by Joan S. Livingston, About.com columnist  [A brief report on Dr. Bell's latest research appeared in the previous CFS-NEWS. This more in-depth article is licensed to About, Inc. which can be found on the Web at www.About.com. All rights reserved. For more articles on Chronic Fatigue Syndrome and Fibromyalgia, visit http://chronicfatigue.about.com.] Dateline: 7/26/00 CFIDS sufferers can celebrate yet more concrete evidence that what they suffer from is not "all in your head (AIYH)," but rather "all in your body (AIYB)" -- but given the nature of the evidence, they'll probably want to celebrate in bed. The findings come from a new study by Dr. David S. Bell of Lyndonville, NY. Lyndonville was the site of a major CFIDS cluster epidemic in the 1980s that morphed Bell from a rural pediatrician into a world-renowned CFIDS researcher as he sought to understand what was happening to his patients. Bell's last major study, with endocrinologist Dr. David Streeten, yielded a startling discovery: that the vast majority of Bell's CFIDS patients had "extraordinarily" low circulating blood volume (a combination of plasma and the red blood cells via which the plasma delivers oxygen throughout the body). While his average patients ran about 70 percent of normal, several patients with chronic fatigue syndrome (PWCs) had only half the blood volume of a healthy person, an amount so low that it would ordinarily cause shock and prove fatal in a car accident (as apparently happened to Princess Diana during a 2 1/2-hour drive to a French hospital). Bell hypothesized that the low blood volume could help account for the prevalence of orthostatic intolerance (worsened symptoms upon standing) in CFIDS, because the limited amount of blood tended to pool in the legs and feet, with a corresponding drop in the amount available to the brain. The result? That common sensation of overwhelming gravity and of wearing lead boots. Other research has added to the mounting evidence that this is a core problem in CFIDS, including reduced cerebral blood flow on SPECT scans and neurally mediated hypotension on tilt-table tests. Data for Diagnosis and Disability Dr. Bell has completed further research on some specific physical ramifications of low circulating blood volume. He and Streeten conducted tests on Bell's patients by tracking their blood pressure and pulse while lying and then standing. Consistent with Bell's long-held assumptions, virtually all of his patients (18 or 19 of 20) exhibited aberrations when upright. This is hard data that could be helpful in diagnosis and ultimately treatment, that generally correlates with disease severity, and that could prove very valuable in fighting for disability benefits. The new findings could be pivotal in bucking conventional notions of CFIDS as a disease of subjective, "self-reported," and possibly overstated symptoms. No physician or Social Security judge can reasonably stick a psychiatric or hypochondriac label on a patient with some of the abnormalities outlined below. SIDEBAR: ABOUT "FATIGUE" In a disease whose formal name is chronic fatigue syndrome, it's noteworthy that Bell shuns the word "fatigue" as a "very inappropriate term for what patients experience. It's not really fatigue at all, which is defined as a normal recovery state from exertion, and that is precisely what does NOT happen in this illness. Anybody who works a 20-hour day will be fatigued, but they'll recover from it -- it's not the same thing. A typical CFS patient might function on a minimal level (housework, minor errands) for a total of 3 or 4 hours a day. They may say they're fatigued, but what's really restricting their activity may be pain, tremulousness, or weakness -- a sense that they are on the verge of collapse. That is not 'fatigue' as we commonly think of it." As background to his most recent findings, Bell shared his observations about the wealth of already existing data on physical anomalies in CFIDS for those clinicians who have been willing to look and do more than a rote physical exam and a standard blood count. "The abnormalities in this illness are numerous and quite striking," Dr. Bell observed. Even before the last few years' research began pinpointing increasingly more aberrations in virtually every body system, he says, "I was always quite annoyed when doctors would say you can't find anything wrong on laboratory evaluation or physical exam. It's just not true. Among other things, the immunological findings are very, very interesting. Sleep-lab studies and tests of cognition are generally quite unusual, he noted, if performed properly. "It's always been said that this is an illness of exclusion, that everything else must be ruled out before the diagnosis of chronic fatigue syndrome can be made," Bell noted. "That is not true. The