ATP production and heart function in Chronic Fatigue Syndrome

     Recent research by Dr. Jonathan Kerr of St George's University of London, Dr. Arnold Peckerman, a cardiopulmonary physiologist at the VA Medical Center in East Orange, New Jersey, and the Center for Disease Control in Atlanta, Georgia, has found credible evidence of serious measurable physical abnormalities in patients with Chronic Fatigue Syndrome (CFS).  These abnormalities include abnormalities in heart function and blood circulation, and abnormalities in gene expression in white blood cells.  The CDC has found genetic abnormalities in single nucleotide polymorphisms in brain cells that regulate metabolic and immune system response to stress, infection, and chemical exposure.  

     Dr. Kerr's team in London has discovered differences in blood proteins related to changes in gene expression that he hopes will lead to new treatments. "We have shown that a significant part of the pathogenesis resides in the white blood cells and in their activity," he says.  "It will open the door to development of pharmacological interventions."  Several of the genes identified by the team in CFS play important roles in mitochondria, the power factories of our cells. "The involvement of such genes does seem to fit with the fact that these patients lack energy and suffer from fatigue," Kerr says.  One of these gene products, EIF4G1, is involved in protein production in mitochondria.

     It has been theorized that CFS may result, in part, from an abnormality of the ability of mitochondria in human cells to produce energy, and this dysfunction produces a cascade of abnormal effects and symptoms which overload the patient's ability to function normally.  Below are excepts from a patient handout produced by Dr. Sarah Myhill, which expresses her theories about how CFS develops.  These new theories could help explain the general orthostatic intolerance and Postural Orthostatic Tachycardia Syndrome (POTS) many patients with CFS experience in terms of a combination of vasodilation of blood vessels due to neurological effects, and as an effect of heart muscle dysfunction (cardiomyopathy) caused by the abnormal cycling of ATP to ADP at the cellular level.  Her ideas are presented here to encourage further medical research to either prove or disprove these theories.  

CFS is Heart Failure Secondary to Mitochondrial Malfunction

By Sarah Myhill, MD

I think this is one of the most important handouts I have ever produced in terms of my understanding of CFS and what to do in order to recover. So please read this very carefully and several times over - because for many sufferers it contains the keys to unlock their illness.

Two papers have come to my notice recently which make great sense of both my clinical observations and also the idea that CFS is a symptom of mitochondrial failure. The two symptoms I am looking for in CFS to make the diagnosis are firstly very poor stamina and secondly, delayed fatigue. I think I can now explain these in terms of what is going on inside cells and the effects on major organs of the body (primarily the heart). More importantly, there are major implications for a test for CFS, and of course management and recovery.

If mitochondria (the little batteries found inside every cell in the body) do not work properly, then the energy supply to every cell in the body will be impaired. This includes the heart.

* Many of the symptoms of CFS could be explained by heart failure because the heart muscle cannot work properly.

* Cardiologists and other doctors are used to dealing with heart failure due to poor blood supply to the heart itself.

* In CFS the heart failure is caused by poor muscle function and therefore strictly speaking is a cardiomyopathy. This means the function of the heart will be very abnormal, but traditional tests of heart failure, such as ECG, ECHOs, angiograms etc, will be normal.

     Thanks to work by Arnold Peckerman, PhD, we now know that cardiac output in CFS patients is impaired.  Dr. Peckerman, a cardiopulmonary physiologist at the VA Medical Center in East Orange, New Jersey, published this groundbreaking article, “Abnormal Impedance Cardiography Predicts Symptom Severity in Chronic Fatigue Syndrome,” in 2003.1

See: http://www.cfids-cab.org/cfs-inform/Coicfs/peckerman.etal.03.pdf

     Dr. Paul Cheney, a pre-eminent U.S. researcher now focused on furthering the investigation of CFS heart dysfunction and treatment, has referred to this article as “The best, most important publication [about CFS] in 20 years."2]  Furthermore, the level of impairment correlates very closely to the level of disability in patients.  Dr. Peckerman was asked by the U.S. National Institutes of Health to develop a test for CFS in order to help them to judge the level of disability in patients claiming Social Security benefits.  Dr. Peckerman is a cardiologist, and on the basis that CFS presents with low blood pressure, low blood volume, and perfusion defects, he surmised CFS patients were in heart failure. To test this he came up with “Q scores.”

