This paper focuses on Dr. Cheney’s new theory of CFS as elucidated by Carol Sieverling which was based on edited versions of her visits with Dr. Cheney in the fall of 2004.
Dr. Cheney is a CFS physician of wide renown with a devoted following among his patients. He was among the first physicians on the scene of the Incline Village outbreak that brought CFS, in its latest iteration, to the attention of the world. Always an articulate advocate for the CFS patient and a notably pro-active and creative physician, he has dedicated his career to finding appropriate treatments for CFS.
A paper by Arnold Peckerman on cardiovascular functioning in CFS patients published, oddly enough, while Dr. Cheney himself was undergoing heart failure, lead to a dramatic re-orientation of Dr. Cheney’s approach to CFS (Peckerman et. al. 2003). Dr. Cheney has purchased, with the help of a grant, a impedance cardiography machine and has now made it and other measures of cardiovascular functioning an integral part of his examination.
In the Sieverling papers and in his videotapes Dr. Cheney has always raised provocative questions regarding the cause and treatment of CFS. Certainly none has been more provocative than his assertion that heart problems are fundamental to CFS.
His presentation, however, contains several inaccuracies, some of which are surprising in a physician of his stature; portions of Dr. Peckerman’s paper are misrepresented, some findings appeared to be inflated, few qualifying statements are ever made. This paper, which was undertaken to elucidate Dr. Cheney’s latest theories to CFS patients turned out to be more critique than celebration .
As noted above we are dealing with an edited transcript. Undoubtedly some qualifying statements and edifying explanations are missing. One must recognize, as well, that Dr. Cheney is speaking to a patient, not to a scientific colleague and his theories are inevitably simplified to make them understandable. In such a setting the intricacies of his thought could be easily lost.
This is, however, how Dr. Cheney chooses to have his thoughts communicated. They are not presented in the rigorous forum of a peer reviewed journal. Instead they are disseminated by papers such as these and through videotape presentations.
Neither of these forums permit Dr. Cheney to present his theories in a rigorous manner. Because of this they will always be open to some degree of misunderstanding, the origins of some his thoughts will remain obscure – and papers such as this one may be the result.
I am, to boot, just a layman just scuffing the surface of the medical sciences. I have no background in medicine or even human biology; the considerations noted below are of a patient not a physician or a researcher. No one pays me $540 an hour to treat them for CFS! .
Three Definitions (Stedman’s Electronic Medical Dictionary)
Cardiomyopathy – “Primary disease process of heart muscle in absence of a known underlying etiology” when referring to idiopathic cardiomyopathy.
Heart failure – 1. inadequacy of the heart so that as a pump it fails to maintain the circulation of blood, with the result that congestion and edema develop in the tissues; Syn: cardiac failure, congestive heart failure, cardiac insufficiency, myocardial insufficiency. 2. resulting clinical syndromes include shortness of breath or nonpitting edema, enlarged tender liver, engorged neck veins, and pulmonary rales in various combinations.
Heart attack (myocardial infarction)- infarction of an segment of the heart muscle, usually as a result of occlusion of a coronary artery. An infarction causes a deficiency of blood supply such that tissues dies (necrosis occurs). Note that heart failure (a disease process involving the heart muscle) differs greatly from heart attack – which usually occurs because of artery blockage not because of heart muscle failure. Accordingly the symptoms for heart failure and heart attack are strikingly different.
A central problem
Dr. Cheney believes CFS patients are in ‘heart failure’ but not a normal type of heart failure; “Let me first of all define heart failure. There are two kinds of heart failure. There’s the kind that any cardiologist can diagnose in about a minute. That you do not have. Which is why cardiologists missed this. What you have is Compensated Idiopathic Cardiomyopathy.”
The key problem Cheney must face by putting heart failure front and center in CFS is the lack of heart attack and overt heart failure even in long term CFS patients. Unlike the diseases of other organs, heart disease does not generally resolve; while it may be ameliorated or deflected by treatments or by the efforts the body makes to compensate for it, it is always progressive and often quickly so. “Heart failure is also generally associated with a very poor prognosis even when the symptoms are mild’ (Francis et.al. 2000).
CFS patients are not, however, dying of heart disease even 20 years after the disease burst onto the scene. As Cheney noted “I’ve been following CFS patients for 20 years and never seen one case of CFIDS go on to transplant’. Even longer term studies of neurasthenic patients in the early part of this century did not find increased levels of heart disease.
While there is a great deal of variation within the CFS patient community, CFS patients generally seem to slowly get better over time, not worse. Indeed in his three stages of disease progression Cheney suggests this happens more often than not.
Cheney, therefore, must find something that is giving CFS patients heart disease but is not giving them heart attacks or causing their hearts to overtly fail. According to Carol Sieverling he does this by first explaining what he believes to be the general cause of idiopathic cardiomyopathy and then producing an essential mechanism that prevents CFS patients with idiopathic cardiomyopathy from progressing other than very slowly with their disease. Essentially he believes CFS is a unique kind of idiopathic cardiomyopathy.
Outline of the argument
Cheney’s basic argument as elucidated by Carol Sieverling, at least as far as I understand it, is as follows:
- Idiopathic cardiomyopathy (IC) is caused by a process involving infection and/or heavy metals.
- During infection large amounts of nitric oxide (NO) are produced. During energy production superoxide (O2-) is produced. When NO and superoxide interact they produce a dangerous free radical peroxynitrite (NO+O2-=ONOO-)
- Heart cells damage from peroxynitrite is either responsible for or contributes greatly to idiopathic cardiomyopathy.
- Because CFS patients have low levels of the substance, glutathione peroxidase (GSH px), used to reduce superoxide, superoxide leaks out of their mitochondria. Because of ongoing inflammatory/infectious processes they also produce large amounts of NO. This means CFS patients have the potential to form large amounts of peroxynitrite (OONO-) and incur a great deal of tissue damage.
