Salut à tous,
Je vous copie/colle ici un texte très intéressante qui aborde un aspect majeur de nos pathologies: le dysfonctionnement des mitochondries, aboutissant a des perturbations cardiaques qui vont ensuite progressivement dérégler les moindres aspects de nos corps. Même si c'est un fait connu que les mitochondries sont affaiblies et au ralentis dans nos pathologies environementales, la vision sous cet angle causatif et les effets boules de neiges expliqués sont vraiment intéréssants.
Cela rejoint et complète également les autres aspects majeurs deja expliqués sur le forum: la baisse de température corporelle (qui ralenti tous les processus du corps via la baisse d'activité enzymatique), ainsi que l'excès de composés oxidants de la théorie "NO/ONOO-" (monoxyde d'azote et peroxinitrite). Au final ces trois aspects sont interépendants et doivent être pris en compte de manière très sérieuse et approfondie par chacun d'entre nous!
Dès que j'ai un moment je m'ocuperais d'ailleurs d'intégrer cet aspect dans le chapitre 2 de mon ebook, car a mes yeux il s'agit bien la d'un élément causatif de premier ordre pour bcp de monde, et donc un verrou clé a connaitre et a traiter.
Pti gars
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Introduction
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!
A very useful analogy is to think of the body as a car. What supplies the energy and the power to make that car work is the engine. Effectively mitochondria are the engines of our cells - they supply the energy necessary for all cellular processes to take place.
We are made up of lots of different cells - heart, blood, muscle nerve cells etc. All these cells are different because they all have a different job of work to do. To do this job of work requires energy. But the way in which energy is supplied is the same for every cell in the body. Indeed all animals share this same system. The mitochondria in my dog, my cat and my horse are exactly the same as mine. Mitochondria are a common biological unit across the animal kingdom. Energy is supplied to cells by mitochondria which I think of as little engines which power every cell in the body.
Chronic fatigue syndrome is the symptom caused by mitochondrial failure
The job of mitochondria is to supply energy in the form of ATP (adenosine triphosphate). This is the universal currency of energy. It can be used for all sorts of biochemical jobs from muscle contraction to hormone production. When mitochondria fail, this results in poor supply of ATP, so cells go slow because they do not have the energy supply to function at a normal speed. This means that all bodily functions go slow.
Every cell in the body can be affected
The following explains what happens inside each cell:
ATP (3 phosphates) is converted to ADP (2 phosphates) with the release of energy for work. ADP passes into the mitochondria where ATP is remade by oxidative phosphorylation (ie a phosphate group is stuck on). ATP recycles approximately every 10 seconds in a normal person - if this goes slow, then the cell goes slow and so the person goes slow and clinically has poor stamina ie CFS.
Problems arise when the system is stressed. If the CFS sufferer asks for energy faster than he can supply it, (and actually most CFS sufferers are doing this most of the time!) ATP is converted to ADP faster than it can be recycled. This means there is a build up of ADP. Some ADP is inevitably shunted into adenosine monophosphate (AMP -1 phosphate). But this creates a real problem, indeed a metabolic disaster, because AMP, largely speaking, cannot be recycled and is lost in urine.
Indeed this is the biological basis of poor stamina. One can only go at the rate at which mitochondria can produce ATP. If mitochondria go slow, stamina is poor.
If ATP levels drop as a result of leakage of AMP, the body then has to make brand new ATP. ATP can be made very quickly from a sugar D-ribose, but D-ribose is only slowly made from glucose (via the pentose phosphate shunt for those clever biochemists out there!). This takes anything from one to four days. So this is the biological basis for delayed fatigue.
However there is another problem. If the body is very short of ATP, it can make a very small amount of ATP directly from glucose by converting it into lactic acid. This is exactly what many CFS sufferers do and indeed we know that CFS sufferers readily switch into anaerobic metabolism. However this results in two serious problems - lactic acid quickly builds up especially in muscles to cause pain, heaviness, aching and soreness ("lactic acid burn"), secondly no glucose is available in order to make D-ribose! So new ATP cannot be easily made when you are really run down. Recovery takes days!
When mitochondria function well, as the person rests following exertion, lactic acid is quickly converted back to glucose (via-pyruvate) and the lactic burn disappears. But this is an energy requiring process! Glucose to lactic acid produces two molecules of ATP for the body to use, but the reverse process requires six molecules of ATP. If there is no ATP available, and this is of course what happens as mitochondria fail, then the lactic acid may persist for many minutes, or indeed hours causing great pain. (for the biochemists, this reverse process takes place in the liver and is called the Cori cycle).
Treatment package for failing mitochondria
The biological basis of treatment is therefore explained:
Pace - do not use up energy faster than your mitos can supply it.
Feed the mitochondria - supply the raw material necessary for the mitochondria to heal themselves and work efficiently. This means feeding the mitos correctly so they can heal and repair.
Address the underlying causes as to why mitochondria have been damaged. This must also be put in place to prevent ongoing damage to mitos. In order of importance this involves:
Pacing activities to avoid undue stress to mitos
Getting excellent sleep so mitos can repair
Excellent nutrition with respect to:
taking a good range of micronutrient supplements
stabilising blood sugar levels
identifying allergies to foods
Detoxifying to unload heavy metals, pesticides, drugs, social poisons (alcohol,tobacco etc) and volatile organic compounds, all of which which poison mitos.
Addressing the common problem of hyperventilation
Address the secondary damage caused by mitochondrial failure such as immune disturbances resulting in allergies and autoimmunity, poor digestive function, hormone gland failure, slow liver detoxification.
And now for a bit of good news! AMP can be recycled, but slowly. Interestingly, the enzyme which does this (cyclic AMP) is activated by caffeine! So the perfect pick-me-up for CFS sufferers could be a real black organic coffee with a teaspoon of D-ribose!
A Vital Test in Chronic Fatigue Syndrome
The central problem of chronic fatigue syndrome is mitochondrial failure resulting in poor production of ATP. ATP is the currency of energy in the body and if the production of this is impaired then all cellular processes will go slow. It is not good enough to measure absolute levels of ATP in cells since this will simply reflect how well rested the sufferer is. The perfect test is to measure the rate at which ATP is recycled in cells and this test has now been developed by John McLaren Howard. He calls it "ATP profiles". It is a test of mitochondrial function.
Not only does this test measure the rate at which ATP is made, it also looks at where the problem lies. Production of ATP is highly dependent on magnesium status and the first part of the test studies this aspect.
The second aspect of the test measures the efficiency with which ATP is made from ADP. If this is abnormal then this could be as a result of magnesium deficiency, of low levels of Co-enzyme Q10, low levels of vitamin B3 (NAD) or of acetyl L-carnitine.
The third possibility is that the protein which transports ATP and ADP across mitochondrial membrane is impaired and this is also measured.
The joy of the ATP profiles test is that we now have an objective test of chronic fatigue syndrome which clearly shows this illness has a physical basis. This test clearly shows that cognitive behaviour therapy, graded exercise and anti-depressants are irrelevant in addressing the root cause of this illness.
To get the full picture I recommend combining this test with measuring levels of Co-enzyme Q10, SODase, Glutathione Peroxidase, L-carnitine, NAD and cell-free DNA. Cell free DNA is very useful because it reflects severity of the illness. When cells are damaged and die, they release their contents into the blood stream - cell free DNA measures the extent of this damage. The levels which come back are similar to those from patients recovering from major infections, trauma, surgery or chemotherapy - so this test puts CFS firmly in the realms of major organic pathology. SODase is an important antioxidant which mops up the free radicals produced in all the inefficient chemical reactions in the cells. Dr John McLaren-Howard has recently developed a serum L-carnitine test and made it available in September 2009. I have now included it in the Mitochondrial Function Profile (http://drmyhill.co.uk/wiki/Mitochondria ... on_Profile)
One other important co-factor in the production of energy in cells is D-ribose. It is used up so quickly by cells that measuring levels is unhelpful, but low levels of ATP imply low levels of D-ribose.
CFS is low cardiac output secondary to mitochondrial malfunction
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 is 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 engines 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 Dr Arnold Peckerman www.cfids-cab.org/cfs-inform/Coicfs/pec ... tal.03.pdf we now know that cardiac output in CFS patients is impaired. Furthermore the level of impairment correlates very closely to the level of disability in patients. Dr Peckerman was asked by the US 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. Peckerman is a cardiologist and on the basis that CFS patients suffer 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" stands for cardiac output in litres per minute and this can be measured using a totally non-invasive method called Impedence Cardiography. This allows one to accurately measure cardiac output by measuring the electrical impedence 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 when supine and again in the upright position. This is because cardiac output in healthy people will vary from 7 litres per min when lying down to 5 litres per min when standing. In healthy people this drop is not enough to affect function. But in CFS sufferers the drop may be from 5 litres lying down to 3.5 litres 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!
Low cardiac output explains the symptoms of CFS
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, i.e. 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. This is called POTS postural orthostatic tachycardia syndrome
Dr Paul Cheney has explored this further with his work with cardiac output in CFS - see Dr Cheney on heart function
Chest pain
This is a common symptom in CFS. Chest pain results when energy delivery to the muscles is impaired. There is a switch to anaerobic metabolism, lactic acid is produced and this results in the symptom of angina. Doctors recognise one cause ie poor blood supply, ie the supply of fuel and oxygen is impeded. However this fuel and oxygen has to be converted to ATP by mitochondria, so if this is slow, the same symptom of angina will result.
One molecule of sugar, when burnt aerobically by mitochondria, will produce 36 molecules of ATP. In anaerobic metabolism, only 2 molecules of ATP are produced. This is very inefficient and lactic acid builds up quickly. The problem is that to convert lactic acid back to sugar (pyruvate) 6 molecules of ATP are needed (the Cori cycle). So in CFS the chest pain is longer lasting because this conversion back is so slow. Clinically this does not look like typical angina. Many patients are told they have non-typical chest pain with the implication that nothing is wrong! Actually they have mitochondrial filure in the heart.
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. This 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
In October 2007 I attended a conference sponsored by the late Dr John Richardson. A Canadian physician Dr 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 suffered 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 recognised 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.
This approach to treating Heart Disease is exactly the same regardlees of the conventionaol diagnosis.
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.
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 firstly produce NAD (nicotinamide adenosine diphosphate) from Kreb's citric acid cycle and this is used to power oxidative phosphorylation which generates 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 ten 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.
In producing energy, ATP (three phosphates) is converted into ADP (two phosphates) and ADP is re-cycled back through mitochondria to produce ATP. However, if the cell is pushed (ie stressed) 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.
So to summarise, 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.
Implications for Treatment
Many patients I see get well with my standard work up with respect to vitamins and minerals, diet, pacing and sleep. However many need the specific package of supplements, to further support mitochondria which includes D-ribose, CoQ10, acetyl-l-carnitine, NAD, magnesium and B12 injections. All these things must be put in place to repair and prevent ongoing damage to mitochondria so allowing them to recover. For mitochondria to recover they need all the essential vitamins, minerals, essential fatty acids and amino acids to manufacture the cellular machinery to restore normal function. The mitochondrial function tests then allow us to identify lesions which can be corrected by attention to nutritional supplements, improving antioxidant status, detoxing, hyperventilation or whatever. CFS sufferers have limited reserves of physical, mental and emotional energy and this test allows us to direct those energies into the most fruitful line of approach.
Clinically the above issues mean that there are two clear stages of fatigue:
1) Mild chronic fatigue syndrome - in mild fatigue there is mild failure of mitochondria. If mitochondria go slow then cells go slow. If cells go slow then organs go slow. The body will become generally less efficient. So for example somebody mildly affected would not be able to increase their fitness - if they try to exercise they would quickly switch into lactic acid metabolism and would be forced to stop. Indeed we now know that mitochondria are responsible for controlling the normal ageing process. Therefore many of the symptoms and diseases associated with ageing are actually the result of mitochondrial function declining. Indeed many of these ageing diseases have now been attributed to mitochondrial failure such as loss of tissues (loss of muscle bulk), organ failures, neurodegenerative conditions, heart disease and cancer. Many symptoms which are attributed to ageing are due to mitochondria. It is not that we can stop the mitochondria from ageing, but we can certainly slow it all down using good nutrition, good diet, freedom from toxic stress, healthy lifestyles and so on.
2) Severe chronic fatigue syndrome - in severe chronic fatigue all the above factors apply. However, there is an additional problem. The most metabolically demanding organ in the body is the heart and if mitochondria cannot supply the heart with sufficient energy then the heart will go into a low output state. This compounds the problem of all mitochondria. If the heart is in a low output state then blood supply is poor and therefore the fuel and oxygen necessary for the engine to work are also impaired. So this compounds all the above problems and makes them proceed even more quickly and people end up with greater disability.
I suspect it is a combination of the underlying poor mitochondrial function, which then suddenly becomes critical when it comes to cardiac output, which precipitates a much more severe illness in someone who is already compromised.
Source: http://drmyhill.co.uk/wiki/CFS_-_The_Ce ... al_Failure
MELODIE
Maladies Environnementales, Les Options: Detoxification Immunité Energétique
Dysfonctionnement des mitochondries, une clé majeure
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Dysfonctionnement des mitochondries, une clé majeure
de un_ptit_gars » Lun 29 Avr 2013 13:15
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Re: Dysfonctionnement des mitochondries, une clé majeure
de un_ptit_gars » Lun 29 Avr 2013 14:35
Top Priority: Blood Pressure
"Now there is one factor that I want to mention before I get into the data display. Natelson requires, as a rule, before you're allowed into his medical school for study (whether it's this particular study or any other study) that you consider coming off of all medications and all nutraceuticals or he may not see you. Furthermore, his team is not treatment oriented."
Patient responds: "Well, I certainly wouldn't agree to do that. I'd be a wreck."
Dr. Cheney continues: "Of course you wouldn't agree. Therefore, the data I'm about to present is not anywhere near as bad as you are." You are more severely affected than anyone in this study. I'm not sure he has patients from the truly severe end of the spectrum of CFS. Those patients don't participate in studies. Just reflect on that as I go through this.
In this study, the normal person and the non-disabled CFIDS patient pump 7 liters a minute through their heart with very little variance: 7 liters plus or minus .5. When they stand up, they drop all the way down to 5 liters per minute, a full 30% drop in output. That's normal.
"First of all, why does it go down when you stand up? Because the heart can only pump as much blood as returns to it. If you drop the return by 2 liters per minute, you will always drop the output by 2 liters per minute. The blood has to go uphill against gravity, so there's an automatic 2 liter per minute drop in return, and therefore an automatic 2 liter drop in output even though the heart is completely normal. Where does that extra 2 liters go? It's pooled in your lower extremities and capacitance vessels. Rapidly, by the way." [Capacitance vessels are the larger veins of the body where most of the blood volume is found and where regional blood volume is regulated. For a great explanation of the circulatory system, including the different types of veins and arteries and their respective functions, go to www.cvphysiology.com/Blood%20Pressure/BP019.htm.]