Q SCORES

"Q" stands for cardiac output in liters per minute, and this can be measured using a totally non-invasive method called Impedance Cardiography. This allows one to accurately measure cardiac output by measuring the electrical impedance across the chest wall. The greater the blood flow the less the impedance. This can be adjusted according to chest and body size to produce a reliable measurement (this is done using a standard algorithm). It is important to do this test in the upright position and again when supine (lying flat on your back). This is because cardiac output in healthy fit people will vary from 7 liters per min when supine to 5 liters per min when standing up. In healthy people this drop is not enough to affect function, but in CFS sufferers the drop may be from 5 liters lying down to 3.5 liters standing up. At this level the sufferer has a cardiac output which causes borderline organ failure.

This explains why CFS patients feel much better lying down. They have acceptable cardiac output lying down, but standing up they are in borderline heart and organ failure. CFS is therefore the symptom which prevents the patient developing complete heart failure. Actually, everyone feels more rested when they are sitting down with their feet up.  The subconscious has worked out that the heart has to work less hard when you are sitting down with your feet up, so we do so because we feel more comfortable.

SYMPTOMS OF CFS EXPLAINED

The job of the heart is to maintain blood pressure. If the blood pressure falls, organs start to fail. If the heart is working inadequately as a pump then the only way blood pressure can be sustained is by shutting down blood supply to organs. Organs are shut down in terms of priority - that is, the skin first, then muscles, followed by liver, gut, brain, and finally the heart, lung, and kidney. As these organ systems shut down, this creates further problems for the body in terms of toxic overload, susceptibility to viruses which damage mitochondria further, thus exacerbating all the problems of the CFS sufferer.

Effects on the skin

If you shut down the blood supply to the skin, this has two main effects.

*  The first is that the skin is responsible for controlling the temperature of the body. This means that CFS patients become intolerant of heat. If the body gets too hot then it cannot lose heat through the skin (because it has no blood supply) and the core temperature increases. The only way the body can compensate for this is by switching off the thyroid gland (which is responsible for the level of metabolic activity in the body and hence heat generation) - and so one gets a compensatory underactive thyroid. This alone worsens the problems of fatigue.

*  The second problem is that if the micro-circulation in the skin is shut down, then the body cannot sweat. Sweating is a major way through which toxins, particularly heavy metals, pesticides and volatile organic compounds, are excreted. Therefore the CFS sufferer's body is much better at accumulating toxins, which of course further damage mitochondria.

Symptoms in muscles

If the blood supply to muscles is impaired, then muscles quickly run out of oxygen when one starts to exercise. With no oxygen in the muscles the cells switch over to anaerobic metabolism, which produces lactic acid - and it is this that makes muscles ache so much.

As well as the above problem, muscles in the CFS patient have very poor stamina because the mitochondria which supply them with energy are malfunctioning.

Symptoms in the liver and gut

Poor blood supply to the gut results in inefficient digestion, poor production of digestive juices and leaky gut syndrome. Leaky gut syndrome causes many other problems such as allergies, autoimmunity, malabsorption, etc., which further compound the problems of CFS.

If liver circulation is inadequate, this will result in poor detoxification, not just of heavy metals, pesticides and volatile organic compounds, but also toxins produced as a result of fermentation in the gut, again further poisoning the mitochondria.

Effects on the brain

Last October I attended a conference sponsored by the late Dr. John Richardson. A Canadian physician - Byron Hyde - showed us some functional scans of the brains of CFS patients. If I had not known the diagnosis, I would have diagnosed strokes. This is because the blood supply to some area of the brain was so impaired.

The default is temporary, and with rest, blood supply recovers. However, this explains the multiplicity of brain symptoms [that CFS patients] suffer from, such as poor short term memory, difficulty multi-tasking, slow mental processing, and so on. Furthermore, brain cells are not particularly well stocked with mitochondria and therefore they run out of energy very quickly.

Effects on the heart

There are two effects on the heart.