- The heart cell destruction in CFS is limited, however, because of low levels of a key antioxidant, glutathione peroxidase (GSH px), that is – according to the Gibb’s Free Energy equation – critical to the cells ability to produce ATP. This equation states that unless cells are able to detoxify the free radicals produced during energy production, free radicals will damage the mitochondria and reduce energy production.
- Because peroxynitrite production is basically a function of superoxide production, which, in turn, is a function of energy production, Cheney asserts that by inhibiting energy production, low levels of GSH px will also inhibit peroxynitrite production. Because peroxynitrite is the main agent of destruction in IC and CFS, halting peroxynitrite will largely halt the progression of heart failure in CFS.
Cheney readily admits he does not know the exact cause of the IC in CFS but he thinks it “takes a combination of a pathogen and the presence of a heavy metal like mercury”. He notes that “Idiopathic cardiomyopathy appears to be caused in the minds of most physicians by a post-viral infectious disorder” and that ‘a great deal of evidence now exists in cardiology literature… (that) heavy metals” are another important factor.
Heavy metals are an important factor in idiopathic cardiomyopathy – As evidence for this Dr. Cheney reports in some detail on a 2001 paper that found extraordinarily high levels of mercury and other heavy metals in the hearts of idiopathic cardiomyopathy patients but not in the hearts of patients with other heart problems (Frustaci et. al. 2001).
As intriguing as this paper was it appears to have been largely ignored by the cardiovascular research community. There has, in fact, been very little research into mercury’s effects on the heart.
While a PubMed search indicates there is research into the role heavy metals play in heart disease these almost invariably involve iron and copper. Since both iron and copper accelerate free radical and reactive oxygen species (ROS) production, they could fit in with Cheney’s theory that oxidative stress plays a key role in CFS.
Far from being wholly negative elements, however, a significant number of these papers examine the beneficial aspects of iron and copper supplementation in certain types of patients.
Do CFS patients have elevated levels of heavy metals in their bodies? A study on antioxidant levels in CFS found normal to low levels of iron but decreased levels of the substance, transferrin, is used to sequester iron (Keenoy et. al. 2001). That antioxidant levels, including urate were not low suggested that iron induced free radical production was not occurring.
Whether heavy metals are raised in CFS patients is a question that CFS physicians like Dr. Cheney are best be able to answer. Physicians associated with CFS often test their patients for heavy metals. They have their own sometimes immense data bases of information that never reach the pages of scientific journals.
Thus while there may be little evidence in the scientific journals on the effects of mercury or other heavy metals on CFS, Dr. Cheney’s clinical findings may (and probably do) indicate otherwise. Physicians often must operate ahead of the scientific curve and draw conclusions unsupported by formal research studies but supported by their own data.
A great deal of work has been done on cardiomyopathy but little, relatively speaking, has been spent elucidating the negative effects of heavy metals. Thus it does not appear that the research community in general believes heavy metals play a significant role in heart failure. However the dramatic effects some CFS patients can derive from heavy metal detoxification suggests heavy metals can play a role in CFS.
Peroxynitrite is a major factor in idiopathic cardiomyopathy and heart disease – Peroxynitrite plays the major role in Cheney’s theory. Most of the treatments he recommends concern ways to reduce either peroxynitrite itself or its precursor, nitric oxide. An inquiry into peroxynitrite’s role in IC and cardiac problems is found in A Guide to Cardiovascular Issues in CFS IVb: Peroxynitrite and the Heart.
Peroxynitrite is produced in CFS when glutathione peroxidase fails to break down superoxide -“Actually SOD breaks (peroxynitrite) down to H202 and then down to water via glutathione peroxidase. For the enzyme to break down superoxide properly, selenium is supposed to bind to glutathione peroxidase”
The problem for CFS patients apparently occurs when ” mercury displaces selenium at the binding site, (and) the function of the enzyme is knocked out. At that point you have no way to oxidize superoxide to water and superoxide starts to leak out.”
At first reading this seemed so incorrect it appeared an editing error was involved. Since it is superoxide dismutase (SOD), not GSH px that degrades superoxide, reduced GSH px levels should not result in increased superoxide (O2-) levels.
Since GSH px degrades hydrogen peroxide it is hydrogen peroxide levels not superoxide levels that should rise if mercury inhibits it. So long as SOD is functioning, except for the small amounts of superoxide that normally leak out of the mitochondria, superoxide levels should not be a problem.
The big proviso is ‘as long as SOD is functioning’. Although hydrogen peroxide is not a particularly reactive free radical, it can inhibit cytosolic SOD at higher levels (Vesala 2002). This reaction takes in several steps; first SOD loses a copper ion and produces superoxide.
In its next interaction with hydrogen peroxide, the altered SOD produces a very dangerous radical called the hydroxyl radical. If the amino acid histidine is present then SOD is inactivated when copper is split off of it (Vesala 2002).
(Interestingly, if carbon dioxide is around the enzyme will be returned to its original form but a carbonate radical is formed which can itself oxidize tyrosine and sulfhydryl groups.) It appears, then, that increased levels of hydrogen peroxide, in concert with low levels of carbon dioxide, can lead to impaired SOD activity and increased superoxide levels. (See the appendix for a possible connection between GSH px and heart disease).
*Update – A patient of Dr. Cheney’s has indicated that Dr. Cheney told him mercury can attack and disable both SOD and glutathione peroxidase.If SOD was inhibited this would lead to increased levels of superoxide and decreased levels of hydrogen peroxide. If this is so then why should we be worried about low levels of glutathione peroxidase? It turns out that glutathione is involved in more than the degradation of hydrogen peroxide. The master antioxidant of the cell, glutathione also detoxifies peroxynitrite. If superoxide levels rise and if nitric oxide is present then peroxynitrite production will occur.