Why don't normal people sense that 30% drop in output? You might assume that their blood pressure would fall 30% and they'd sense it. Nevertheless, their blood pressure either stays normal or goes up when they stand. Blood pressure is so vitally important that the body compensates to prevent blood pressure from dropping.
Think about how significant blood pressure is. Physicians are allowed by law to pronounce people dead. That's a lot of power. And how do we do that? Think about the movies. They always check for a pulse—blood pressure. No pulse—you're dead. And, of course, they check to see if you're breathing. However, if you don't have a pulse and aren't breathing, you'll be pronounced dead. Doctors don't even have to check for brain activity.
Why does the law give doctors such power? Because there's never been an exception to this rule. No breath, no pulse, you're dead. No exceptions—unless you're ice cold. "It points to how important blood pressure is to the body, because blood pressure is, in fact, life. And so, your body will defend your blood pressure beyond anything else. Or, to put it another way, it will sacrifice everything—even your brain—to keep the pulse going."
Nozzles
"Now, when your Q (total blood volume the heart pump iin one minute) drops 30%, your pressure will not drop, because your body will defend that pressure, even to the loss of your brain. This is critical to understanding what happens in CFIDS patients." [Let's use an analogy from gardening.] "Here's the hose attached to a spigot at the side of the house. I have the spigot turned fully counterclockwise [on] and it has maximum Q at 7 liters per minute coming out of that hose. Because it's coming out fast enough, there's enough pressure for this water to shoot out of the hose and I can water all the plants out there, all the way out to the 4th row tomato plants, 6 feet beyond this hose. So, I can sit there and water all day long providing sufficient nutrients and stuff to the plants, because I have adequate Q.
"Now let's take the knob and crank it down so that we drop it down from 7 liters to 5. That would be a normal drop on standing up. The pressure should drop at least 30% or more, but doesn't. Why?" Because, if you turn the flow down, the water can't get out to the tomato plants anymore. There's not enough pressure and it's just dribbling out, so what do I do? I take my thumb and I press it on the end to partially block it and create backpressure. That builds the pressure back up sufficiently to allow that stream of water to shoot out at sufficient velocity to water the tomato plants in the 4th row—even though I had a 30% drop in (cardiac) output. Because my thumb gets tired, I put a nozzle on the end of the hose and tighten it down so I can spray all the way out there at a low Q [pressure]. That's what a nozzle is for.
And you have a nozzle in you. It's called the end arteriole or resistance vessel. It regulates the resistance against which flow occurs to keep your pressure within normal range—despite a large fluctuation in Q produced by standing up or laying down. Because I can maintain the pressure, I can water the plants all the way out to the tomato plants in the fourth row regardless of the Q, because the pressure is maintained.
Now, let's crank it to down to 50%, taking it from 7 liters per minute, all the way down to 3.5 liters per minute. I still have the same nozzle attached but when I drop the flow to 3.5 liters, I can't reach the tomato plants, unless I really tighten down on the nozzle. Moreover, if I tighten it all the way down just a little tiny spray spits out. Maybe only a drop or two will reach all the way out to the tomato plants. Now I'm sacrificing water perfusion of the plants in order to maintain pressure, because without blood pressure you're dead. [Perfusion: the injection of fluid into a blood vessel in order to reach an organ or tissues, usually to supply nutrients and oxygen.]
When faced with a low Q, the body sacrifices tissue perfusion in order to maintain blood pressure, and that's all you need to know to understand this concept. Microcirculation to the tissues of the body is sacrificed to maintain blood pressure so you will not die in the face of a low Q, and that is what is going on in the disabled CFIDS patient.
In Peckerman's study, the data of the disabled CFIDS patients reveals that when they are supine (laying down), their Q is 5 liters per minute. So laying down they can perfuse out to the extremities, but admittedly not as much volume gets out there as would occur at 7 [the Q of the controls and mild CFIDS patients when laying down], but there's enough volume that you are really not that badly affected.
Let's look at what happens when the disabled CFS patients stand up. They drop to 3.7 liters per minute, a 50% drop from the normal of 7, and that means they can't water the tomato plants! The tomato plants start to shrivel up and experience trouble. Big trouble! At 3.7 liters per minute, they do not have adequate Q to function. There will be a functiovnal contraction [lowering of what you are able to do] determined by the drop in Q. The lower the "Q" goes from there, the more in bed you will be, because lying down is the only time you come close to sufficient Q.
Patient asks: "So basically, the tomato plants are all the organs and tissues in the body?"
Dr. Cheney replies: "Yes!"
And those "severe" patients in the study who dropped to 3.7 liters per minute would be mild or moderately ill patients in my practice. How do I know that? I know it by virtue of their pressure changes and their heart rate changes. Look particularly at the MAP (mean arterial pressure)—MAP is the average of your systolic and diastolic pressure. If your blood pressure is 120 over 80, your MAP is 100. All groups in the study had virtually the same MAP when they stood. There is no real difference in the MAP of the controls and the patients in this paper. That's not true in my practice. My patients are virtually always lower than normal. Same for their heart rates.
Sacrificial Prioritization
Now here's an important, critical idea. The body does not sacrifice tissue perfusion equally across all organ systems. It prioritizes the order of sacrifice, and you can see the progression of your disease in this prioritization.
The heart pumps out blood to the artery and the artery produces blood pressure. It pumps down to the smallest arteriole called the resistance vessel, which we will call the nozzle. The nozzle then breaks out into a capillary bed that delivers a certain capillary pressure to the tissues. In the human body, every cell in your body is within 1 millimeter of a capillary, (except in cartilage, periosteal bone and the cornea). Then, the blood returns to the heart via the veins, the venous return.
"There are two organ systems that have a super nozzle in addition to the main nozzle. They have a super built-in nozzle—it's called the Renin Angiotension System, or RAS. It's built into two organs: the lung and the kidneys. They have the greatest nozzle in the body. They can spit water out all the way to the tomato plants with practically no Q at all; they just need a little bit. They can sustain the greatest degree of Q problems, because they have this extra fancy nozzle, the Renin Angiotension System."
Additionally, the heart and the brain also have secondary nozzles. Although not as powerful as the RAS, these secondary nozzles protect that tissue even in the face of extremely low Q. Therefore, the lung, the brain, the kidneys, and the heart are a little bit more protected than the liver, gut, muscles and skin from a drop in Q.
First Compromised: Skin and Compensatory Hypothyroidism
Having said this, in what order are things sacrificed and what are the consequences? The first is the skin. If you sacrifice the microcirculation of the skin, several problems can arise. One is that without adequate microcirculation to the skin, the body cannot thermoregulate anymore. [Thermoregulate: regulate body temperature]
You cannot stand heat or cold, although heat will be more difficult at first than cold—in part because if you're too cold you just put on more clothes, but how do you rip your skin off when you get too hot? If your core temperature rises high enough, you will not sleep and your body will activate your immune system. In order to regulate that problem, your body will kick in thyroid regulation and you will downregulate [reduce or suppress a response to a stimulus] your thyroid to keep your temperature from going too high, and you will develop "compensatory hypothyroidism"! Now you will have trouble with cold.
The second thing your body will not be able to do is get rid of VOCs (Volatile Organic Compounds), which are shed in the skin's oil ducts. VOCs build up in the fat stores of your body and you become progressively chemically poisoned by whatever is present in your environment, and whatever you are genetically susceptible to—different things in different people. If that's pretty significant, we call that Multiple Chemical Sensitivities (MCS). If all you've got is microcirculatory deficiency of the skin, we'll call that MCS and the treatment is to put you in a sauna to outgas you—to detoxify you—which is in fact the primary treatment of MCS patients. We'll also exercise you, which is another MCS treatment.
Next Up: Muscles
If it gets worse than that, the next thing you'll sacrifice are your muscles. You'll have exercise intolerance—you can't go up stairs or climb mountains as easily. When you move your muscles, you feel like you got hit by a ten-ton truck. Very minor activity on day one produces a day two on which you say, "What did I do, it's almost like I ran a marathon."
If it gets still worse, you begin to get fibromyalgic pain. If it affects the joints, it may precipitate pyrophosphoric acid and uric acid crystals and you start to have arthralgias and myalgias linked to this microcirculatory defect. Microcirculation problems have been suggested by Fibromyalgia research in Toronto. Moldofsky tried to induce FM symptoms by interrupting the sleep of study participants and was successful with a significant number of the women. It was harder to induce clinical FM in men, and almost impossible in male athletes. It came down to microcirculation. Men had a higher capillary cross-sectional area (more capillaries) than women. Athletes have more than non-athletes. Male athletes are therefore more resistant to microcirculatory problems within the muscles, whereas sedentary women are the most vulnerable. Microcirculatory problems will be much worse for sedentary women because such problems are modified by the capillary cross-sectional area. Low cardiac output further exacerbates microcirculatory problems.
Third System Down: Liver/Gut
The next thing affected is your liver/gut. Probably the very first thing you'll notice is that there are fewer and fewer foods you can tolerate. If it gets really bad, there will be only a handful of foods you'll be able to eat—for a lot of odd reasons. In part because microcirculation is necessary for proper digestion. Also, your body won't secrete digestive juices so you won't digest your food. If you can't digest your food you'll get peptides that are only partially digested and highly immune-reactive. They'll leak out of your gut [into your bloodstream] and you'll get food allergies and/or sensitivities.
Your body will also fail to detoxify your gut ecology, so your gut will begin to poison you. That's manifested as feeling yucky and a sense of toxic malaise. You get diarrhea, constipation, flatulence, and all kinds of GI problems, including bacterial overgrowth, yeast overgrowth, parasitic overgrowth.
It's a problem because you have poor microcirculation. If it gets worse, you'll get malabsorption syndromes because the nutrients that are—by some miracle—digested, are not absorbed well because there's no microcirculation. At which point, you will begin to become increasingly toxic, which can manifest as a variety of skin disturbances, and you don't feel good, and other interesting things—particularly in the brain.
Fourth Affected: The Brain
In the brain, there's a devastating effect with respect to liver/gut dysfunction—it can quickly toxify the brain. That's perceived initially as, "I only have problems when I have to use my brain." Then it becomes a problem even when you don't use your brain that much. You have all kinds of cognitive complaints like memory disturbance and processing speed. Then you begin to get central brain structures that can destabilize you psychiatrically. You can get hypothalamic structures that begin to destabilize you from an autonomic nervous system perspective and/or neuroendocrine response defects. [neuroendocrine: the interaction between the nervous system and the hormones of the endocrine glands] Whatever the brain does, it doesn't do it as well.
The brain and the heart probably get hit about the same time, but patients usually notice their brain being affected much earlier than their heart. That's because heart muscle cells have the greatest mitochondrial content of any tissue in the body. Thus, when mitochondria are impaired, the heart muscle has the greatest reserve and is the least vulnerable. Neurons have far less mitochondria and they run out long before the heart, especially if you're sedentary. If you're sedentary there's not too much demand on your heart, but you can still think and make great demands on your brain. Energy is energy, whether it's being used physically or cognitively. The effect on the brain is noticed first because it has less reserve, especially if you're thinking—unless you do meditation. Patients who are both sedentary and meditating regularly may actually preserve their brain longer than those who are just sedentary and use their brain a lot.
Fifth: Heart—A Two-Parter
Part A: Manifestation of Microcirculatory Impairment
The effect on the heart has an "a" part and a "b" part. "The initial manifestation of microcirculatory impairment of the heart is arrhythmia. What kind? You name it, you've got it."
"You'll also notice, again, exercise intolerance, because the heart is indeed a muscle just like your leg muscle. When you go up flights of stairs or up mountainsides, you need more cardiac output and you can't sustain it. Therefore, you're going to have trouble. As it gets worse, you'll begin to see mitral valve prolapse (MVP) because that inadequate capillary function affects the papillary muscle and results in prolapse of the mitral valve. Finally, when you get even more severe microcirculation problems, you start to get chest pain as you begin to knock off myocardial cells [heart muscle cells] because they can't get adequate oxygen."
Part B: "The Event Horizon"
"And finally you get to the 'B' part of the heart, and I'll put a line here [on one of many drawings] which I'll call the Event Horizon, after a movie I saw by that name. 'Event Horizon' is a movie in which a group of space explorers discovers a black hole. They park their space vessel outside the event horizon because if they pass that line they can't get back, and if they pass it they're drawn down into a vortex into the black hole and vanish from this universe."
"The Event Horizon with respect to the heart is this: when the microcirculation defect within the heart itself (produced by a low Q), begins to impact Q itself, you enter a vicious cycle. Microcirculation impairment reduces the Q, which produces more microcirculation impairment which produces even more Q problems, and back and forth, zigzagging into a vortex, and down you go "through the Event Horizon" to the next phase of cardiac failure, which is the lung."
Sixth System: Lung & Kidney
"Cardiac failure in the lung produces Congestive Heart Failure (CHF) and Pulmonary Edema. Then comes the kidney—because remember the kidney and lung have the super-duper RAS system. So the last to go turns out to be the kidney which has the biggest RAS system of all buried in its cells, the Renin Angiotension System. When the kidneys go, you go into renal failure, which combined with the liver, is often dubbed hepatorenal failure, and that is the requisite cause of death due to Idiopathic Cardiomyopathy." [After crossing the Event Horizon and spiraling down into Congestive Heart Failure]. I've been there and done that. I'm an expert on that particular journey. And this is the exact sequence I went through over a two—to three-year time period."
The Good News: CFIDS Prevents Us from Crossing the Event Horizon
"You'll notice that the last things afflicted are the lung and the kidney because they have the RAS, and therefore you really have to cross the Event Horizon to involve those. I crossed it. One third of all cases of ICM cross it, and once you cross it, there's no turning back. You either die or get a transplant. There is no turning back."
"Now, for some interesting reason, CFIDS patients do not cross the Event Horizon, at least in any significant way. We don't see them in Pulmonary Edema; we don't see them in renal failure; and, we certainly don't see them needing a transplant. Therefore there is something about this disease that keeps you from progressing across the Event Horizon, though you can get cardiac involvement in the milder sense."
Since no CFIDS patient that I've ever known or heard about has crossed the Event Horizon, I maintain that this means that CFIDS must prevent it from happening in the first place. I crossed the Event Horizon and spiraled down because I did not have CFIDS. You have CFIDS; therefore, you're very unlikely to cross the Event Horizon, which doesn't mean that you won't over time. Peckerman believes that a certain percentage of CFIDS patients are headed right for that. However, they may take a long, long time, or die of something else before that happens.