*  The first effect of poor micro-circulation to the heart is disturbance of the electrical conductivity which causes dysrhythmias. Many patients with Chronic Fatigue Syndrome complain of palpitations, missed heart beats, or whatever. This is particularly the case in patients with poisoning by chemicals since the chemicals are also directly toxic to nerve cells.

*  The second obvious result is poor exercise tolerance. Heart muscle fatigues in just the same way that other muscles fatigue. Symptomatically this causes chest pain and fatigue. In the longer term it can cause heart valve defects because the muscles which normally hold the mitral valve open also fatigue.

The difference between this type of heart failure and medically recognized congestive cardiac failure is that patients with CFS protect themselves from organ failure because of their fatigue symptoms. Patients with congestive cardiac failure initially do not get fatigue and often present with organ failures such as kidney failure or overt heart failure. At present I do not know why there is this difference.

So patients with angina, high blood pressure, heart failure, cardiomyopathy, some valve defects, as well as patients with cardiac dysrhythmias, also have mitochondrial problems and will respond in the same way to nutritional therapies and detox therapies. This approach to treating heart disease is exactly the same, regardless of the conventional diagnosis.

Effects on lung and kidney

The lung and kidney are relatively protected against poor micro-circulation because they have the largest renin angiotensin system, which keeps the blood pressure up in these vital organs. Therefore, clinically one does not see patients with kidney failure or pulmonary hypoperfusion in CFS.

EXPLANATION OF THE FATIGUE PROBLEMS IN CFS PATIENTS

Energy to the body is supplied by mitochondria, which produce NAD (nicotinamide adenosine diphosphate) and ATP (adenosine triphosphate). These molecules are the “currency” of energy in the body. Almost all energy requiring processes in the body have to be “paid for” with NAD and ATP, but largely ATP. The reserves of ATP in cells are very small. At any one moment in heart muscle cells there is only enough ATP to last about 10 contractions. Thus the mitochondria have to be extremely good at re-cycling ATP to keep the cell constantly supplied with energy.

If the cell is not very efficient at re-cycling ATP, then the cell runs out of energy very quickly and this causes the symptoms of weakness and poor stamina. The cell literally has to “hibernate” and wait until more ATP has been manufactured.

Energy is produced when ATP (three phosphates) is converted into ADP (two phosphates). ADP is then re-cycled back through mitochondria to create more ATP for future energy production.

However, if the cell is pushed when there is no ATP about, then it will start to use ADP instead. The body can create energy from ADP to AMP (one phosphate), but the trouble is that AMP cannot be re-cycled. The only way that ADP can be regenerated is by making from fresh ingredients, but this takes days to do. This explains the delayed fatigue seen in Chronic Fatigue Syndrome.

To summarize: The basic pathology in CFS is slow re-cycling of ATP to ADP and back to ATP again. If patients push themselves and make more energy demands, then ADP is converted to AMP, which cannot be recycled, and it is this which is responsible for the delayed fatigue. This is because it takes the body several days to make fresh ATP from new ingredients. When patients overdo things and "hit a brick wall" this is because they have no ATP or ADP to function at all.

References:

1. “Abnormal Impedance Cardiography Predicts Symptom Severity in Chronic Fatigue Syndrome,” A. Peckerman, et al., The American Journal of Medical Sciences, 2003 Aug; 326(2):55-60.

2. “The Heart of the Matter,” by Carol Sieverling, at the website of the CFS & FM Support Group of Dallas-Fort Worth http://www.dfwcfids.org/medical/cheney/heart04.part1a.htm. Also, on September 9, 2006, the DFW Support Group hosted Dr. Cheney’s presentation of his treatment protocol and latest study findings. DVD recordings of the presentation are available for purchase at http://www.dfwcfids.org/videos/video200609cheney_about.shtml.

3. "The importance of the gastrointestinal system in the pathogenesis of heart failure."  Krack A, Sharma R, Figulla HR, Anker SD. Clinical Cardiology, NHLI, Imperial College School of Medicine, London, UK. Eur Heart J. 2005 Nov;26(22):2368-74. Epub 2005 Jun 24. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=AbstractPlus&list_uids=15980032&query_hl=1&itool=pubmed_docsum

4. Press releases on CDC and Peckerman research into CFS. http://home.att.net/~potsweb/cfs-news.html  -