There is another slant to this. Dr. Cheney has over the past few years been regularly having CFS patients take tests to see if they exhibit polymorphisms (mutations) in some of the genes involved in the immune system, in detoxification, in the cardiovascular system, etc. Most genes in the body come in a number of different forms or alleles.
Someone with a polymorphism has a slightly different form of a gene than is normally expressed in the population. A genes activity level or efficiency can be altered depending on which polymorphism is found. It is the recollection of Dr. Cheney’s patient that CFS patients often exhibit polymorphisms in one of the genes governing superoxide dismutase production.
Just to show how tricky the detoxification system is, it turns out that too much SOD or too little superoxide is dangerous as well. When superoxide pairs its free electron with the free electrons in some of the free radicals produced during lipid peroxidation, it acts, paradoxically enough, in a positive manner to terminate the lipid peroxidation process.
Since neither GSH px, Vit. C or E appear able to quench these particular free radicals, superoxide may, in fact, be an essential factor at one stage of this detoxification process. Thus while too much superoxide has very negative effects, an adequate supply of superoxide is absolutely necessary to good health.
Indeed, increased levels of the cytoplasmic form of SOD (CuZnSOD) have been implicated in Down’s syndrome. This kind of good guy/bad guy picture occurs often with regard to free radicals. As we will see in Part III of this series even peroxynitrite plays a positive role in certain situations.
Peroxynitrite formation in CFS is a function of mitochondrial superoxide formation and energy production “As long as superoxide stays in the mitochondria and never leaks out, there’s no way you will make peroxynitrite…..The primary driving force behind peroxynitrite is, in fact, the production of superoxide….peroxynitrite is purely a function of energy production.”
(One does not expect Dr. Cheney, great expounder that he is, to go through all the various means of peroxynitrite production in a patient conference. The statement made above (‘no way you will make peroxynitrite… peroxynitrite is purely a function of energy production’, however, is inaccurate.)
(1) Superoxide is not only produced in the mitochondria. There are two forms of superoxide dismustase, one (CuZnSOD) found in the cytoplasm and one found outside the cell. A great deal of superoxide formation during inflammation occurs outside of the mitochondria in the phagolysosomal membranes that house the NADPH oxidase complex in phagocytic cells.
Superoxide is also produced by other enzymes in the cell such as xanthine oxidase, lipoxygenase, nitric oxide synthase as well as hemoglobin. Macrophages and neutrophils use the free radicals they produce (including peroxynitrite) during this period to destroy pathogens and toxins.
Thus peroxynitrite production is not simply a byproduct of energy production.The question is whether this process is relevant for CFS patients?
Macrophages are the key players in atherosclerosis. Heart attack is, however, not the same as heart failure. Heart attack usually occurs when an occlusion in the arteries cuts off enough blood flow to the heart that some of the heart tissue dies.
Heart failure is a much more insidious disease that involves a disease of the heart muscle itself. The heart can be so damaged by a heart attack that it causes heart failure but most heart attacks are not caused by heart failure. In contrast to the suddenness of a heart attack, heart failure is usually diagnosed long before the spectre of a heart attack occurs.
Much of the data on peroxynitrite and the heart involves atherosclerosis (which leads to heart attack) and the ischemic-reperfusion process (which usually occurs after a heart attack). It does not appear, given the paucity of heart attacks in CFS patients, that these two processes occur with any frequency in CFS.
(2) In contrast to Dr. Cheney’s scenario of increased energy production causing increased peroxynitrite production the opposite can be true. Two scenario’s suggest increased peroxynitrite production can be a function of decreased energy production.
They involve not superoxide leaking out but nitric oxide ‘leaking in’. When nitric oxide is synthesized in high enough amounts during the immune response (iNOS) it is able to shut down energy production by binding with cytochrome c oxidase in the mitochondria.
This has been demonstrated in heart as well as other cells. The most intriguing part of this process is that when NO inhibits energy production, superoxide and H202 levels increase dramatically! This indicates high peroxynitrite levels appear to be inherent in the low energy state that accompanies high NO mitochondrial levels.
This would suggest CFS could be a state of high peroxynitrite production – as Pall envisions – not the state of limited peroxynitrite production Cheney envisions (Pall 2000). Since high NO levels are a major concern in CFS this seems to be a not unlikely scenario.
Pall also points out that tissue hypoxia (low oxygen levels) could also cause increased NO production in CFS. He notes that by increasing nitric oxide levels relative to oxygen levels, tissue hypoxia could easily result in increased superoxide and peroxynitrite levels. Several mechanisms in CFS (reduced Q, low blood volume, blood pooling) could result in low levels of tissue hypoxia.
(3) Peroxynitrite is also formed by endothelial (eNOS) or inducible nitric oxide synthase (iNOS) during ischemia/reperfusion episodes when they become depleted in essential co-factors and begin to create superoxide as well as nitric oxide. It is unclear at this point whether ischemia/reperfusion episodes occur in CFS.
Thus it appears that three scenarios may be occurring in CFS which could result in significant peroxynitrite production during or just following low energy states.
The Gibb’s Free Energy Equation and glutathione
Cheney believes CFS patients are limited from producing too much peroxynitrite because of the Gibbs Free Energy which equates low GSH levels with mitochondrial membrane damage; “the lack of glutathione will actually result in injury to the mitochondrial membrane (from superoxide) and a drop in ATP. That’s the Gibb’s Free Energy Equation which says glutathione concentration and ATP generation are intimately linked.”