Almost everyone with CFIDS has Compensated Idiopathic Cardiomyopathy [based on the test results he's getting]. It's the degree of compensation that varies. Some compensate very well, others less so. How will you know if you eventually lose your ability to compensate and cross the event horizon? You'll know it because you'll lie down and you'll be short of breath. When you lie down you'll no longer be able to breathe. Rather than lying down and feeling better, you'll lie flat and get short of breath. Then you know you've crossed over.
Recovery Takes Time
When I had my heart replaced, one of the first things that came back was my kidneys. My brain came back, but slowly. Even though my cardiac output was a whopping 10 liters per minute with the transplant, my brain did not come back fully for 6 to 7 months. Even then, there was continued progression for about four more months before I reached near 100% or greater. In fact, what's interesting is that I now think my brain is functioning at a much higher level than has been present since I was 20. That's interesting because age 20 is when you see 10 liters per minute output. The point is that, at some interesting level, brain functionality depends on microcirculation and when you have sufficient amounts of it, you have excellent brain function.
The next thing that came back was my liver/gut; I couldn't stop eating, and my gut functioned perfectly. Then, my muscles started to come back and that took 8 months. Interestingly, my skin took a long time. So, my body resuscitated in reverse order. "It's taken me over a year to fully come back despite an almost instantaneous restoration of Q, which was my only problem in the first place."
"Which speaks to something very important, and that is, fundamental therapy does not instantaneously result in improvement. As a matter of fact, anything that would improve you within a matter of minutes, hours, or days is, in fact, not therapy at all. It is palliation—symptom suppression—which in fact may not be helping you at all."
Marshall Protocol & "Q"
My hat is off to Trevor Marshall for identifying that the Renin Angiotensin System (RAS) is a key element in the pathology of this disease and pointing out that it acts locally as well as systemically. I didn't know that before. But I'm concerned that an ARB (Angiotensin Receptor Blocker) is being used in CFIDS patients without an awareness of its effect on "Q."
Angiotensin II has two receptors that we know of, and we only understand the first, AT1. When Angiotensin II binds to AT1, it increases the hormone Aldosterone, which in turn increases blood volume. Big issue! If you block AT1 with an ARB [like Benicar], down will go your Aldosterone, and down will go your blood volume, and you could be in a heap of trouble. ARBs that bind to AT1 will constrict blood volume.
I'm also concerned that the other receptor [AT2] is being ignored. No one knows what it does. Not even Merck! I suspect that it has an immune effect. An ARB like Benicar selectively binds very tightly to AT1, resulting in a two—to three-fold increase of Angiotensin II, which then binds to the wide-open AT2 receptor. And who knows what kind of immune responses that is setting off. This is just speculation, but I am concerned.
"I don't believe that you can block a regulatory pathway, especially tightly, with a rebound upregulation of Angiotensin II, two or three fold, when you leave unblocked an unexplained receptor that you have no idea what that thing is doing and then hope that down the road everything will be rosy."
Etiology (Cause)
What is the etiology, the cause, of this cardiac output problem? The short version is that cardiac muscles have lost power because their mitochondria are dysfunctional. They're not functioning well because of a redox-state problem. [Redox: a reversible chemical reaction in which one reaction is an oxidation and the reverse is a reduction. Look for a future article explaining redox states.] But, what causes the redox-state problem? I don't know. I just know that, like MCS and GWS and many other illnesses, we're looking at a redox-state problem. But, there's something unique about CFIDS, because this redox problem seems centered on the heart. It's not focused on the heart, at least to the extent that we can tell, in these other disorders. But there is one big, big clue. It ties in to what we know about Idiopathic Cardiomyopathy (ICM), so we need to look at that first. It may shed some light on CFIDS-linked cardiomyopathy.
Viruses
According to the textbook of medicine, the list of things associated with cardiomyopathy is as long as your arm and covers three pages. But most of the things listed are infectious diseases, and viruses are at the top of the list. ICM appears to be caused, in the minds of most physicians, by a post-viral infectious disorder that evolves following a viral infection, sometimes at a relatively young age. Doesn't that sound a little bit like CFIDS?
Heavy Metals
The second thing that is mentioned, for which a great deal of evidence now exists in cardiology literature, including recent publications in the Journal of American Cardiology, is heavy metals. This is the big, big clue I referred to earlier. There's an Italian article published in one of the cardiology journals about a link between ICM and mercury. The authors looked at about 13 cases of ICM, 24 cases of other types of heart disease, and 4 controls. They biopsied the heart muscle of all the participants and radiated it with neutron flux to make any heavy metals radioactive. Then they put the tissue in a chromatograph to determine with great precision exactly how many molecules of mercury were in each of the tissues.
What they found was astounding. All 13 cases of ICM had 23,000 times more mercury than the controls, and 18,000 times more than the other types of heart disease. One hundred percent of the people with ICM were mercury toxic at the tissue level. Does that necessarily mean that the cause of ICM is mercury? Or, is mercury linked to some other phenomena?
A professor at the University of Kentucky whom I greatly admire analyzed that data. He determined that in normal heart muscle there are not enough mercury-binding sites to have that much mercury. He said the only way you could load that much mercury into the heart muscle was if something else carried it in. There may be a cardiotropic pathogen and/or an immune-system dysregulation associated with a cardiotropic pathogen that is required to load that much mercury into the heart. [Cardio: heart; tropic: affinity for, or influencing]
I doubt the cardiotropic pathogen by itself can produce ICM. I think takes a combination of a pathogen and the presence of a heavy metal like mercury.
The Nexus: Virus/Bacteria/Toxins/Allergies and Heavy Metals
I believe that the proximate etiology of cardiomyopathy is a nexus between an infectious, allergic, or toxic experience, as well as heavy metals. I'll go through why I think that, but I'm not claiming I know the exact cause. I'm just claiming that, based on the medical literature on cardiomyopathy as well as what we know about CFIDS, I would lay my wagers on those two entities, and I think they both may be required, not just one. That's why I call it a nexus between the two, and you'll see why. Because the underlying issues for the etiology of a Q loss need those two entities to really get going."
Pall: Nitric Oxide + Superoxide = Peroxynitrite
The pathophysiology [functional changes that accompany a disease] at the cellular level that underpins this pathophysiologic state is well elucidated by Martin Pall. [A search for "Martin Pall" on immunesupport.com will produce several articles.]
One nitric oxide molecule plus one superoxide molecule equals one peroxynitrite molecule. Peroxynitrite is a reactive oxygen species, is deadly, and highly damaging. At the cellular level, it is the proximate cause of human mortality. Even if you are healthy and your body handles peroxynitrite as well as possible, you will still die of old age.
"These molecules [nitric oxide and superoxide] have to be generated because they are essential for life. They are the end products of a complex scheme of oxidation reactions in the human body; necessary for, among other things, energy generation, and their production is inevitable. Indeed, if they weren't produced you would not be alive. But because they are produced, you will die of oxidation. If you live by the sword, you die by the sword. If you live by oxidation then, like any piece of iron set in an oxygen environment, you will eventually rust away, and we call that death by old age. This is called 'The Free Radical Theory of Aging.' "
What do humans die of, usually? The top killer is Coronary Artery Disease [CAD], and the next is cancer. It turns out that CAD and cancer are also driven in part by peroxynitrite formation. Neurodegenerative diseases like Parkinson's and Alzheimer's are also suspected of being driven by free radical formation. Even suicide is increasingly thought to be generated by oxidative stress in the central nervous system. And, of course, MS and autoimmune diseases. And finally ICM, the path down which you seem to be going, though halted by CFS itself.
But your path deviated right here, just above the Event Horizon to CFS, and you went down the CFS path for a very interesting reason. Why didn't you go down the cancer or MS or Parkinson's pathway? For some reason you started down the CFS pathway over those, and I think that's a result of preordained genetics and environmental influences that combined in a unique fashion to produce that particular road I went down—the ICM pathway. But I could not deviate [from the ICM path] because I never developed CFIDS and I went straight to a near-death experience and came back.
I want to talk a little bit about these two guys [nitric oxide and superoxide], show you why they're necessary and that you have to make them, and how they can modulate your disease process. Especially how they're related to etiology. [They cause many, if not most, of our symptoms—directly or indirectly.]
Nitric Oxide is made by iNOS, eNOS, and nNOS, so far identified. [The small letter in front indicates the source.] The iNOS is of particular interest because it comes from the immune system. When any kind of virus, bacteria, mold, toxin, microbe, or allergy activates your immune system, it induces iNOS, which makes copious amounts of Nitric Oxide. iNOS can make far more Nitric Oxide than eNOS and nNOS can ever make.
eNOS is made by the endothelial cells in the blood vessels and is responsible for regulating microcirculation, basically.
nNOS is made in neurons and is responsible for memory and learning. It is also, when highly activated, very much responsible for MCS, EMR sensitivity [electromagnetic radiation], light and noise sensitivity, and can make sleep difficult. Over-activation also amplifies pain.
Your body has to make nitric oxide. If you don't make it, you have no immune system, no circulation, no brain. The question isn't do you make it; the question is do you make a lot of it. If you make a lot of it there can be repercussions downstream. What those repercussions are depends on what you're [your body is] doing with superoxide.
Now superoxide is produced by the act of making energy [ATP]. It's made in the mitochondria, and for every molecule of ATP generated, you generate one molecule of superoxide—one for one. The more energy you make, the more superoxide you make. However, superoxide is generally found inside the mitochondria. Generally. Nitric oxide is found outside the mitochondria. As long as superoxide stays in the mitochondria and never leaks out, there's no way you will make peroxynitrite, because it takes one nitric oxide plus one superoxide to make one molecule of peroxynitrite.
A Little Math
Now, let's stop here for a moment to talk about the coupling effect. If I have 50 molecules of nitric oxide, and five molecules of superoxide have leaked out of the mitochondria, how many peroxynitrite molecules do I generate? Five. If I make 10,000 nitric oxide molecules, and only 5 superoxide, how many peroxynitrite molecules do I generate? Again, five! Do you see what is happening? What dictates peroxynitrite is not the one with the highest amount, but rather the one with the lowest.
Super Oxide—Out of Control
Therefore, the primary driving force behind peroxynitrite is in fact the production of superoxide. However, if superoxide is well controlled, peroxynitrite formation is limited. However, if superoxide is out of control, there are few limits to the formation of peroxynitrite. It's purely a function of energy production. The more energy you produce, the higher the peroxynitrite may go, especially if nitric oxide is also out of control.
If everything worked as intended, the mitochondria would take in oxygen and nutrition, and output carbon dioxide, water, and ATP (energy). You have enzyme systems embedded in the mitochondria that can break superoxide down to water to prevent superoxide from leaking out of the mitochondria. One enzyme system is called Superoxide Dismutase (SOD). Actually, the enzyme breaks it down to hydrogen peroxide and then down to water, via Glutathione Peroxidase, which depends on selenium and glutathione. [Without proper amounts of selenium and glutathione, the enzyme cannot do its job.]
For the enzyme [SOD] to break superoxide down properly, selenium is supposed to bind to Glutathione Peroxidase. However, if mercury is present in any amount and you have no defense against it [and there are defenses], it competes for that binding site and blocks the selenium. When mercury displaces selenium at the binding site, the function of that enzyme is knocked out. At that point, you have no way to oxidize superoxide down to water, and superoxide starts to leak out contributing to the formation of deadly peroxynitrite. How much superoxide leaks out depends on how much energy you're generating [and thus how much superoxide], as well as the presence of other defense mechanisms. CoEnzyme Q10 is one and Lipoic Acid is another.
CoQ10 within the mitochondria and Lipoic Acid in the cytoplasm bind excess superoxide so it's unavailable to couple with nitric oxide to produce peroxynitrite. Taking sufficient CoQ10 under certain redox state conditions, would allow you to make more energy and not get creamed with peroxynitrite. [Redox will be discussed in another article.] But, if you keep raising CoQ10 in an inappropriate redox state you may actually generate more superoxide, and that's when the CoQ10 bites you. [Some patients who cannot tolerate CoQ10 find that its analogue, Idebenone, works better.]
Glutathione production is linked to ATP production, because the more ATP (energy) you make, the more Glutathione you need to keep the enzyme breaking the resulting superoxide down to water. If you don't, then the lack of Glutathione will actually result in injury to the mitochondrial membrane and a drop in ATP. That's the Gibbs Free Energy Equation, which says that Glutathione concentration and ATP generation are intimately linked.
Which brings me to the most important statement I'll make about this peroxynitrite diagram. If you are immune-activated from virus, bacteria, mold, and/or toxin exposures, then you're generating an excess amount of nitric oxide. And if you also make a significant amount of ATP, it can result in superoxide, which then binds with the nitric oxide to produce large amounts of peroxynitrite. Then you're set up for major problems. [Oxygen transport, microcirculatory impairment, lack of tissue perfusion, etc.]
"Now there is one factor that I want to mention before I get into the data display. Natelson requires, as a rule, before you're allowed into his medical school for study (whether it's this particular study or any other study) that you consider coming off of all medications and all nutraceuticals or he may not see you. Furthermore, his team is not treatment oriented."
Patient responds: "Well, I certainly wouldn't agree to do that. I'd be a wreck."
Dr. Cheney continues: "Of course you wouldn't agree. Therefore, the data I'm about to present is not anywhere near as bad as you are." You are more severely affected than anyone in this study. I'm not sure he has patients from the truly severe end of the spectrum of CFS. Those patients don't participate in studies. Just reflect on that as I go through this.
In this study, the normal person and the non-disabled CFIDS patient pump 7 liters a minute through their heart with very little variance: 7 liters plus or minus .5. When they stand up, they drop all the way down to 5 liters per minute, a full 30% drop in output. That's normal.
"First of all, why does it go down when you stand up? Because the heart can only pump as much blood as returns to it. If you drop the return by 2 liters per minute, you will always drop the output by 2 liters per minute. The blood has to go uphill against gravity, so there's an automatic 2 liter per minute drop in return, and therefore an automatic 2 liter drop in output even though the heart is completely normal. Where does that extra 2 liters go? It's pooled in your lower extremities and capacitance vessels. Rapidly, by the way." [Capacitance vessels are the larger veins of the body where most of the blood volume is found and where regional blood volume is regulated. For a great explanation of the circulatory system, including the different types of veins and arteries and their respective functions, go to www.cvphysiology.com/Blood%20Pressure/BP019.htm.]
Why don't normal people sense that 30% drop in output? You might assume that their blood pressure would fall 30% and they'd sense it. Nevertheless, their blood pressure either stays normal or goes up when they stand. Blood pressure is so vitally important that the body compensates to prevent blood pressure from dropping.
