exercise tests to get his result; he simply measured heart blood flows at rest, had his subjects exercise, and then measured blood flows at rest again.

In 2003 at the American Physiological Association conference Peckerman reported that 13/16 ME/CFS patients had significantly reduced blood flows at rest after exercise.  WebMD ran a story titled “Tricky Heart May Cause Chronic Fatigue Syndrome” in which Peckerman, obviously no shrinking violet, stated that the reduction of blood flows he had seen was the very definition of heart failure.

An Emory cardiologist in the story agreed. The finding of reduced heart blood flows was, in fact, what he saw in people with serious heart disease:

 “Typically we see this in people with three-vessel heart disease. A drop in [blood pumped by the heart] during exercise is not a typical response. It is actually a marker of significant coronary artery obstruction.”

Dr. Natelson described being quite excited at the results but we now know that “heart failure” is not present in ME/CFS.  Heart failure is a progressive condition that ultimately ends in death for just about everyone who has it, and, the fact that ME/CFS patients were not dropping dead from heart failure puzzled both Peckerman and Miller.  They both recommended that further study be done.

The study was never published, however, and we don’t know why.  After one more study on ME/CFS – which did not find differences in cognition before or after exercise – Peckerman was done. He’d participated in 13 studies on ME/CFS and GWS and never published again.

The cardiovascular connection to ME/CFS has never died, however.  As noted above both Newton and Miwa have found significantly reduced blood flows and filling in their studies. It now appears that those issues probably reflect significant problems with the cardiovascular system not the heart.

The outstanding question remaining from Peckerman’s unpublished study, though, is what happened during exercise to so dramatically affect the blood flows to the hearts of his ME/CFS cohort the next day?   The vascular system in ME/CFS and FM is a subject that continues to fascinate.

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Unexpected findings & promoting monocausal claims, a cautionary tale

Posted on 06/30/2016 by wames

Article abstract:

Stories of serendipitous discoveries in medicine incorrectly imply that the path from an unexpected observation to major discovery is straightforward or guaranteed.

In this paper, I examine a case from the field of research about chronic fatigue syndrome (CFS). In Norway, an unexpected positive result during clinical care has led to the
development of a research programme into the potential for the immunosuppressant drug rituximab to relieve the symptoms of CFS. The media and public have taken up researchers’ speculations that their research results indicate a causal mechanism for CFS – consequently, patients now have great hope that ‘the cause’ of CFS has been found, and
thus, a cure is sure to follow.

I argue that a monocausal claim cannot be correctly asserted, either on the basis of the single case of an unexpected, although positive, result or on the basis of the empirical
research that has followed up on that result. Further, assertion and promotion of this claim will have specific harmful effects: it threatens to inappropriately narrow the scope of research on CFS, might misdirect research altogether, and could directly and indirectly harm patients.

Therefore, the CFS case presents a cautionary tale, illustrating the risks involved in drawing a theoretical hypothesis from an unexpected observation. Further, I draw attention to the tendency in contemporary clinical research with CFS to promote new research directions on the basis of reductive causal models of that syndrome.  Particularly, in the case of CFS research, underdetermination and causal complexity undermine the potential value of a monocausal claim.

In sum, when an unexpected finding occurs in clinical practice or medical research, the value of following up on that finding is to be found not in the projected value of a singular causal relationship inferred from the finding but rather in the process of research that follows.

Unexpected findings and promoting monocausal claims, a cautionary tale, by Samantha Marie Copeland in Journal of Evaluation in Clinical Practice [Published online 10 Jun 2016]

NB The Norwegian researchers have never made a ‘monocausal claim’ for CFS and there is no sign that research has been limited as a result of their speculation.

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