Although the Gibbs Free Energy Equation/glutathione interaction has played a central role in Cheney’s theories for some time I have been unable to find any information on these two in the immense biological database PubMed or the Internet. The Gibbs free energy equation isG (Gibbs free energy), = H – TS, where H is the enthalpy (heat content) of a system, T the absolute temperature, and S the entropy.
It describes how ‘chemical reactions proceed spontaneously in the direction that involves a net decrease in the free energy of the system (i.e., !G less than 0)’ (Stedman’s Medical Dictionary). Cheney is likely talking about a application of the Gibb’s equation that is beyond my understanding.
Whatever it is it has not found a following in medical research. So far as I am able to tell Dr. Cheney is the first person to connect the Gibbs Free Energy equation with low glutathione levels.
Low glutathione levels in CFS?
Reduced glutathione (GSH) activity has been a key aspect of Dr. Cheney’s theories for many years but the evidence for such is lacking. Glutathione has, in recent years, become a well studied subject in CFS. The Krurup study found reduced levels of GSH but the abstract made no mention of a control group.
The Kennedy study found reduced levels of GSH in a subset of obese hyptensive CFS patient, a finding they suggested was related to obesity not CFS. The Manuel Study found reduced GSH readings in a subset of CFS patients. Three have studies found normal GSH reading. One (Jammes) found a tendency for increased GSH levels, two more (McGregor) found increased GSH levels in two studies examining blood erythrocytes. The
Glutathione contraindicated in CFS, mercury helpful?
Cheney’s belief that low glutathione levels are actually saving CFS patients can easily lead one to the peculiar conclusion that glutathione supplementation, long advocated by Dr. Cheney, would be detrimental to the health of CFS patients. After all he indicates that the Gibbs Free Energy equation – which states (somewhere?) that energy production is a function of glutathione levels – explains the ‘relative health’ of CFS patients.
Without those low glutathione levels – at least according to this paper – CFS patients would be producing a lot of peroxynitrite and dying of heart disease. It is intriguing that while Cheney argues an altered redox state is at the core of CFS he does not – at least in Carol Sieverling’s paper – suggest any means of increasing glutathione in the treatment section.
Yet what how could increasing glutathione activity be harmful? A Cheney patient has indicated that Dr. Cheney is concerned about the negative effects of increasing glutathione levels. Glutathione, the master antioxidant, is one of the chief peroxynitrite scavengers. If glutathione is scavenging peroxynitrite then why worry about superoxide?
Oddly enough since it is mercury that knocks out selenium, which then knocks out glutathione (and reduces energy levels), it actually appears that it is mercury, the very heavy metal Cheney posits is accumulating in the hearts of IC patients, that is preventing CFS patients from generating enough energy to enter the ‘death spiral’.
It is interesting given Cheney’s emphasis on the Frustaci paper and heavy metals that there is little talk of mercury detoxification in the treatment section of the paper.
A logical impasse?
If high levels of free radicals damage the mitochondrial membranes and thus shut down ATP production, how then does enough superoxide ever escape to produce much peroxynitrite production in anyone? Given the fatigue experienced by CFS patients it appears that very little energy production must be occurring.
If on the other hand one has enough glutathione then superoxide – according to this paper, anyway – is degraded and never leaks out. Either way, as Cheney asserts, the system appears to be self-limiting for CFS patients.
If peroxynitrite is a central agent in heart failure and if CFS patients are not progressing towards overt heart failure, one must conclude they are not producing much peroxynitrite. After all Dr. Cheney stated that when CFS patients stop making energy this ‘results in significant reduction in superoxide, and knocks out peroxynitrite.
Thus you cannot and will not advance (toward the event horizon…I couldn’t do that…and almost died’. (This suggests Dr. Cheney believes his heart failure was largely due to peroxynitrite production – a conclusion many cardiologists might not agree with given the many other processes that contribute to heart failure.)
One might question the focus of a treatment protocol on an issue that appears to be, for the most part, safely self-limiting anyway. If it was not should we not would see CFS patients commonly undergoing overt heart failure? Carol Sieverling’s paper suggests peroxynitrite cannot be the cause of BOTH the reduced energy production and the halt towards complete heart failure.
If peroxynitrite levels are low enough that they do not damage heart cells then it would be difficult to imagine they are high enough to limit energy production. This would seem to suggest some other oxidant such as superoxide must be responsible for the poor energy production seen.
It would seem that the way to safely increase energy production would be to increase both superoxide and peroxynitrite degradation. Yet it is the glutathione peroxidase depletion that Carol Sieverling’s report suggests Dr. Cheney believes is protective. With regard to this question the Sieverling paper seems incomplete.
Cheney has long stated he believes the low energy state in CFS may be protective. “This also brings into focus the idea that maybe fatigue isn’t as bad as we think it is. Sometimes fatigue could actually be a protective mechanism against damage from these toxins…..I call this the energy conundrum.
The energy deficit may actually be a defense mechanism as much as a problem in itself, and the real solution to the energy deficit is to get at the deeper problem (Cheney 2001)” This theory is apparently prompted by the negative effects that seemingly innocuous treatments often bring to CFS patients. Some CFS patients seem to be partially frozen into a state of limited energy and efforts to release them from that state must often be done slowly and carefully.
(This certainly brings up an interesting existential question – which would be better? – a debilitating disease (CFS) with no resolution but which appears to present little chance of death or a possibly fatal situation (idiopathic cardiomyopathy) that could be resolved at least somewhat satisfactorily?)
The ‘Event Horizon’ Cheney implies his heart disease is analogous to that suffered by CFS patients except that CFS patients do not cross the ‘event horizon’ and he did. The event horizon is reached when the heart is unable to maintain adequate circulation to itself and a vicious cycle of ever increasing destruction begins that culminates in heart failure.