Think about how significant blood pressure is. Physicians are allowed by law to pronounce people dead. That's a lot of power. And how do we do that? Think about the movies. They always check for a pulse—blood pressure. No pulse—you're dead. And, of course, they check to see if you're breathing. However, if you don't have a pulse and aren't breathing, you'll be pronounced dead. Doctors don't even have to check for brain activity.
Why does the law give doctors such power? Because there's never been an exception to this rule. No breath, no pulse, you're dead. No exceptions—unless you're ice cold. "It points to how important blood pressure is to the body, because blood pressure is, in fact, life. And so, your body will defend your blood pressure beyond anything else. Or, to put it another way, it will sacrifice everything—even your brain—to keep the pulse going."
Nozzles
"Now, when your Q (total blood volume the heart pump iin one minute) drops 30%, your pressure will not drop, because your body will defend that pressure, even to the loss of your brain. This is critical to understanding what happens in CFIDS patients." [Let's use an analogy from gardening.] "Here's the hose attached to a spigot at the side of the house. I have the spigot turned fully counterclockwise [on] and it has maximum Q at 7 liters per minute coming out of that hose. Because it's coming out fast enough, there's enough pressure for this water to shoot out of the hose and I can water all the plants out there, all the way out to the 4th row tomato plants, 6 feet beyond this hose. So, I can sit there and water all day long providing sufficient nutrients and stuff to the plants, because I have adequate Q.
"Now let's take the knob and crank it down so that we drop it down from 7 liters to 5. That would be a normal drop on standing up. The pressure should drop at least 30% or more, but doesn't. Why?" Because, if you turn the flow down, the water can't get out to the tomato plants anymore. There's not enough pressure and it's just dribbling out, so what do I do? I take my thumb and I press it on the end to partially block it and create backpressure. That builds the pressure back up sufficiently to allow that stream of water to shoot out at sufficient velocity to water the tomato plants in the 4th row—even though I had a 30% drop in (cardiac) output. Because my thumb gets tired, I put a nozzle on the end of the hose and tighten it down so I can spray all the way out there at a low Q [pressure]. That's what a nozzle is for.
And you have a nozzle in you. It's called the end arteriole or resistance vessel. It regulates the resistance against which flow occurs to keep your pressure within normal range—despite a large fluctuation in Q produced by standing up or laying down. Because I can maintain the pressure, I can water the plants all the way out to the tomato plants in the fourth row regardless of the Q, because the pressure is maintained.
Now, let's crank it to down to 50%, taking it from 7 liters per minute, all the way down to 3.5 liters per minute. I still have the same nozzle attached but when I drop the flow to 3.5 liters, I can't reach the tomato plants, unless I really tighten down on the nozzle. Moreover, if I tighten it all the way down just a little tiny spray spits out. Maybe only a drop or two will reach all the way out to the tomato plants. Now I'm sacrificing water perfusion of the plants in order to maintain pressure, because without blood pressure you're dead. [Perfusion: the injection of fluid into a blood vessel in order to reach an organ or tissues, usually to supply nutrients and oxygen.]
When faced with a low Q, the body sacrifices tissue perfusion in order to maintain blood pressure, and that's all you need to know to understand this concept. Microcirculation to the tissues of the body is sacrificed to maintain blood pressure so you will not die in the face of a low Q, and that is what is going on in the disabled CFIDS patient.
In Peckerman's study, the data of the disabled CFIDS patients reveals that when they are supine (laying down), their Q is 5 liters per minute. So laying down they can perfuse out to the extremities, but admittedly not as much volume gets out there as would occur at 7 [the Q of the controls and mild CFIDS patients when laying down], but there's enough volume that you are really not that badly affected.
Let's look at what happens when the disabled CFS patients stand up. They drop to 3.7 liters per minute, a 50% drop from the normal of 7, and that means they can't water the tomato plants! The tomato plants start to shrivel up and experience trouble. Big trouble! At 3.7 liters per minute, they do not have adequate Q to function. There will be a functiovnal contraction [lowering of what you are able to do] determined by the drop in Q. The lower the "Q" goes from there, the more in bed you will be, because lying down is the only time you come close to sufficient Q.
Patient asks: "So basically, the tomato plants are all the organs and tissues in the body?"
Dr. Cheney replies: "Yes!"
And those "severe" patients in the study who dropped to 3.7 liters per minute would be mild or moderately ill patients in my practice. How do I know that? I know it by virtue of their pressure changes and their heart rate changes. Look particularly at the MAP (mean arterial pressure)—MAP is the average of your systolic and diastolic pressure. If your blood pressure is 120 over 80, your MAP is 100. All groups in the study had virtually the same MAP when they stood. There is no real difference in the MAP of the controls and the patients in this paper. That's not true in my practice. My patients are virtually always lower than normal. Same for their heart rates.
Sacrificial Prioritization
Now here's an important, critical idea. The body does not sacrifice tissue perfusion equally across all organ systems. It prioritizes the order of sacrifice, and you can see the progression of your disease in this prioritization.
The heart pumps out blood to the artery and the artery produces blood pressure. It pumps down to the smallest arteriole called the resistance vessel, which we will call the nozzle. The nozzle then breaks out into a capillary bed that delivers a certain capillary pressure to the tissues. In the human body, every cell in your body is within 1 millimeter of a capillary, (except in cartilage, periosteal bone and the cornea). Then, the blood returns to the heart via the veins, the venous return.
"There are two organ systems that have a super nozzle in addition to the main nozzle. They have a super built-in nozzle—it's called the Renin Angiotension System, or RAS. It's built into two organs: the lung and the kidneys. They have the greatest nozzle in the body. They can spit water out all the way to the tomato plants with practically no Q at all; they just need a little bit. They can sustain the greatest degree of Q problems, because they have this extra fancy nozzle, the Renin Angiotension System."
Additionally, the heart and the brain also have secondary nozzles. Although not as powerful as the RAS, these secondary nozzles protect that tissue even in the face of extremely low Q. Therefore, the lung, the brain, the kidneys, and the heart are a little bit more protected than the liver, gut, muscles and skin from a drop in Q.
First Compromised: Skin and Compensatory Hypothyroidism
Having said this, in what order are things sacrificed and what are the consequences? The first is the skin. If you sacrifice the microcirculation of the skin, several problems can arise. One is that without adequate microcirculation to the skin, the body cannot thermoregulate anymore. [Thermoregulate: regulate body temperature]
You cannot stand heat or cold, although heat will be more difficult at first than cold—in part because if you're too cold you just put on more clothes, but how do you rip your skin off when you get too hot? If your core temperature rises high enough, you will not sleep and your body will activate your immune system. In order to regulate that problem, your body will kick in thyroid regulation and you will downregulate [reduce or suppress a response to a stimulus] your thyroid to keep your temperature from going too high, and you will develop "compensatory hypothyroidism"! Now you will have trouble with cold.
The second thing your body will not be able to do is get rid of VOCs (Volatile Organic Compounds), which are shed in the skin's oil ducts. VOCs build up in the fat stores of your body and you become progressively chemically poisoned by whatever is present in your environment, and whatever you are genetically susceptible to—different things in different people. If that's pretty significant, we call that Multiple Chemical Sensitivities (MCS). If all you've got is microcirculatory deficiency of the skin, we'll call that MCS and the treatment is to put you in a sauna to outgas you—to detoxify you—which is in fact the primary treatment of MCS patients. We'll also exercise you, which is another MCS treatment.
Next Up: Muscles
If it gets worse than that, the next thing you'll sacrifice are your muscles. You'll have exercise intolerance—you can't go up stairs or climb mountains as easily. When you move your muscles, you feel like you got hit by a ten-ton truck. Very minor activity on day one produces a day two on which you say, "What did I do, it's almost like I ran a marathon."
If it gets still worse, you begin to get fibromyalgic pain. If it affects the joints, it may precipitate pyrophosphoric acid and uric acid crystals and you start to have arthralgias and myalgias linked to this microcirculatory defect. Microcirculation problems have been suggested by Fibromyalgia research in Toronto. Moldofsky tried to induce FM symptoms by interrupting the sleep of study participants and was successful with a significant number of the women. It was harder to induce clinical FM in men, and almost impossible in male athletes. It came down to microcirculation. Men had a higher capillary cross-sectional area (more capillaries) than women. Athletes have more than non-athletes. Male athletes are therefore more resistant to microcirculatory problems within the muscles, whereas sedentary women are the most vulnerable. Microcirculatory problems will be much worse for sedentary women because such problems are modified by the capillary cross-sectional area. Low cardiac output further exacerbates microcirculatory problems.
Third System Down: Liver/Gut
The next thing affected is your liver/gut. Probably the very first thing you'll notice is that there are fewer and fewer foods you can tolerate. If it gets really bad, there will be only a handful of foods you'll be able to eat—for a lot of odd reasons. In part because microcirculation is necessary for proper digestion. Also, your body won't secrete digestive juices so you won't digest your food. If you can't digest your food you'll get peptides that are only partially digested and highly immune-reactive. They'll leak out of your gut [into your bloodstream] and you'll get food allergies and/or sensitivities.
Your body will also fail to detoxify your gut ecology, so your gut will begin to poison you. That's manifested as feeling yucky and a sense of toxic malaise. You get diarrhea, constipation, flatulence, and all kinds of GI problems, including bacterial overgrowth, yeast overgrowth, parasitic overgrowth.
It's a problem because you have poor microcirculation. If it gets worse, you'll get malabsorption syndromes because the nutrients that are—by some miracle—digested, are not absorbed well because there's no microcirculation. At which point, you will begin to become increasingly toxic, which can manifest as a variety of skin disturbances, and you don't feel good, and other interesting things—particularly in the brain.
Fourth Affected: The Brain
In the brain, there's a devastating effect with respect to liver/gut dysfunction—it can quickly toxify the brain. That's perceived initially as, "I only have problems when I have to use my brain." Then it becomes a problem even when you don't use your brain that much. You have all kinds of cognitive complaints like memory disturbance and processing speed. Then you begin to get central brain structures that can destabilize you psychiatrically. You can get hypothalamic structures that begin to destabilize you from an autonomic nervous system perspective and/or neuroendocrine response defects. [neuroendocrine: the interaction between the nervous system and the hormones of the endocrine glands] Whatever the brain does, it doesn't do it as well.
The brain and the heart probably get hit about the same time, but patients usually notice their brain being affected much earlier than their heart. That's because heart muscle cells have the greatest mitochondrial content of any tissue in the body. Thus, when mitochondria are impaired, the heart muscle has the greatest reserve and is the least vulnerable. Neurons have far less mitochondria and they run out long before the heart, especially if you're sedentary. If you're sedentary there's not too much demand on your heart, but you can still think and make great demands on your brain. Energy is energy, whether it's being used physically or cognitively. The effect on the brain is noticed first because it has less reserve, especially if you're thinking—unless you do meditation. Patients who are both sedentary and meditating regularly may actually preserve their brain longer than those who are just sedentary and use their brain a lot.
Fifth: Heart—A Two-Parter
Part A: Manifestation of Microcirculatory Impairment
The effect on the heart has an "a" part and a "b" part. "The initial manifestation of microcirculatory impairment of the heart is arrhythmia. What kind? You name it, you've got it."
"You'll also notice, again, exercise intolerance, because the heart is indeed a muscle just like your leg muscle. When you go up flights of stairs or up mountainsides, you need more cardiac output and you can't sustain it. Therefore, you're going to have trouble. As it gets worse, you'll begin to see mitral valve prolapse (MVP) because that inadequate capillary function affects the papillary muscle and results in prolapse of the mitral valve. Finally, when you get even more severe microcirculation problems, you start to get chest pain as you begin to knock off myocardial cells [heart muscle cells] because they can't get adequate oxygen."
Part B: "The Event Horizon"
"And finally you get to the 'B' part of the heart, and I'll put a line here [on one of many drawings] which I'll call the Event Horizon, after a movie I saw by that name. 'Event Horizon' is a movie in which a group of space explorers discovers a black hole. They park their space vessel outside the event horizon because if they pass that line they can't get back, and if they pass it they're drawn down into a vortex into the black hole and vanish from this universe."
"The Event Horizon with respect to the heart is this: when the microcirculation defect within the heart itself (produced by a low Q), begins to impact Q itself, you enter a vicious cycle. Microcirculation impairment reduces the Q, which produces more microcirculation impairment which produces even more Q problems, and back and forth, zigzagging into a vortex, and down you go "through the Event Horizon" to the next phase of cardiac failure, which is the lung."
Sixth System: Lung & Kidney
"Cardiac failure in the lung produces Congestive Heart Failure (CHF) and Pulmonary Edema. Then comes the kidney—because remember the kidney and lung have the super-duper RAS system. So the last to go turns out to be the kidney which has the biggest RAS system of all buried in its cells, the Renin Angiotension System. When the kidneys go, you go into renal failure, which combined with the liver, is often dubbed hepatorenal failure, and that is the requisite cause of death due to Idiopathic Cardiomyopathy." [After crossing the Event Horizon and spiraling down into Congestive Heart Failure]. I've been there and done that. I'm an expert on that particular journey. And this is the exact sequence I went through over a two—to three-year time period."
The Good News: CFIDS Prevents Us from Crossing the Event Horizon
"You'll notice that the last things afflicted are the lung and the kidney because they have the RAS, and therefore you really have to cross the Event Horizon to involve those. I crossed it. One third of all cases of ICM cross it, and once you cross it, there's no turning back. You either die or get a transplant. There is no turning back."
"Now, for some interesting reason, CFIDS patients do not cross the Event Horizon, at least in any significant way. We don't see them in Pulmonary Edema; we don't see them in renal failure; and, we certainly don't see them needing a transplant. Therefore there is something about this disease that keeps you from progressing across the Event Horizon, though you can get cardiac involvement in the milder sense."
Since no CFIDS patient that I've ever known or heard about has crossed the Event Horizon, I maintain that this means that CFIDS must prevent it from happening in the first place. I crossed the Event Horizon and spiraled down because I did not have CFIDS. You have CFIDS; therefore, you're very unlikely to cross the Event Horizon, which doesn't mean that you won't over time. Peckerman believes that a certain percentage of CFIDS patients are headed right for that. However, they may take a long, long time, or die of something else before that happens.
Almost everyone with CFIDS has Compensated Idiopathic Cardiomyopathy [based on the test results he's getting]. It's the degree of compensation that varies. Some compensate very well, others less so. How will you know if you eventually lose your ability to compensate and cross the event horizon? You'll know it because you'll lie down and you'll be short of breath. When you lie down you'll no longer be able to breathe. Rather than lying down and feeling better, you'll lie flat and get short of breath. Then you know you've crossed over.