Essentially Cheney suggests that over several decades, probably, at least some CFS patients will retrace the stages he went through over two or three years. Very few CFS patients apparently cross the Event Horizon because while they display evidence of going through the first four stages of dysfunction (skin, muscles, liver, gut) they don’t reach the stage at which the Event Horizon is crossed and the defective heart begins to inhibit its own circulation. Until CFS patients reach that stage they have not crossed the ‘event horizon’ that denotes eventual heart failure.
Cheney’s explanation of the Event Horizon, however, doesn’t appear at least at first, to exclude CFS patients at all. He states the Event Horizon is reached when ‘the microcirculation defect within the heart itself begins to impact ‘Q’ itself”.
He has already, however, stated low ‘Q’ is already a major component of CFS and that the more ‘disabled’ CFS patients are in heart failure. (“all disabled CFIDS patients…..have low ‘Q’ and are in heart failure.”). It would seem that Q has already been impacted by the heart.
It appears that Cheney believes that the initial viral attack was eventually either completely or almost completely resolved but that it left behind a damaged heart with an oxidative dysfunction. After that it appears it is the oxidative process that drives the pathogenic process in CFS. Thus while the low Q in CFS is caused by the heart it appears most of the damage to the heart occurs early in CFS. This is in line with Cheney’s prior theory.
Lerner has provided evidence for potentially heart damaging viral activity in some CFS patients and has found antiviral drug therapy useful in these patients. These patients, however, make up only a subset of CFS patients.
An ‘Appalling’ Attribution? – While Cheney acknowledges Pall in this paper, ‘By the way, all this is Pall’s model’, his theory appears to differ substantially from Pall in several points. Pall (2000) believes CFS is a disorder characterized by positive feedback loops that increase nitric oxide and peroxynitrite levels.
Cheney suggests that peroxynitrite production is inherently limited in CFS by reduced ATP production. By positing that the reduced peroxynitrite levels are the reason for the non-progression of heart failure in CFS patients, Cheney essentially suggests the numerous positive feedback cycles that Pall posits increase peroxynitrite in CFS patients are not operating.
It is, after all, because of the CFS patient’s ability to limit peroxynitrite formation that he/she is not after all advancing pell-mell toward the ‘Event Horizon’.
A non-vicious circle
In order to combat heart dysfunction in CFS Cheney focuses on reducing peroxynitrite levels in CFS. He asserts that because during low ATP production one of the chief scavengers of peroxynitrite, CO2, is also low, CFS patients are in the midst of a ‘vicious circle’. ‘Now if you keep lowering ATP production…….you also reduce the production of CO2. “The result is you have less and less primary defense against peroxynitrite. It’s a vicious circle…especially in the lowest energy states.”
Cheney has already said, however, that reduced ATP production inhibits peroxynitrite formation, and saves CFS patients. Thus at the same time CO2 is being limited so is peroxynitrite. A vicious circle occurs when in a positive feedback loop one negative factor enhances the production of another which, in turn, enhances the production of the first. Instead of a vicious circle this paper describes a scenario of mutual diminishment.
Heart failure in CFS is ‘hidden’
One of the biggest questions regarding Dr. Cheney’s theory of endemic heart failure in the more severely ill CFS patients appears to be the lack of symptom correlation between CFS patients and heart failure patients.
It is true that it is not uncommon for people in the first stages of heart failure to be unaware of it or display symptoms characteristic of it. (No one, on the other hand would say CFS patients are asymptomatic). But it is also true that the diagnosis of patients with more advanced heart failure – such as some of the more severely ill CFS patients must have, if Cheney is correct – is not a difficult one to make.
This is because heart failure can be diagnosed largely on a symptomatic basis. Despite all the complicated tests and machinery ‘heart failure remains largely a clinical or bedside diagnosis. There is no ‘gold standard’ laboratory test. The combination of a careful history (breathlessness, fatigue, fluid retention) and physical examination….is how one makes the diagnosis….There should be some direct evidence of structural heart disease and the echocardiogram is most useful in this regard. However it remains a clinical, bedside diagnosis’ (Francis et. al. 2000 ).
This is apparently because the symptom set in heart failure is quite distinctive. ‘The dominant and most recognizable symptom of congestive heart failure is ‘shortness of breath’ (Francis et. al 2000).. (Congestive heart failure appears to be the most common form of heart failure.
Breathlessness is also the major symptom of non-congestive heart failure.) Breathlessness is one of the things that produces the exercise intolerance in heart failure; when the patient attempts to exercise or even move around they get winded and have to stop. As their heart failure increases these patients can feel breathless even at rest or even as Cheney notes, when lying down.
“The other typical complaint is fatigue”. Other common symptoms include wheezing and coughing as well as nausea and vomiting and edema (bloating) in the extremities. Swelling of the ankles, particularly at days end, is often the first symptom that brings a patient into a physician’s office.
The veins of the neck are often distended and the upper right abdomen may ache. A cardiovascular examination often finds distinctive heart (‘gallop’, knock, murmurs, ‘heave’) and lung sounds (‘rales’). (These are all signs of blood backing up and causing problems either in the lungs or in the lower extremities.)
Interestingly the American Academy of Family Physicians recommends using the Valsalva Maneuver – a test that essentially requires one to blow hard while ones mouth is closed – to assess the possibility of systolic and diastolic dysfunction. The Valsalva Maneuver apparently is abnormal in a high percentage of heart failure patients. This test is usually normal in CFS patients (see Orthostatic Intolerance I: The Evidence).
These symptoms are distinctive enough that heart failure is ‘relatively straightforward to diagnose’ (Francis et. al. 2000).
Lerner, Peckerman and Cheney all theorize that heart dysfunction in CFS could account for many of the symptoms in CFS (Lerner 2003). They believe CFS patients portray symptoms of a more subtle heart failure – of a heart problem severe enough to dramatically effect the functioning of CFS patients but subtle enough to so far fly below the radar, so to speak, of most physicians.