Recovery Takes Time
When I had my heart replaced, one of the first things that came back was my kidneys. My brain came back, but slowly. Even though my cardiac output was a whopping 10 liters per minute with the transplant, my brain did not come back fully for 6 to 7 months. Even then, there was continued progression for about four more months before I reached near 100% or greater. In fact, what's interesting is that I now think my brain is functioning at a much higher level than has been present since I was 20. That's interesting because age 20 is when you see 10 liters per minute output. The point is that, at some interesting level, brain functionality depends on microcirculation and when you have sufficient amounts of it, you have excellent brain function.
The next thing that came back was my liver/gut; I couldn't stop eating, and my gut functioned perfectly. Then, my muscles started to come back and that took 8 months. Interestingly, my skin took a long time. So, my body resuscitated in reverse order. "It's taken me over a year to fully come back despite an almost instantaneous restoration of Q, which was my only problem in the first place."
"Which speaks to something very important, and that is, fundamental therapy does not instantaneously result in improvement. As a matter of fact, anything that would improve you within a matter of minutes, hours, or days is, in fact, not therapy at all. It is palliation—symptom suppression—which in fact may not be helping you at all."
Marshall Protocol & "Q"
My hat is off to Trevor Marshall for identifying that the Renin Angiotensin System (RAS) is a key element in the pathology of this disease and pointing out that it acts locally as well as systemically. I didn't know that before. But I'm concerned that an ARB (Angiotensin Receptor Blocker) is being used in CFIDS patients without an awareness of its effect on "Q."
Angiotensin II has two receptors that we know of, and we only understand the first, AT1. When Angiotensin II binds to AT1, it increases the hormone Aldosterone, which in turn increases blood volume. Big issue! If you block AT1 with an ARB [like Benicar], down will go your Aldosterone, and down will go your blood volume, and you could be in a heap of trouble. ARBs that bind to AT1 will constrict blood volume.
I'm also concerned that the other receptor [AT2] is being ignored. No one knows what it does. Not even Merck! I suspect that it has an immune effect. An ARB like Benicar selectively binds very tightly to AT1, resulting in a two—to three-fold increase of Angiotensin II, which then binds to the wide-open AT2 receptor. And who knows what kind of immune responses that is setting off. This is just speculation, but I am concerned.
"I don't believe that you can block a regulatory pathway, especially tightly, with a rebound upregulation of Angiotensin II, two or three fold, when you leave unblocked an unexplained receptor that you have no idea what that thing is doing and then hope that down the road everything will be rosy."
Etiology (Cause)
What is the etiology, the cause, of this cardiac output problem? The short version is that cardiac muscles have lost power because their mitochondria are dysfunctional. They're not functioning well because of a redox-state problem. [Redox: a reversible chemical reaction in which one reaction is an oxidation and the reverse is a reduction. Look for a future article explaining redox states.] But, what causes the redox-state problem? I don't know. I just know that, like MCS and GWS and many other illnesses, we're looking at a redox-state problem. But, there's something unique about CFIDS, because this redox problem seems centered on the heart. It's not focused on the heart, at least to the extent that we can tell, in these other disorders. But there is one big, big clue. It ties in to what we know about Idiopathic Cardiomyopathy (ICM), so we need to look at that first. It may shed some light on CFIDS-linked cardiomyopathy.
Viruses
According to the textbook of medicine, the list of things associated with cardiomyopathy is as long as your arm and covers three pages. But most of the things listed are infectious diseases, and viruses are at the top of the list. ICM appears to be caused, in the minds of most physicians, by a post-viral infectious disorder that evolves following a viral infection, sometimes at a relatively young age. Doesn't that sound a little bit like CFIDS?
Heavy Metals
The second thing that is mentioned, for which a great deal of evidence now exists in cardiology literature, including recent publications in the Journal of American Cardiology, is heavy metals. This is the big, big clue I referred to earlier. There's an Italian article published in one of the cardiology journals about a link between ICM and mercury. The authors looked at about 13 cases of ICM, 24 cases of other types of heart disease, and 4 controls. They biopsied the heart muscle of all the participants and radiated it with neutron flux to make any heavy metals radioactive. Then they put the tissue in a chromatograph to determine with great precision exactly how many molecules of mercury were in each of the tissues.
What they found was astounding. All 13 cases of ICM had 23,000 times more mercury than the controls, and 18,000 times more than the other types of heart disease. One hundred percent of the people with ICM were mercury toxic at the tissue level. Does that necessarily mean that the cause of ICM is mercury? Or, is mercury linked to some other phenomena?
A professor at the University of Kentucky whom I greatly admire analyzed that data. He determined that in normal heart muscle there are not enough mercury-binding sites to have that much mercury. He said the only way you could load that much mercury into the heart muscle was if something else carried it in. There may be a cardiotropic pathogen and/or an immune-system dysregulation associated with a cardiotropic pathogen that is required to load that much mercury into the heart. [Cardio: heart; tropic: affinity for, or influencing]
I doubt the cardiotropic pathogen by itself can produce ICM. I think takes a combination of a pathogen and the presence of a heavy metal like mercury.
The Nexus: Virus/Bacteria/Toxins/Allergies and Heavy Metals
I believe that the proximate etiology of cardiomyopathy is a nexus between an infectious, allergic, or toxic experience, as well as heavy metals. I'll go through why I think that, but I'm not claiming I know the exact cause. I'm just claiming that, based on the medical literature on cardiomyopathy as well as what we know about CFIDS, I would lay my wagers on those two entities, and I think they both may be required, not just one. That's why I call it a nexus between the two, and you'll see why. Because the underlying issues for the etiology of a Q loss need those two entities to really get going."
Pall: Nitric Oxide + Superoxide = Peroxynitrite
The pathophysiology [functional changes that accompany a disease] at the cellular level that underpins this pathophysiologic state is well elucidated by Martin Pall. [A search for "Martin Pall" on immunesupport.com will produce several articles.]
One nitric oxide molecule plus one superoxide molecule equals one peroxynitrite molecule. Peroxynitrite is a reactive oxygen species, is deadly, and highly damaging. At the cellular level, it is the proximate cause of human mortality. Even if you are healthy and your body handles peroxynitrite as well as possible, you will still die of old age.
"These molecules [nitric oxide and superoxide] have to be generated because they are essential for life. They are the end products of a complex scheme of oxidation reactions in the human body; necessary for, among other things, energy generation, and their production is inevitable. Indeed, if they weren't produced you would not be alive. But because they are produced, you will die of oxidation. If you live by the sword, you die by the sword. If you live by oxidation then, like any piece of iron set in an oxygen environment, you will eventually rust away, and we call that death by old age. This is called 'The Free Radical Theory of Aging.' "
What do humans die of, usually? The top killer is Coronary Artery Disease [CAD], and the next is cancer. It turns out that CAD and cancer are also driven in part by peroxynitrite formation. Neurodegenerative diseases like Parkinson's and Alzheimer's are also suspected of being driven by free radical formation. Even suicide is increasingly thought to be generated by oxidative stress in the central nervous system. And, of course, MS and autoimmune diseases. And finally ICM, the path down which you seem to be going, though halted by CFS itself.
But your path deviated right here, just above the Event Horizon to CFS, and you went down the CFS path for a very interesting reason. Why didn't you go down the cancer or MS or Parkinson's pathway? For some reason you started down the CFS pathway over those, and I think that's a result of preordained genetics and environmental influences that combined in a unique fashion to produce that particular road I went down—the ICM pathway. But I could not deviate [from the ICM path] because I never developed CFIDS and I went straight to a near-death experience and came back.
I want to talk a little bit about these two guys [nitric oxide and superoxide], show you why they're necessary and that you have to make them, and how they can modulate your disease process. Especially how they're related to etiology. [They cause many, if not most, of our symptoms—directly or indirectly.]
Nitric Oxide is made by iNOS, eNOS, and nNOS, so far identified. [The small letter in front indicates the source.] The iNOS is of particular interest because it comes from the immune system. When any kind of virus, bacteria, mold, toxin, microbe, or allergy activates your immune system, it induces iNOS, which makes copious amounts of Nitric Oxide. iNOS can make far more Nitric Oxide than eNOS and nNOS can ever make.
eNOS is made by the endothelial cells in the blood vessels and is responsible for regulating microcirculation, basically.
nNOS is made in neurons and is responsible for memory and learning. It is also, when highly activated, very much responsible for MCS, EMR sensitivity [electromagnetic radiation], light and noise sensitivity, and can make sleep difficult. Over-activation also amplifies pain.
Your body has to make nitric oxide. If you don't make it, you have no immune system, no circulation, no brain. The question isn't do you make it; the question is do you make a lot of it. If you make a lot of it there can be repercussions downstream. What those repercussions are depends on what you're [your body is] doing with superoxide.
Now superoxide is produced by the act of making energy [ATP]. It's made in the mitochondria, and for every molecule of ATP generated, you generate one molecule of superoxide—one for one. The more energy you make, the more superoxide you make. However, superoxide is generally found inside the mitochondria. Generally. Nitric oxide is found outside the mitochondria. As long as superoxide stays in the mitochondria and never leaks out, there's no way you will make peroxynitrite, because it takes one nitric oxide plus one superoxide to make one molecule of peroxynitrite.
A Little Math
Now, let's stop here for a moment to talk about the coupling effect. If I have 50 molecules of nitric oxide, and five molecules of superoxide have leaked out of the mitochondria, how many peroxynitrite molecules do I generate? Five. If I make 10,000 nitric oxide molecules, and only 5 superoxide, how many peroxynitrite molecules do I generate? Again, five! Do you see what is happening? What dictates peroxynitrite is not the one with the highest amount, but rather the one with the lowest.
Super Oxide—Out of Control
Therefore, the primary driving force behind peroxynitrite is in fact the production of superoxide. However, if superoxide is well controlled, peroxynitrite formation is limited. However, if superoxide is out of control, there are few limits to the formation of peroxynitrite. It's purely a function of energy production. The more energy you produce, the higher the peroxynitrite may go, especially if nitric oxide is also out of control.
If everything worked as intended, the mitochondria would take in oxygen and nutrition, and output carbon dioxide, water, and ATP (energy). You have enzyme systems embedded in the mitochondria that can break superoxide down to water to prevent superoxide from leaking out of the mitochondria. One enzyme system is called Superoxide Dismutase (SOD). Actually, the enzyme breaks it down to hydrogen peroxide and then down to water, via Glutathione Peroxidase, which depends on selenium and glutathione. [Without proper amounts of selenium and glutathione, the enzyme cannot do its job.]
For the enzyme [SOD] to break superoxide down properly, selenium is supposed to bind to Glutathione Peroxidase. However, if mercury is present in any amount and you have no defense against it [and there are defenses], it competes for that binding site and blocks the selenium. When mercury displaces selenium at the binding site, the function of that enzyme is knocked out. At that point, you have no way to oxidize superoxide down to water, and superoxide starts to leak out contributing to the formation of deadly peroxynitrite. How much superoxide leaks out depends on how much energy you're generating [and thus how much superoxide], as well as the presence of other defense mechanisms. CoEnzyme Q10 is one and Lipoic Acid is another.
CoQ10 within the mitochondria and Lipoic Acid in the cytoplasm bind excess superoxide so it's unavailable to couple with nitric oxide to produce peroxynitrite. Taking sufficient CoQ10 under certain redox state conditions, would allow you to make more energy and not get creamed with peroxynitrite. [Redox will be discussed in another article.] But, if you keep raising CoQ10 in an inappropriate redox state you may actually generate more superoxide, and that's when the CoQ10 bites you. [Some patients who cannot tolerate CoQ10 find that its analogue, Idebenone, works better.]
Glutathione production is linked to ATP production, because the more ATP (energy) you make, the more Glutathione you need to keep the enzyme breaking the resulting superoxide down to water. If you don't, then the lack of Glutathione will actually result in injury to the mitochondrial membrane and a drop in ATP. That's the Gibbs Free Energy Equation, which says that Glutathione concentration and ATP generation are intimately linked.
Which brings me to the most important statement I'll make about this peroxynitrite diagram. If you are immune-activated from virus, bacteria, mold, and/or toxin exposures, then you're generating an excess amount of nitric oxide. And if you also make a significant amount of ATP, it can result in superoxide, which then binds with the nitric oxide to produce large amounts of peroxynitrite. Then you're set up for major problems. [Oxygen transport, microcirculatory impairment, lack of tissue perfusion, etc.]
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Re: Dysfonctionnement des mitochondries, une clé majeure
de un_ptit_gars » Lun 29 Avr 2013 14:51
Protection from the Death Spiral
So to protect yourself from going down the death spiral, your body stops making energy—at least to a point. That results in significant reduction of superoxide, and knocks out peroxynitrite. Thus, you cannot and will not advance [toward the event horizon], or, if you do, you will advance very, very slowly. I couldn't do that, and therefore I crossed the event horizon and almost died.
By the way, all this is Dr. Pall's model. The only added dimension here is the NMDA receptor, which sits on a neuron and when activated, triggers nitric oxide production. So blocking NMDA reduces nitric oxide.
Klonopin/Neurontin
Patient asks:"Klonopin only upregulates the GABA receptor, is that right?"
Dr. Cheney responds:"Yes. But that has an indirect effect on the NMDA receptor, through the GABA receptor. By upregulating [increase a response to a stimulus] GABA, you downregulate NMDA and reduce nitric oxide." [Thus, Klonopin and Neurontin can help reduce nitric oxide.]
Avoid Provigil: It Stimulates Nitric Oxide
"Provigil does the opposite. Provigil does several things, but is mostly an NMDA-activator —it's a stimulant similar to cocaine—it will actually stimulate nitric oxide production. It may also stimulate ATP generation, which is the benefit perhaps that one sees. With more nitric oxide, you can think better, your memory improves, you can focus better, and you have more energy. But what you're doing is generating more peroxynitrite and this may not be felt for a while, but ultimately it's probably felt—in the brain at least—as Alzheimer's or Parkinson's Disease or worse, ten years from now."
How to Block Peroxynitrite
1) Increase CO2
Let's turn to peroxynitrite. According to the Textbook of Medicine, and Dr. Pall himself, what is your primary scavenger of peroxynitrite? The answer is CO2. Carbon dioxide. When ATP is generated in the mitochondria, CO2 is produced as a by-product. So, when you make energy [ATP], you produce the very thing needed to scavenge peroxynitrite. It's a beautiful system! When everything works perfectly, you can make a lot of ATP because superoxide is being broken down into water. And CO2 is produced which will get rid of any peroxynitrite that accidentally happens to be produced.
What a great system! If that system could be maintained in the state it was in when you were born, you should live to 120 to 140 years of age. It's just that things creep in that degrade that operation, that system, and we just exit out earlier than we should.
Now, if you keep lowering ATP production, which then reduces the amount superoxide produced, you also reduce the production of CO2. "The result is you have less and less primary defense against peroxynitrite. It's a vicious cycle. And especially in the lowest energy states of all you really have that problem."
How do you increase CO2? Well, first let me ask how you decrease CO2, which we definitely don't want! Hyperventilation. If you hyperventilate, you dramatically decrease CO2, which would be highly damaging. It can produce carpal-pedal spasms in some patients (carpal: wrist; pedal: foot). Its most damaging effect is to your brain, however.
Rebreathing: You can increase CO2—and stop hyperventilation—by rebreathing. By inhaling your expired CO2, you actually scavenge peroxynitrite. [Rebreathing involves cupping your hands over your nose and mouth so that when you exhale, your CO2 is trapped there and then you inhale it. Do this for a minute at a time, about once every four or five minutes during a thirty-minute period once or twice a day. You can also do this while breathing oxygen through a nasal cannula. Rebreathing can also help address respiratory alkalosis, extremely common in CFIDS, thereby improving microcirculation by shifting blood pH—thus allowing more oxygen to be transported off the hemoglobin.]
Klonopin: Taking Klonopin knocks out Nitric Oxide Synthetase (NOS) and that defends against peroxynitrite. Klonopin can also slow the breathing and that will raise CO2.
Barometric Pressure: Another way to do it is to walk in Death Valley. Below sea level, with all the extra oxygen, you hypoventilate and that will increase CO2. [hypoventilate: breathe abnormally slow and shallow] The opposite is flying in aircraft at 10K feet, causing you to hyperventilate, so flying in airplanes is not good. CFIDS patients often feel bad when low pressure comes through their area and they ache, among other things. Low pressures are like climbing to high altitude, and you don't do as well, because you tend to hyperventilate more.
2) Uric Acid
Uric acid is a powerful scavenger of peroxynitrite. Uric acid levels in CFIDS patients are among the lowest I've ever measured, in all of medicine. [Keep in mind that before specializing in CFIDS, Dr. Cheney served as a Major in the Air Force Medical Corps and was Chief of Medicine at Mt. Home Air Force Base hospital in Idaho for several years before moving on to a private practice in Internal Medicine at Incline Village, Nevada. He was also the Chief of Medicine at the Lakeside Community Hospital in Incline Village, Nevada. In Charlotte, before opening his own CFS clinic, he was the Senior Staff Physician in the Department of Internal Medicine at The Nalle Clinic.] CFIDS patients are the only ones you see at 1 or 2. Everybody else is up at 4, 5, and 6. Most CFIDS patients are quite low. The lowest I've ever seen as a group. [Dr. Cheney currently checks blood levels and 24-hour urine levels of uric acid.]
What do you make uric acid from? You make it from RNA and DNA metabolism and that is produced endogenously [within the body] and exogenously [outside the body]. Endogenous production is by apoptosis [normal, programmed cell death.] "Or by fasting in which you lose muscle mass or even by exercise which can produce muscle mass loss. In any event, you can produce your own endogenous RNA and DNA for uric acid production, which then scavenges peroxynitrite."
Sushi: Exogenously there are certain foods you can eat that do it. [When considering the following foods, take your own food sensitivities and allergies into account!] The best foods that produce RNA and DNA are on the meat and the vegetable side. On the meat side, the best RNA and DNA production is in sushi. Sushi is very high in digestible RNA and DNA.
Patient asks: "Now what do you mean by sushi? Is that raw meat?"
Dr. Cheney replies:"Yes, raw meat. Raw meat of any kind is better than cooked meat." [Assuming it's safe and not contaminated.] Cooking destroys the RNA and DNA, depending on how much you cook it. If you overcook it, you definitely destroy it. But the most efficient way to destroy RNA and DNA is by microwaving.
Eggs & Raw Milk (Cheese): Secondly, young food is better than old because it has a higher RNA and DNA content. How young can you go on the meat side before you can't go any younger? The egg. Eggs are very rich in RNA and DNA. And milk, if it's not pasteurized. It has to be raw milk. Raw milk has a high content of RNA and DNA. It also, interestingly, has a very high proportion of whey protein.
Moreover, if it's undenatured there's likely to be RNA and DNA embedded in that. So I have a sneaky feeling that part of the power of undenatured whey protein may in fact be its RNA and DNA. And if you could raise your uric acid level, you would allow yourself to make more energy, which will allow you to raise your Glutathione. That could well be the mechanism [of the effectiveness of undenatured whey protein].
Of course, raw milk is hard to deal in. There are laws against it. So how can you fix raw milk and make it legal? Make cheese out of it. Cheese made from raw milk and stored in caves—which is the traditional European methodology—actually saves raw milk in a form that can be stored for long periods of time, and has rich RNA and DNA content. You can go to most health food stores and ask for cheeses that are made from raw milk—that's what you want—and ask for the butter that is imported from France or Europe, which is also made from raw milk and is far better for you and is less processed.
Isoprinosine/Imunovir: There's a drug that raises uric acid called Isoprinosine or Imunovir. It's a very good immune-modulator; whose only potential side effect is an increase is uric acid levels. But that's not a problem for CFIDS patients! That "side effect" would have a profound ability to arbitrate this disease at its most fundamental level.
Soy: One of the highest RNA and DNA content foods on the vegetable side is soy. So, soy could very helpful here. Be aware though that soy binds thyroxin [T4] in the gut and is problematic at best if you have hypothyroidism. [I buy frozen, shelled soybeans, let them thaw in the refrigerator, and eat them raw. Quick, easy, and, with or without salt, very good.]
Nuts & Seeds: How young can vegetables be before they can't get any younger? Nuts and seeds!
Patient asks: "So baby lettuce and things like that?"
Dr. Cheney replies: "Yes, exactly like that." Young foods are better than old. Unprocessed foods are better than processed. Uncooked raw vegetables better than cooked. What is the best way to prepare raw vegetables? Juice them, especially if you have problems with digestion. Juiced raw vegetables, especially organic raw vegetables, would be very high in RNA and DNA content and would be quite easy to digest. Definitely, do not microwave them. Steam them or juice them.
3) Consume Reduced Cholesterol
HDL cholesterol binds peroxynitrite. When it binds peroxynitrite, it produces oxidized LDL. So LDL is what's left after having bound peroxynitrite, and HDL is what's ready to bind it. "So what you're looking at with cholesterol to HDL ratio, is actually how well you are in fact scavenging, or capable of scavenging, peroxynitrite."
It could be that you generate higher levels to protect yourself. When Anthony Komaroff looked at cholesterol in CFIDS patients, it was typically elevated. Which means, I think, that CFIDS patients may have an enhanced ability to scavenge peroxynitrite via the cholesterol pathway than a normal person does.
[Reviewing patient's lipid panel lab] Good, your HDL is high—77.6. Total cholesterol is not very high at 141. But your HDL is high, so this is a mixed picture.
Patient asks: "Which means? So what do I need to do?"
Dr. Cheney replies: "Well, you need to eat reduced cholesterol. What is reduced cholesterol? It's found in unprocessed cheeses, butter, and raw milk. When you process these things, you oxidize the cholesterol. [It's no longer "reduced".] If you don't have a source of exogenous cholesterol [i.e. the unprocessed cheese and butter made from raw milk, mentioned earlier], you excessively oxidize your own endogenous cholesterol. Both are bad —consuming processed forms of cholesterol and excessively oxidizing your own cholesterol.
The cholesterol elevation associated with Coronary Artery Disease (CAD) is not the cause of CAD; it's reflective of it. That's why treating cholesterol is a misapplication of therapy [statins] to the wrong thing [cholesterol]. You're treating your defense mechanism [cholesterol], as well as being in big trouble later down the road. Why? Because statin drugs lower CoQ10 levels. This generates yet even more peroxynitrite; at the very time, you're reducing your defense [cholesterol] against it [peroxynitrite].
That's a prescription for disaster. And you know what that disaster is in the published medical literature? People on statin drugs actually die of many cancers faster than people on placebo. The Harvard study said that in the New England Journal of Medicine in 1996. This was also reported in animals on statin drugs. That's why, although there was a 3% improvement of death rate from CAD in the treated group, the net mortality was identical to the placebo group because those on statin drugs died of cancer more often than the placebo group. So there was no net gain. You just traded out what you died of. And if they'd followed the study out 10 years, they would have seen more Parkinson's disease. However, they ended the study at five years.
They have also seen rhabdomyolysis [destruction or degeneration of skeletal muscle tissue accompanied by the release of muscle cell contents into the bloodstream resulting in hypovolemia (decrease in the volume of the circulating blood); hyperkalemia (the presence of an abnormally high concentration of potassium in the blood); and sometimes acute renal failure] in all the developing statin drugs, resulting in one being recalled. I suspect rhabdomyolysis is involved by CoQ10 deficiency produced by the statin drugs.
Three Ways to Block Nitric Oxide
1) Hemoglobin
The best endogenous scavenger of nitric oxide is hemoglobin. [Hemoglobin: the "red" in red blood cells—a protein that transports oxygen from the lungs to the tissues.] "When hemoglobin scavenges nitric oxide, the nitric oxide bends the hemoglobin, causing the red blood cells to deform. Dr. Les Simpson in New Zealand found that the red blood cells of CFIDS patients were deformed, and when they're deformed they can't get through the capillary bed very well and can cause pain."
"An indication of this [RBC deformation] is it also drops the SED rate. CFIDS patients have the lowest SED rates I've ever recorded, and the ones with the lowest SED rate may have the greatest degree of pain." [SED rate refers to sedimentation rate, and is listed as ESR on many lab tests.]
"Do you know what your SED rate is by chance? Normal for you would be 15 plus or minus five. That's according to the British literature. A female your age has a higher SED rate than children and males. And you're probably down around 0 to 3. Which means you have Nitric Oxide binding hemoglobin, and therefore you have an induced hemoglobinopathy [a problem with the hemoglobin—nitric oxide bends it], and red cell deformation, and a low SED rate on that basis."
In the Laboratory Textbook of Medicine, there are only three diseases that lower the SED rate to that level. One is Sickle Cell Anemia—a genetic hemoglobinopathy. The second is CFS—an acquired hemoglobinopathy (acquired by Nitric Oxide binding). And guess what the third disease with a low SED rate is? Idiopathic Cardiomyopathy!
The more deformed red blood cells you have, the more pain you may experience. It's bad enough when you don't perfuse your muscles and your joints [because of poor microcirculation], but it's even worse when your red blood cells are so deformed that they can barely get through the capillaries, or are blocked entirely. Some CFIDS patients have a problem similar to that of Sickle Cell patients in this regard, and Sickle Cell patients have unbelievable pain—you have to give them IV morphine and fluids. That's how they're treated.
2) Hydroxycobalalmin Injections (B12)
Another important scavenger of Nitric Oxide is B12—it binds Nitric Oxide quite vigorously. [This form of B12 is available from compounding pharmacies with a script from a doctor. One cc a day is recommended, at a concentration of 10,000 mcg/ml. The injection can be intramuscularly or subcutaneous. Some patients need to work up to this dose slowly since it also detoxifies you. Patients report more energy, less brain fog, better sleep. Some patients report a significant benefit at a higher dose, perhaps 2 cc's. I usually take one cc a day, but if I've done too much and am crashing, I take two cc's. It helps!]
3) Magnesium Sulfate Injections
Magnesium blocks the production of nitric oxide by calcium channel blockade. [Many patients benefit from magnesium injections, which are virtually painless with the addition of taurine. The Magnesium used by most is Magnesium Sulfate—standard 50% solution—1/2 cc drawn into the syringe first, followed by 1 1/2 cc's of Taurine. The Taurine is compounded at 50 mg/cc. The taurine makes the injection virtually painless and the ratio eliminates the hard knots many are familiar with. The injection is intramuscular, given in upper, outer quadrant of either buttock. Both require scripts from a doctor.]
Other Treatments
Numerous other treatments are used by Dr. Cheney as appropriate with certain patients. Some of the more common ones are zinc and selenium supplements that help block mercury. [Zinc Picolinate: 50 mg, once a day; Liquid Selenium by Allergy Research Group: 1 tsp a day.]
CoQ10 and/or Idebenone. Idebenone comes in 40 or 45 mg capsules, and one such capsule is roughly equivalent to 200 mg of CoQ10. [600 mg of CoQ10, or an equivalent combination of the two, is highly recommended. There is a lot of poor quality CoQ10 on the market —the cheaper products may not be worth your money. Douglas Lab's "CoQMelt" is a good product and is available from needs.com. Kirkman Labs sells Idebenone, kirkmanlabs.com. It's also available at some local health food stores—20% off on the first Tuesday of each month at Sunflower Shoppe in Fort Worth and Healthy Approach in Colleyville.]
Proanthocyanidins or bioflavonoids. The most powerful of these antioxidants are in Grape Skins or Pycnogenol. It just makes good sense to supplement with these.
Essential Fatty Acids, such as Fish Oil, Evening Primrose Oil, and Borage Oil. "I tend to recommend Fish Oil only. It has certain advantages over the others." [Tyler's Eskimo-3 liquid, one teaspoon a day, manufactured by Cardinova in Sweden.]
Physiology: Preload and Afterload
Turning to physiology, how does a cardiologist treat the heart problem? He uses the Frank-Starling Curve. [Dr. Cheney drew a curve for his other patient that I don't have. See http://www.nda.ox.ac.uk/wfsa/html/u10/u1002_02.htm for sample curves.]
[To understand this diagram and the rest of this section, the following somewhat simplified definitions may be helpful. Stroke Volume (SV): the amount of blood pumped by one contraction of the heart. Cardiac Output: the volume pumped out in one minute (SV x heart rate). The ventricle is a lower chamber of the heart. Oxygenated blood is ejected from the left ventricle to the body; unoxygenated blood travels from the right ventricle to the lungs.
Preload is the amount of blood in the left ventricle waiting to be pumped out to the body, or —as on the diagram—the volume in the ventricle at the end of diastole. It's mainly dependent on the venous return of blood from the body. Diastole is when the muscles relax and a chamber of the heart expands and fills with blood; compared with Systole, when the muscles contract and expel blood from the chamber. Afterload is the resistance the blood encounters when ejected from the heart—remember how arteries constrict like nozzles?]
[The diagram could be seen as plotting the amount of blood waiting in the ventricle to go to the body (horizontal axis) against the amount of blood that is actually ejected from the ventricle (vertical axis). Four curves are shown, the highest two (A and B) being healthy hearts with good cardiac output during exercise and at rest. The lower two curves (C and D) indicate diseased hearts that cannot produce sufficient cardiac output. While they have lower cardiac output, they also have greater ventricular volume—there is more blood in the heart, but the heart muscle isn't strong enough to pump as much out. There are also three dotted horizontal lines at increasing heights indicating the necessary cardiac output for rest, walking and maximal activity.]