As noted above, many people in the first stages of heart failure can, in fact, walk around largely symptom free, if the many compensatory mechanisms the body uses to make up for heart failure are working.
But there is a subset of CFS patients who, if Cheney’s theory is correct, should display overt signs of heart failure. If disability in CFS is indeed a function of low cardiac output and low cardiac output is caused by heart failure, then the very ill CFS patient – who, after all, display a level of disability that must match and probably exceeds that found in many patients with overt heart failure – should also display the classic symptoms of heart failure.
Of the four stages of heart failure these patients are in Stage Four. They are defined as “Patients with cardiac disease resulting in inability to carry on any physical activity without discomfort.”
There is little evidence that, however, that really severely ill CFS are often diagnosed with heart failure. There are many stories of CFS patients going from doctor to doctor and hospital to hospital trying in vain to find an answer for their affliction, only, after all the tests are done, and all the thousands and thousands of dollars are spent, to draw a blank.
Those with the resources go to foremost medical institutions of the world such as the Mayo Clinic. They get done all the tests the medical profession can provide. Yet after all the thumping and prodding and listening and sophisticated testing even severely ill CFS patients do not often appear to have been diagnosed with heart failure.
If they were then heart disease would be one of the diseases contraindicated in CFS; it would be on the ‘watch list’ of diseases that could mimic CFS, such as hypothyroidism.
Indeed CFS patients do not generally display most of the symptoms of heart failure. They do not commonly exhibit ‘breathlessness upon exertion”, nausea, vomiting, edema, upper right abdominal pain, extended neck veins or distinctive heart and lung sounds.
They do complain of extreme fatigue and exercise intolerance but also display a host of symptoms that are not characteristic of heart failure (sore throats, fevers, headaches, poor cognition, allergies, sensitivities, visual changes, etc.).
As noted above breathlessness upon exertion is one of the cardinal symptoms that immediately leads a physician to suspect heart failure. While the CDC definition of CFS does not have include breathlessness as a major symptom, the Canada definition which is much more inclusive and detailed does includes dyspnea (breathlessness) upon exertion as one of the symptoms associated with autonomic nervous dysfunction in CFS.
The exercise intolerance occurring in CFS, however, appears to be of an unusual form with the symptom exacerbation increasing sometimes for days rather than being immediately apparent This unusual process is not mentioned in symptom sets of heart failure.
Cheney, however, posits that the heart failure or heart dysfunction in CFS is of an entirely different type that manifests itself only when CFS patients are standing. Since most heart tests are done lying down he argues that they usually miss the heart dysfunction present in CFS.
This is a intriguing point. Most patients with heart failure have more trouble lying down than when standing. This is because the heart actually has to pump more blood when one is lying down. As heart failure reaches its terminal point heart failure patients are forced to stay standing 24 hours a day to prevent them from drowning in their own fluids.
It is my understanding that every type of heart failure patient eventually reaches this point; over time the inability of the heart to pump effectively causes blood to back up and flood the lungs. Nevertheless Cheney’s finding of increased heart dsyfunction while standing seems important and implies, at least to me, a laymen, that circulatory problems invoked during standing produce increased stress upon the heart.
The combination of low blood volume, problems with circulation and impaired heart functioning may lead the heart to exhibit the abnormalities seen during standing. Bear in mind this is a laymen’s speculation.
Thus while CFS patients do have symptoms in common with heart failure patients there are divergences both in type and degree. Since Dr. Cheney has proposed CFS patients have an atypical form of heart failure some divergence in the symptom sets might be expected.
It is unlikely, as well, that Dr. Cheney would suggest all the symptoms in CFS are due to heart failure; plainly other systems and other dysfunctions are involved in CFS. It will be intriguing to learn how Dr. Cheney reconciles the different symptom sets of the two diseases.
Confirming diastolic dysfunction
Of all the types of heart failure, diastolic heart failure, unfortunately is the most difficult to diagnose. (This is so typical for CFS – how quickly we enter into the gray area once again! Are we doomed to always inhabit it?) Diastolic heart failure is often assumed when exercise intolerance and shortness of breath is present but no lung disease or systolic abnormalities have been found. (Diastolic dysfunction often accompanies systolic dysfunction but can be separate from it.)
Diastolic heart failure is often confirmed when an echocardiography finds enlargement of the left ventricle (hypertrophy) and diastolic dysfunction. Apparently left ventricle hypertrophy is relatively easy to measure but ‘there is no agreement as to what constitutes abnormal diastolic dysfunction”.
Several indices suggest diastolic dysfunction (altered ventricular wall tension, decreased left ventricular distension, altered ventricular wall motion, flow velocity) but according to Hurst’s The Heart, one of the standard reference texts on the the heart, since these measures are influenced by so many factors (loading conditions, ischemia, age, heart rate) it is apparently difficult to tell how much diastolic dysfunction contributes to heart failure.
The ‘recognition, evaluation and treatment of diastolic heart failure remains an obvious challenge (Francis et. al. 2000), (See an expanded version of this subject in Cardiovascular Issues in CFS IV: Diastolic Heart Failure, An Overview.)
The critical question for most CFS patients at this point is, however, simply whether they have heart failure and echocardiography is the “most important imaging tool for evaluating patients with symptoms of heart failure” (Francis et. al. 2000). Echocardiographs are effective at evaluating left ventricular size, mass and function (Out of the gray area into the clear skies we go).
While some measures of echocardiography are open to interpretation, these measures of echocardiography appear to be objective enough to be accepted by all.
Compensation for heart failure
Cheney believes it is not necessarily the degree of heart damage that is necessarily so important in determining how well or ill a CFS patient is, it is largely how well they compensate for it that does. ‘Almost everyone with CFIDS has compensated Idiopathic Cardiomyopathy. It’s the degree of compensation that varies. Some compensate very well, others less so.”
Indeed, compensatory mechanisms to maintain circulation to the tissues are underway in everyone with heart failure or heart problems. Whether or not they are present in CFS patients appears to provide another indirect check of how common heart failure is in CFS.
If CFS have heart failure then they should display the compensatory mechanisms that come with it. (Interestingly while these compensatory mechanisms have short term benefits they are all damaging to the heart in long run. They are designed to maintain blood pressure and blood perfusion to the tissues, not to enhance the heart’s health.
Most of the pharmacological drugs used in treating heart failure attempt to cancel out the negative effects of the way the body compensates for low cardiac output.) Among others these compensatory mechanisms include:
- Altered autonomic nervous system activity
- Activation of the renin-aldosterone-angiotensin system.
- Enlargement or dilatation of the heart muscle.
Autonomic nervous system activity (ANS)
The ANS is the main regulator of heart function. The ANS attempts to compensate for heart failure by increased sympathetic activity (‘fight or flight’) and decreased parasympathetic nervous system (‘rest and digest’) activity.
This can be seen in increased norepinephrine levels, reduced heart rate variability (see Orthostatic intolerance I) and increased muscle sympathetic nerve activity (MSNA) (Kaye and Esler 2005). CFS patients appear to exhibit ALL these findings (Bonyhay and Freeman 2004, Naschitz, et al. 2003, Stewart 2003, 2004).
Beta blockers, however, which are an accepted treatment for autonomic dysfunction in heart failure patients often have extremely negative side effects in CFS patients. This suggests a different kind of ANS dysfunction could be involved in CFS. Since the type of heart failure CFS patients have – if indeed they do commonly display it – is apparently distinctive type, this would, perhaps, not be surprising.
Renin-angiotensin/ blood volume
If CFS patients have idiopathic diastolic cardiomyopathy then they have problems with ‘preload’. (Preload is the pressure on the walls of the left ventricule when it is at maximum volume just before it contracts. A key problem in diastolic dysfunction is greatly increased left ventricular pressure.)
Because the main regulator of blood volume, the renin-aldersterone-angiotensin (RAA) system, is activated in heart failure, blood volume usually increases. (Because increased blood volume, however, increases preload, reducing RAA activity is one of the major pharmaceutical interventions taken in heart failure.)
Instead of increased RAA activity and increased blood volume, however, there is evidence that a substantial subset of CFS patients have not only have reduced blood volume but a profoundly impaired renin-angiotensin system (Raj et. al. 2005).
A recent study by Stewart suggested, however, that CFS patients with postural tachycardia syndrome may indeed have increased angiotensin II levels that indirectly lead to the vascular problems seen in those patients.
Heart muscle changes
The changes evident in heart muscle structure seen during echocardiography occur as heart cells attempt to compensate (lengthen, widen) when the heart is overloaded. As they lengthen and widen the heart displays hypertrophy (is enlarged).
The studies have not been done to verify whether this is so in CFS. Dr. Cheney is apparently having at least some of this patients undergo echocardiographies which will be able to detect structural abnormalities of the heart.
Thus there is evidence both for and against the supposition that CFS patients typically display compensatory mechanisms that make up for the heart failure they may have undergone.
Stages of compromise
The Sieverling paper states Cheney believes the low cardiac output of the CFS patient results in stages of reduced tissue perfusion that proceed in a logical fashion. Since the most vital organs have the first priority in blood perfusion Cheney posits that the lesser organs such as the skin and muscles are first effected.
Thus the skin and the muscles are the first to go in CFS, followed by the liver and the gut, then the brain, heart, lungs and finally the kidneys. Notably Dr. Cheney suggests that as CFS patients get sicker and sicker they apparently trace in reverse the stages he went through as he healed after he received his heart transplant.
Based on this progression all it seems logical that all CFS patients should first have symptoms characteristic of reduced skin microcirculation, most CFS patients should have fatigue associated with low blood muscle flows, those with more severe CFS should have liver/gut problems, followed by cognitive problems, etc., etc.
Cheney believes an interference with temperature regulation is the first consequence of reduced skin circulation in CFS. Most CFS patient do indeed appear to have problems with temperature regulation but there is little evidence, however, for the compensatory hypothyroidism Cheney posits results from this.
Because hypothyroidism can mimic many of the symptoms of CFS, thyroid levels in CFS patients are frequently checked in order to ensure CFS patients do not have hypothyroidism, an eminently treatable condition. It may be that Cheney is referring to a sort of ‘hidden’ hypothyroidism but this is speculation that is unaddressed by the Sieverling paper.
Cheney’s idea that reduced skin microcirculation leads to volatile organic chemical (VOC) accumulations in the fat cells and therefore MCS in CFS patients flies in the face of the leading theories of MCS causation. Almost all theories of MCS published in the past five years posit that, in one way or another, exquisitely sensitized neural networks are cause of MCS (Clauw 2001, Miller 2001, Gilbert 2001, Winder 2002, Sorg and Newlin 2002, Gilbert 2001).
Nor is MCS simply the result of high toxin stores in the body as Dr. Cheney appears to imply. Just because sauna therapy helps reduce the chemical loads and symptoms of people with MCS doesn’t mean increased chemical loads are the cause of MCS. MCS patients do not always have increased chemical loads.
It is the exquisite sensitization to even very small amounts of chemicals that makes the difference in MCS. Dr. Rea tells his patients that even after the completion of sauna therapy if they return to the same environment they will relapse.
After weeks of demanding sauna therapy these patients will typically have very low levels of chemicals in their system yet they are still at risk for MCS. Nor do diseases of severely impaired circulation such as diabetes, Raynaud’s disease or indeed heart failure lead to increased rates of MCS. If they did then MCS would be a legitimate disease in the eyes of the medical profession..