Dr. Cheney states, "This is the normal Starling Curve." [Presumably something like Curve B.] This curve is where most CFIDS patients are. [I suspect CFIDS curves are between B and C; i.e.—a curve not shown on this diagram.] The point at the top of that curve is the sweet spot. That would give you the most cardiac out output and thus the greatest tissue perfusion, and that would be the best. On either side of that peak, the cardiac output goes down. Most CFIDS patients sit right here. [Probably somewhere on the left side of the curve.]
Now, here is a Congestive Heart Failure curve. [Curve C] Those patients are treated with Lasix to make them eliminate the extra volume, and then they are able to move up the curve and improve their cardiac output. "Most of you, on the other hand, need volume, and as we give you more volume you will come up onto the peak and will maximize your cardiac output. But, if we overshoot, you're going to go down the other side and you actually lose volume. And if you keep going down you'll actually go into heart failure." It's critical to understand the Frank-Starling Curve of Cardiac Output, where you [the PWC] are and how to manipulate it. [Notice that the healthy hearts in the diagram (curves A & B) have little to no drop after their peak!]
Preload: Lying Down
How do you augment preload—which is blood volume—to improve cardiac output? You lie down. When you lie down, you increase the cardiac output a whopping 2 liters per minute. Don't sit, don't recline—lie down. Some patients need to lie down and augment volume anytime, all the time.
But, what if you're one of the ones right near the top of the curve and you increase your volume (preload) 2 liters by lying down? You could actually go over the peak and down the other side. Do you know what that means clinically? Some patients can't lie down! Some tell me, "When I lay down I cannot rest well or sleep." They went right over the top and dropped their cardiac output by lying down!
Preload Chronobiology: Daytime vs. Bedtime
There is a chronobiology to this curve: the time of day affects it. In the daytime, patients need to increase blood volume by taking in fluids. That allows them to be up more. But some can over treat by drinking fluids and lying down in the daytime. [Some with this problem who can't be up find a semi-recumbent position helpful. Use pillows to raise your torso.]
However, at nighttime, the opposite happens. The chronobiology drops your cortisol and aldosterone so you don't hold fluids as well, and all that combines to allow this type of patient to lay down without this problem. Patients with this problem (lying down makes them feel worse) should only expand volume in the first six or seven hours of their day with the Hydralate (Gookinaid) or Home Brew mentioned below, then switch to water. And if they lie down while over-expanding volume with Home Brew or other supplements or drugs, they'll get creamed. These patients should not use the Home Brew during the six or seven hours before bedtime. If they do, they may not be able to sleep.
Preload: Hydralate (Gookinaid)/HomeBrew
"Volume loading using appropriate volume expanders can be quite helpful. This can be done in a variety of ways, but falls best under the term of isotonic [same salt concentration as normal cells and blood] volume expansion. Hydralate (Gookinaid) is a well-documented isotonic volume expander and is used in athletic events such as marathon running." [Gookinaid.com] "It has an advantage of rapid absorption and is maintained in the intravascular volume far longer than hypotonic [less salt concentration] drinks such as water itself. The disadvantage to Hydralate (Gookinaid) is that it has sugar in it in the form of glucose."
"Another option would be a HomeBrew mixture of sea salt and "No Salt". [HomeBrew: one cup of filtered or spring water, 1/8 teaspoon of Sea Salt, and 1/8 teaspoon of "No Salt" salt substitute (potassium). Add lime juice or an herbal teabag as well as stevia for taste.] Four to eight glasses of Hydralate (Gookinaid) or HomeBrew are recommended.
Why is potassium in these drinks? Potassium induces Aldosterone , a hormone that significantly increases blood volume.
Preload: Cortisol as Licorice Root
For those with low blood pressure—most CFIDS patients have low blood pressure—cortisol could also be useful and can be improved adaptogenically using Licorice Root Extract at 1 to 2 tsp every other day. [Adaptogenic substances respond to what your body needs. I take licorice root capsules. Only the type with glycyrrhizin works for this purpose.]
Afterload Reduction: Magnesium
The second thing you need to do after increasing your Preload, is reduce your Afterload. This means reducing the resistance the blood encounters. The best Afterload-reducing agent I know of is Magnesium, an adaptogenic vasodilator [opens up/relaxes the blood vessels as needed]. Magnesium and taurine injections have been very effective for many patients [see details on these injections in the earlier section]. You could also use oral Magnesium Glycinate capsules in the form of Magnesium Glycinate Forte 300 to 500 mg at bedtime. [I use both the oral and the injectible forms.]
Will implementing these treatment measures cure you? Absolutely not, because none of this is getting at the primary issue. It is directed at what is most dysfunctional about this disease. If we're trying to get you functional, this is where we start.
So to protect yourself from going down the death spiral, your body stops making energy—at least to a point. That results in significant reduction of superoxide, and knocks out peroxynitrite. Thus, you cannot and will not advance [toward the event horizon], or, if you do, you will advance very, very slowly. I couldn't do that, and therefore I crossed the event horizon and almost died.
By the way, all this is Dr. Pall's model. The only added dimension here is the NMDA receptor, which sits on a neuron and when activated, triggers nitric oxide production. So blocking NMDA reduces nitric oxide.
Klonopin/Neurontin
Patient asks:"Klonopin only upregulates the GABA receptor, is that right?"
Dr. Cheney responds:"Yes. But that has an indirect effect on the NMDA receptor, through the GABA receptor. By upregulating [increase a response to a stimulus] GABA, you downregulate NMDA and reduce nitric oxide." [Thus, Klonopin and Neurontin can help reduce nitric oxide.]
Avoid Provigil: It Stimulates Nitric Oxide
"Provigil does the opposite. Provigil does several things, but is mostly an NMDA-activator —it's a stimulant similar to cocaine—it will actually stimulate nitric oxide production. It may also stimulate ATP generation, which is the benefit perhaps that one sees. With more nitric oxide, you can think better, your memory improves, you can focus better, and you have more energy. But what you're doing is generating more peroxynitrite and this may not be felt for a while, but ultimately it's probably felt—in the brain at least—as Alzheimer's or Parkinson's Disease or worse, ten years from now."
How to Block Peroxynitrite
1) Increase CO2
Let's turn to peroxynitrite. According to the Textbook of Medicine, and Dr. Pall himself, what is your primary scavenger of peroxynitrite? The answer is CO2. Carbon dioxide. When ATP is generated in the mitochondria, CO2 is produced as a by-product. So, when you make energy [ATP], you produce the very thing needed to scavenge peroxynitrite. It's a beautiful system! When everything works perfectly, you can make a lot of ATP because superoxide is being broken down into water. And CO2 is produced which will get rid of any peroxynitrite that accidentally happens to be produced.
What a great system! If that system could be maintained in the state it was in when you were born, you should live to 120 to 140 years of age. It's just that things creep in that degrade that operation, that system, and we just exit out earlier than we should.
Now, if you keep lowering ATP production, which then reduces the amount superoxide produced, you also reduce the production of CO2. "The result is you have less and less primary defense against peroxynitrite. It's a vicious cycle. And especially in the lowest energy states of all you really have that problem."
How do you increase CO2? Well, first let me ask how you decrease CO2, which we definitely don't want! Hyperventilation. If you hyperventilate, you dramatically decrease CO2, which would be highly damaging. It can produce carpal-pedal spasms in some patients (carpal: wrist; pedal: foot). Its most damaging effect is to your brain, however.
Rebreathing: You can increase CO2—and stop hyperventilation—by rebreathing. By inhaling your expired CO2, you actually scavenge peroxynitrite. [Rebreathing involves cupping your hands over your nose and mouth so that when you exhale, your CO2 is trapped there and then you inhale it. Do this for a minute at a time, about once every four or five minutes during a thirty-minute period once or twice a day. You can also do this while breathing oxygen through a nasal cannula. Rebreathing can also help address respiratory alkalosis, extremely common in CFIDS, thereby improving microcirculation by shifting blood pH—thus allowing more oxygen to be transported off the hemoglobin.]
Klonopin: Taking Klonopin knocks out Nitric Oxide Synthetase (NOS) and that defends against peroxynitrite. Klonopin can also slow the breathing and that will raise CO2.
Barometric Pressure: Another way to do it is to walk in Death Valley. Below sea level, with all the extra oxygen, you hypoventilate and that will increase CO2. [hypoventilate: breathe abnormally slow and shallow] The opposite is flying in aircraft at 10K feet, causing you to hyperventilate, so flying in airplanes is not good. CFIDS patients often feel bad when low pressure comes through their area and they ache, among other things. Low pressures are like climbing to high altitude, and you don't do as well, because you tend to hyperventilate more.
2) Uric Acid
Uric acid is a powerful scavenger of peroxynitrite. Uric acid levels in CFIDS patients are among the lowest I've ever measured, in all of medicine. [Keep in mind that before specializing in CFIDS, Dr. Cheney served as a Major in the Air Force Medical Corps and was Chief of Medicine at Mt. Home Air Force Base hospital in Idaho for several years before moving on to a private practice in Internal Medicine at Incline Village, Nevada. He was also the Chief of Medicine at the Lakeside Community Hospital in Incline Village, Nevada. In Charlotte, before opening his own CFS clinic, he was the Senior Staff Physician in the Department of Internal Medicine at The Nalle Clinic.] CFIDS patients are the only ones you see at 1 or 2. Everybody else is up at 4, 5, and 6. Most CFIDS patients are quite low. The lowest I've ever seen as a group. [Dr. Cheney currently checks blood levels and 24-hour urine levels of uric acid.]
What do you make uric acid from? You make it from RNA and DNA metabolism and that is produced endogenously [within the body] and exogenously [outside the body]. Endogenous production is by apoptosis [normal, programmed cell death.] "Or by fasting in which you lose muscle mass or even by exercise which can produce muscle mass loss. In any event, you can produce your own endogenous RNA and DNA for uric acid production, which then scavenges peroxynitrite."
Sushi: Exogenously there are certain foods you can eat that do it. [When considering the following foods, take your own food sensitivities and allergies into account!] The best foods that produce RNA and DNA are on the meat and the vegetable side. On the meat side, the best RNA and DNA production is in sushi. Sushi is very high in digestible RNA and DNA.
Patient asks: "Now what do you mean by sushi? Is that raw meat?"
Dr. Cheney replies:"Yes, raw meat. Raw meat of any kind is better than cooked meat." [Assuming it's safe and not contaminated.] Cooking destroys the RNA and DNA, depending on how much you cook it. If you overcook it, you definitely destroy it. But the most efficient way to destroy RNA and DNA is by microwaving.
Eggs & Raw Milk (Cheese): Secondly, young food is better than old because it has a higher RNA and DNA content. How young can you go on the meat side before you can't go any younger? The egg. Eggs are very rich in RNA and DNA. And milk, if it's not pasteurized. It has to be raw milk. Raw milk has a high content of RNA and DNA. It also, interestingly, has a very high proportion of whey protein.
Moreover, if it's undenatured there's likely to be RNA and DNA embedded in that. So I have a sneaky feeling that part of the power of undenatured whey protein may in fact be its RNA and DNA. And if you could raise your uric acid level, you would allow yourself to make more energy, which will allow you to raise your Glutathione. That could well be the mechanism [of the effectiveness of undenatured whey protein].
Of course, raw milk is hard to deal in. There are laws against it. So how can you fix raw milk and make it legal? Make cheese out of it. Cheese made from raw milk and stored in caves—which is the traditional European methodology—actually saves raw milk in a form that can be stored for long periods of time, and has rich RNA and DNA content. You can go to most health food stores and ask for cheeses that are made from raw milk—that's what you want—and ask for the butter that is imported from France or Europe, which is also made from raw milk and is far better for you and is less processed.
Isoprinosine/Imunovir: There's a drug that raises uric acid called Isoprinosine or Imunovir. It's a very good immune-modulator; whose only potential side effect is an increase is uric acid levels. But that's not a problem for CFIDS patients! That "side effect" would have a profound ability to arbitrate this disease at its most fundamental level.
Soy: One of the highest RNA and DNA content foods on the vegetable side is soy. So, soy could very helpful here. Be aware though that soy binds thyroxin [T4] in the gut and is problematic at best if you have hypothyroidism. [I buy frozen, shelled soybeans, let them thaw in the refrigerator, and eat them raw. Quick, easy, and, with or without salt, very good.]
Nuts & Seeds: How young can vegetables be before they can't get any younger? Nuts and seeds!
Patient asks: "So baby lettuce and things like that?"
Dr. Cheney replies: "Yes, exactly like that." Young foods are better than old. Unprocessed foods are better than processed. Uncooked raw vegetables better than cooked. What is the best way to prepare raw vegetables? Juice them, especially if you have problems with digestion. Juiced raw vegetables, especially organic raw vegetables, would be very high in RNA and DNA content and would be quite easy to digest. Definitely, do not microwave them. Steam them or juice them.
3) Consume Reduced Cholesterol
HDL cholesterol binds peroxynitrite. When it binds peroxynitrite, it produces oxidized LDL. So LDL is what's left after having bound peroxynitrite, and HDL is what's ready to bind it. "So what you're looking at with cholesterol to HDL ratio, is actually how well you are in fact scavenging, or capable of scavenging, peroxynitrite."
It could be that you generate higher levels to protect yourself. When Anthony Komaroff looked at cholesterol in CFIDS patients, it was typically elevated. Which means, I think, that CFIDS patients may have an enhanced ability to scavenge peroxynitrite via the cholesterol pathway than a normal person does.
[Reviewing patient's lipid panel lab] Good, your HDL is high—77.6. Total cholesterol is not very high at 141. But your HDL is high, so this is a mixed picture.
Patient asks: "Which means? So what do I need to do?"
Dr. Cheney replies: "Well, you need to eat reduced cholesterol. What is reduced cholesterol? It's found in unprocessed cheeses, butter, and raw milk. When you process these things, you oxidize the cholesterol. [It's no longer "reduced".] If you don't have a source of exogenous cholesterol [i.e. the unprocessed cheese and butter made from raw milk, mentioned earlier], you excessively oxidize your own endogenous cholesterol. Both are bad —consuming processed forms of cholesterol and excessively oxidizing your own cholesterol.
The cholesterol elevation associated with Coronary Artery Disease (CAD) is not the cause of CAD; it's reflective of it. That's why treating cholesterol is a misapplication of therapy [statins] to the wrong thing [cholesterol]. You're treating your defense mechanism [cholesterol], as well as being in big trouble later down the road. Why? Because statin drugs lower CoQ10 levels. This generates yet even more peroxynitrite; at the very time, you're reducing your defense [cholesterol] against it [peroxynitrite].