It is important to note as well that some recent studies have found, increased rather than decreased skin circulation in CFS patients (Spence et. al. 2004). There is also evidence of reduced skin microcirculation in one subset of CFS patients (see Orthostatic Intolerance in CFS II – Types).
Dr. Cheney is the first to suggest, however, that the reason for it lies in the heart . Finally, if the skin is the first organ ‘to go’ in CFS, and MCS is a logical outcome of reduced skin circulation, then one could assume that virtually all CFS patients should have MCS. Instead while MCS is undoubtedly a great deal more common in CFS than in the general population, it does not appear to commonly occur even in CFS.
Any reader who has been able to make it through this long paper is aware that I have many doubts regarding the efficacy of Dr. Cheney’s latest theory. I did not expect this paper to turn out this way.
A former patient of Dr. Cheney’s I plunged into this examination full of enthusiasm for the new opening he appeared to provide into CFS. What appear to be some mischaracterizations, some of which are noted in A Guide to Cardiovascular Issues in CFS: Part I – Testing the Heart, Stroke Volume, Future Research, as well as what appear to me – a layman – to be questionable conclusions have, however, dampened my enthusiasm. I must re-iterate again I am just a laymen! Please take this discussion with as many grains of salt as it deserves.
If doing this paper left me with anything it was questions. How could Dr. Cheney know what the process is behind the idiopathic cardiomyopathy he believes his patients have? Idiopathic cardiomyopathy is heart disease of unknown origin. This is a disease, after all, that many researchers – some whom have spent their entire careers in the field – have trouble explaining.
Could halting idiopathic cardiomyopathy really just boil down just to inhibiting peroxynitrite? It’s possible that I am simple unable to penetrate the depths of Dr. Cheney’s thought. It is also very possible, that the edited transcript Carol Sieverling produced cannot do justice to his thought. Still I had many more questions about Dr. Cheney’s theory than any other I have encountered in my studies of CFS research.
While these papers raised several questions for me regarding Dr. Cheney’s new theory they do not impact on any findings regarding low cardiac output and should not impact on the findings Cheney is expected to announce in his June 2005 presentation.
While physicians and researchers have differed in their assessment of the severity and the causes of low cardiac output in CFS patients, there seems to be little doubt that at least a subset of CFS patients do exhibit low cardiac output and therefore suffer from chronically low circulation.
Since Dr. Cheney is recommending his patients undergo echocardiography and other tests of cardiac function he will very quickly obtain quite a bit of data on the type and extent of structural abnormalities and/or problems with left ventricular dysfunction in CFS.
If, has been suggested by his patients, he is indeed finding extensive abnormalities his latest report will likely indicate many CFS patients have a heart dysfunction. Identifying the extent of these dysfunctions and explaining why they have occurred and how to treat them should become an an important part of CFS research.
While Dr. Cheney is a highly effective communicator, if he is committed to re-orienting research priorities in the CFS research field it will be important that he publish a paper in a peer-reviewed journal.
GSH px – a vital role in heart disease?
The idea that reduced selenium/GSH px levels play a role in cardiomyopathy first came up in a 1993 study that indicated rats feed a selenium deficient diet had an increased risk of, among other things (muscular dystrophy, cancers, infertility), cardiomyopathy. Because selenium is an important co-factor for GSH px, this was proposed to be due to reduced GSH px levels.
As selenium is a co-factor for other proteins than GSH px a series of studies attempted to pin down the cause of the abnormalities seen. A 1997 study that developed GSH px null mice (mice with no GSH px) found, surprisingly, that they exhibited normal development and no abnormalities were found in any organs, including the heart, in red blood cell counts or even in indices of oxidative stress (tissue carbonyl, malondialdehyde, 4-hydroxynenol).
Even more surprising given GSH px’s role in the cell, rates of hydrogen peroxide degradation were not lower either. The authors concluded that cardiomyopathy’s resulting from selenium deficiency did not involve GSH px.
A second study in 2000 using these same GSH px1 null mice examined the role GSH px1 reductions played in mitochondrial free radical levels. It found that while the mitochondria in liver cells in the GSH px1 null mice had higher levels of free radicals, those in the heart cells did not.
An examination of three different measures of ATP production found reduced ATP production in the liver cells of GSH px1 null mice, but once again, not in the heart cells. They concluded that “GSH p1 is not a major factor in protecting heart mitochondria against oxidative stress” (Esposito et. al. 2000).
(Interestingly there was no indication either of increased mitochondria membrane permeability or of the opening of the mitochondrial permeability transition pore (MPTP) even in the liver cells. Opening of the MPTP is often associated with cell death.
Thus even though ATP production in the liver cells was reduced by about 30% by free radicals, there was still no damage to the mitochondrial membranes. Just as a side note, the GSH px null mice – in contrast to the tendency in CFS patients – were underweight.)
To mix things up a bit a 2002 study by another group using heterozygous GSH px mice (+/-) found these mice displayed worsened diastolic function (but normal coronary blood flow), significantly increased isoprostane levels (increased oxidative stress) and structural changes in the heart muscle.)
Interestingly, these mice exhibited a bizarre response to acetylcholine; instead of dilating their arterioles constricted. Constricting the arteries instead of dilating them would seem to be a good way to cut off blood flow to the heart.
- A Guide to Cardiovascular Issues in CFS: Part I – Testing the Heart, Stroke Volume, Future Research
- Cardiovascular Issues in CFS/ME Part III: Assessing Diastolic Heart Failure
- A Guide to Cardiovascular Issues in Chronic Fatigue Syndrome Part IVa: Superoxide and the Heart
- A Guide to Cardiovascular Issues in CFS IVb: Peroxynitrite and the Heart
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