That's a prescription for disaster. And you know what that disaster is in the published medical literature? People on statin drugs actually die of many cancers faster than people on placebo. The Harvard study said that in the New England Journal of Medicine in 1996. This was also reported in animals on statin drugs. That's why, although there was a 3% improvement of death rate from CAD in the treated group, the net mortality was identical to the placebo group because those on statin drugs died of cancer more often than the placebo group. So there was no net gain. You just traded out what you died of. And if they'd followed the study out 10 years, they would have seen more Parkinson's disease. However, they ended the study at five years.
They have also seen rhabdomyolysis [destruction or degeneration of skeletal muscle tissue accompanied by the release of muscle cell contents into the bloodstream resulting in hypovolemia (decrease in the volume of the circulating blood); hyperkalemia (the presence of an abnormally high concentration of potassium in the blood); and sometimes acute renal failure] in all the developing statin drugs, resulting in one being recalled. I suspect rhabdomyolysis is involved by CoQ10 deficiency produced by the statin drugs.
Three Ways to Block Nitric Oxide
1) Hemoglobin
The best endogenous scavenger of nitric oxide is hemoglobin. [Hemoglobin: the "red" in red blood cells—a protein that transports oxygen from the lungs to the tissues.] "When hemoglobin scavenges nitric oxide, the nitric oxide bends the hemoglobin, causing the red blood cells to deform. Dr. Les Simpson in New Zealand found that the red blood cells of CFIDS patients were deformed, and when they're deformed they can't get through the capillary bed very well and can cause pain."
"An indication of this [RBC deformation] is it also drops the SED rate. CFIDS patients have the lowest SED rates I've ever recorded, and the ones with the lowest SED rate may have the greatest degree of pain." [SED rate refers to sedimentation rate, and is listed as ESR on many lab tests.]
"Do you know what your SED rate is by chance? Normal for you would be 15 plus or minus five. That's according to the British literature. A female your age has a higher SED rate than children and males. And you're probably down around 0 to 3. Which means you have Nitric Oxide binding hemoglobin, and therefore you have an induced hemoglobinopathy [a problem with the hemoglobin—nitric oxide bends it], and red cell deformation, and a low SED rate on that basis."
In the Laboratory Textbook of Medicine, there are only three diseases that lower the SED rate to that level. One is Sickle Cell Anemia—a genetic hemoglobinopathy. The second is CFS—an acquired hemoglobinopathy (acquired by Nitric Oxide binding). And guess what the third disease with a low SED rate is? Idiopathic Cardiomyopathy!
The more deformed red blood cells you have, the more pain you may experience. It's bad enough when you don't perfuse your muscles and your joints [because of poor microcirculation], but it's even worse when your red blood cells are so deformed that they can barely get through the capillaries, or are blocked entirely. Some CFIDS patients have a problem similar to that of Sickle Cell patients in this regard, and Sickle Cell patients have unbelievable pain—you have to give them IV morphine and fluids. That's how they're treated.
2) Hydroxycobalalmin Injections (B12)
Another important scavenger of Nitric Oxide is B12—it binds Nitric Oxide quite vigorously. [This form of B12 is available from compounding pharmacies with a script from a doctor. One cc a day is recommended, at a concentration of 10,000 mcg/ml. The injection can be intramuscularly or subcutaneous. Some patients need to work up to this dose slowly since it also detoxifies you. Patients report more energy, less brain fog, better sleep. Some patients report a significant benefit at a higher dose, perhaps 2 cc's. I usually take one cc a day, but if I've done too much and am crashing, I take two cc's. It helps!]
3) Magnesium Sulfate Injections
Magnesium blocks the production of nitric oxide by calcium channel blockade. [Many patients benefit from magnesium injections, which are virtually painless with the addition of taurine. The Magnesium used by most is Magnesium Sulfate—standard 50% solution—1/2 cc drawn into the syringe first, followed by 1 1/2 cc's of Taurine. The Taurine is compounded at 50 mg/cc. The taurine makes the injection virtually painless and the ratio eliminates the hard knots many are familiar with. The injection is intramuscular, given in upper, outer quadrant of either buttock. Both require scripts from a doctor.]
Other Treatments
Numerous other treatments are used by Dr. Cheney as appropriate with certain patients. Some of the more common ones are zinc and selenium supplements that help block mercury. [Zinc Picolinate: 50 mg, once a day; Liquid Selenium by Allergy Research Group: 1 tsp a day.]
CoQ10 and/or Idebenone. Idebenone comes in 40 or 45 mg capsules, and one such capsule is roughly equivalent to 200 mg of CoQ10. [600 mg of CoQ10, or an equivalent combination of the two, is highly recommended. There is a lot of poor quality CoQ10 on the market —the cheaper products may not be worth your money. Douglas Lab's "CoQMelt" is a good product and is available from needs.com. Kirkman Labs sells Idebenone, kirkmanlabs.com. It's also available at some local health food stores—20% off on the first Tuesday of each month at Sunflower Shoppe in Fort Worth and Healthy Approach in Colleyville.]
Proanthocyanidins or bioflavonoids. The most powerful of these antioxidants are in Grape Skins or Pycnogenol. It just makes good sense to supplement with these.
Essential Fatty Acids, such as Fish Oil, Evening Primrose Oil, and Borage Oil. "I tend to recommend Fish Oil only. It has certain advantages over the others." [Tyler's Eskimo-3 liquid, one teaspoon a day, manufactured by Cardinova in Sweden.]
Physiology: Preload and Afterload
Turning to physiology, how does a cardiologist treat the heart problem? He uses the Frank-Starling Curve. [Dr. Cheney drew a curve for his other patient that I don't have. See http://www.nda.ox.ac.uk/wfsa/html/u10/u1002_02.htm for sample curves.]
- cardiac.gif (10.34 Kio) Vu 28353 fois
[To understand this diagram and the rest of this section, the following somewhat simplified definitions may be helpful. Stroke Volume (SV): the amount of blood pumped by one contraction of the heart. Cardiac Output: the volume pumped out in one minute (SV x heart rate). The ventricle is a lower chamber of the heart. Oxygenated blood is ejected from the left ventricle to the body; unoxygenated blood travels from the right ventricle to the lungs.
Preload is the amount of blood in the left ventricle waiting to be pumped out to the body, or —as on the diagram—the volume in the ventricle at the end of diastole. It's mainly dependent on the venous return of blood from the body. Diastole is when the muscles relax and a chamber of the heart expands and fills with blood; compared with Systole, when the muscles contract and expel blood from the chamber. Afterload is the resistance the blood encounters when ejected from the heart—remember how arteries constrict like nozzles?]
[The diagram could be seen as plotting the amount of blood waiting in the ventricle to go to the body (horizontal axis) against the amount of blood that is actually ejected from the ventricle (vertical axis). Four curves are shown, the highest two (A and B) being healthy hearts with good cardiac output during exercise and at rest. The lower two curves (C and D) indicate diseased hearts that cannot produce sufficient cardiac output. While they have lower cardiac output, they also have greater ventricular volume—there is more blood in the heart, but the heart muscle isn't strong enough to pump as much out. There are also three dotted horizontal lines at increasing heights indicating the necessary cardiac output for rest, walking and maximal activity.]
Dr. Cheney states, "This is the normal Starling Curve." [Presumably something like Curve B.] This curve is where most CFIDS patients are. [I suspect CFIDS curves are between B and C; i.e.—a curve not shown on this diagram.] The point at the top of that curve is the sweet spot. That would give you the most cardiac out output and thus the greatest tissue perfusion, and that would be the best. On either side of that peak, the cardiac output goes down. Most CFIDS patients sit right here. [Probably somewhere on the left side of the curve.]
Now, here is a Congestive Heart Failure curve. [Curve C] Those patients are treated with Lasix to make them eliminate the extra volume, and then they are able to move up the curve and improve their cardiac output. "Most of you, on the other hand, need volume, and as we give you more volume you will come up onto the peak and will maximize your cardiac output. But, if we overshoot, you're going to go down the other side and you actually lose volume. And if you keep going down you'll actually go into heart failure." It's critical to understand the Frank-Starling Curve of Cardiac Output, where you [the PWC] are and how to manipulate it. [Notice that the healthy hearts in the diagram (curves A & B) have little to no drop after their peak!]
Preload: Lying Down
How do you augment preload—which is blood volume—to improve cardiac output? You lie down. When you lie down, you increase the cardiac output a whopping 2 liters per minute. Don't sit, don't recline—lie down. Some patients need to lie down and augment volume anytime, all the time.
But, what if you're one of the ones right near the top of the curve and you increase your volume (preload) 2 liters by lying down? You could actually go over the peak and down the other side. Do you know what that means clinically? Some patients can't lie down! Some tell me, "When I lay down I cannot rest well or sleep." They went right over the top and dropped their cardiac output by lying down!
Preload Chronobiology: Daytime vs. Bedtime
There is a chronobiology to this curve: the time of day affects it. In the daytime, patients need to increase blood volume by taking in fluids. That allows them to be up more. But some can over treat by drinking fluids and lying down in the daytime. [Some with this problem who can't be up find a semi-recumbent position helpful. Use pillows to raise your torso.]
However, at nighttime, the opposite happens. The chronobiology drops your cortisol and aldosterone so you don't hold fluids as well, and all that combines to allow this type of patient to lay down without this problem. Patients with this problem (lying down makes them feel worse) should only expand volume in the first six or seven hours of their day with the Hydralate (Gookinaid) or Home Brew mentioned below, then switch to water. And if they lie down while over-expanding volume with Home Brew or other supplements or drugs, they'll get creamed. These patients should not use the Home Brew during the six or seven hours before bedtime. If they do, they may not be able to sleep.
Preload: Hydralate (Gookinaid)/HomeBrew
"Volume loading using appropriate volume expanders can be quite helpful. This can be done in a variety of ways, but falls best under the term of isotonic [same salt concentration as normal cells and blood] volume expansion. Hydralate (Gookinaid) is a well-documented isotonic volume expander and is used in athletic events such as marathon running." [Gookinaid.com] "It has an advantage of rapid absorption and is maintained in the intravascular volume far longer than hypotonic [less salt concentration] drinks such as water itself. The disadvantage to Hydralate (Gookinaid) is that it has sugar in it in the form of glucose."
"Another option would be a HomeBrew mixture of sea salt and "No Salt". [HomeBrew: one cup of filtered or spring water, 1/8 teaspoon of Sea Salt, and 1/8 teaspoon of "No Salt" salt substitute (potassium). Add lime juice or an herbal teabag as well as stevia for taste.] Four to eight glasses of Hydralate (Gookinaid) or HomeBrew are recommended.
Why is potassium in these drinks? Potassium induces Aldosterone , a hormone that significantly increases blood volume.
Preload: Cortisol as Licorice Root
For those with low blood pressure—most CFIDS patients have low blood pressure—cortisol could also be useful and can be improved adaptogenically using Licorice Root Extract at 1 to 2 tsp every other day. [Adaptogenic substances respond to what your body needs. I take licorice root capsules. Only the type with glycyrrhizin works for this purpose.]
Afterload Reduction: Magnesium
The second thing you need to do after increasing your Preload, is reduce your Afterload. This means reducing the resistance the blood encounters. The best Afterload-reducing agent I know of is Magnesium, an adaptogenic vasodilator [opens up/relaxes the blood vessels as needed]. Magnesium and taurine injections have been very effective for many patients [see details on these injections in the earlier section]. You could also use oral Magnesium Glycinate capsules in the form of Magnesium Glycinate Forte 300 to 500 mg at bedtime. [I use both the oral and the injectible forms.]
Will implementing these treatment measures cure you? Absolutely not, because none of this is getting at the primary issue. It is directed at what is most dysfunctional about this disease. If we're trying to get you functional, this is where we start.
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un_ptit_gars - Administrateur
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Re: Dysfonctionnement des mitochondries, une clé majeure
de tuchiana » Lun 29 Avr 2013 19:30
un_ptit_gars a écrit:Protection from the Death Spiral
By the way, all this is Dr. Pall's model. The only added dimension here is the NMDA receptor, which sits on a neuron and when activated, triggers nitric oxide production. So blocking NMDA reduces nitric oxide.
Dr Pall ca doit etre le Dr Martin Pall je suppose
![[img]images/icones/icon10.gif[/img]](./images/smilies/icon10.gif "smile")
merci ptit_gars
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tuchiana - Sage de l'intoxication
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Re: Dysfonctionnement des mitochondries, une clé majeure
de Lebowski » Jeu 2 Mai 2013 13:18
Ah cool, une synthèse succinte et facile à lire...euh ![[img]images/icones/icon18.gif[/img]](./images/smilies/icon18.gif "bizarre")
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Re: Dysfonctionnement des mitochondries, une clé majeure
de un_ptit_gars » Jeu 2 Mai 2013 13:21
Lebowski a écrit:Ah cool, une synthèse succinte et facile à lire...euh
C'est deja bien qu'on ai l'info lebo... 
Après de mon coté j'essayerais d'intégrer ça dans mon Ebook qd je pourrais, mais c'est loooooong et j'ai la flegme de m'y coller dessuite... on verra dans les semaines/mois a venir
Pti gars
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un_ptit_gars - Administrateur
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Re: Dysfonctionnement des mitochondries, une clé majeure
de Lebowski » Jeu 2 Mai 2013 13:24
mon sarcasme n'est que le reflet de mon énoooorme paresse à lire ce texte! 
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Re: Dysfonctionnement des mitochondries, une clé majeure
de un_ptit_gars » Jeu 2 Mai 2013 13:32
Lebowski a écrit:mon sarcasme n'est que le reflet de mon énoooorme paresse à lire ce texte!
Alors imagine l'énorme paresse supplémentaire que tu aurais eut en plus, s'il avait fallu chercher, lire 10 fois ce genre de textes avant d'en trouver un "bon" et utile....
Alors fais pas ta feignasse et vois le verre "a moitié plein", jt'ai deja fais le plus gros du boulot!!!
Pti gars
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un_ptit_gars - Administrateur
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Re: Dysfonctionnement des mitochondries, une clé majeure
de Lebowski » Jeu 2 Mai 2013 14:54
C'est vrai, et je te remercie de nous mâcher le travail ainsi!
Je reviendrai lire ce texte un peu plus tard ou demain, quand j'aurai le temps...
Je reviendrai lire ce texte un peu plus tard ou demain, quand j'aurai le temps...
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Re: Dysfonctionnement des mitochondries, une clé majeure
de jibouille » Jeu 4 Juin 2015 18:36
Article très intéressant sur les mitochondries :
http://globalresearch.ca/mitochondrial- ... ma/5447650
http://globalresearch.ca/mitochondrial- ... ma/5447650
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