pattern of symptoms is unique; there is no other illness in general medical practice that looks like this one. When doctors say that the physical exam is normal, that's also inaccurate," Bell continued. "Virtually all patients will have abnormalities on physical exam, but on average the patient will look pretty healthy. What the doctor is thinking is that the physical exam is not abnormal enough to explain why someone says they can be up only two hours a day. The degree of reported activity restriction is so dramatic physicians frequently just don't believe it's possible." But understanding low blood volume and severe orthostatic intolerance makes the degree of activity restriction more than "possible." In fact, it makes it hard to believe patients function as well as they do because, as the data below suggest, many PWCs may function in a continuous state of hypotension, tachycardia, and/or other posture- related abnormalities, including circulatory shock. One Possible Etiology: The ANS Gone MIA Dr. Bell noted that one theory of CFIDS etiology receiving increasing attention is autonomic nervous system injury or dysfunction. Consisting of the parasympathetic and sympathetic nervous systems, the autonomic nervous system or ANS is responsible for controlling involuntary bodily functions like breathing, pulse, and blood pressure, as well as the adrenal and other glands, among dozens of other functions. It's the reason you keep breathing and your heart keeps pumping while you're asleep, as well as why your system goes into overdrive and why you sweat more when you're nervous. The ANS is the home of orthostatic problems, and of many chemicals, that may explain a range of CFIDS symptoms. A clear majority of the patients in Bell and Streeten's first study had a "marked, striking" decrease in circulating blood volume. "One nice thing about that finding," Bell said wryly, "is that it is a discrete physiological abnormality that cannot possibly be explained as psychosomatic." How severe were the irregularities? The percentages varied (70% of normal volume was average); still, "we have six people with only 50% of normal blood volume here who're still walking around. It seems to be a different mechanism than what happens to a healthy person [who loses that much blood] in a car accident." For some reason, the blood vessels in CFIDS seem to be constricted dramatically, and attempts to restore normal volume (through fluids, Florinef, salt, saline injections, transfusions) have met with very limited and short-term success so far. "All of the body's normal mechanisms to restore blood [when it's lost in other ways] seem to be turned off." It's as if the CFIDS body wants to have low blood volume and that its blood vessels want to stay constricted. Bell likens the blood vessels to furnace pipes that are only half the proper diameter -- and you simply can't make a metal pipe hold more fluid than the pipe is built to carry. Straight off the Presses: The New Physiological Findings Bell and Streeten obtained their most recent, detailed findings about ANS dysfunction through "a very simple test, one that can be performed anywhere, using only a blood-pressure cuff." The patient lies down quietly for 10 minutes while a nurse takes his or her pulse and blood pressure (BP) several times; then the patient is asked to stand quietly for 30 minutes while the same measurements are taken. Bell pointed out that when a normal person stands up, the pulse may or may not rise slightly at first; the blood pressure usually remains stable (a graph of the systolic and diastolic numbers is notable for its constancy -- a "band" that stays the same size); and the pulse pressure remains constant. Despite the fact that their pulses and BPs were "pretty normal" while lying down, study participants consistently displayed orthostatic irregularities -- last-ditch efforts to force blood to the brain -- which were categorized into five basic patterns or subgroups. Many patients, however, actually had more than one of the following abnormalities: * Orthostatic systolic hypotension A fall in systolic (upper) BP of 20 mmHg (millimeters of mercury) or more. * Orthostatic diastolic hypotension A fall in diastolic (lower) BP of 10 mmHg or more. Dr. Bell notes, "This seems to be the least common abnormality in the CFS patients I have tested. The body will put out adrenaline and other chemicals as a result of decreased blood circulation, which narrows the blood vessels further." * Orthostatic diastolic hypertension A rise in diastolic BP to 98 mmHg or more. Explains Bell, "The lower number of the BP often reflects systemic resistance, and while standing many CFS patients seem to 'raise' this lower number up in an attempt to push blood to the brain." * Orthostatic postural tachycardia An increase in heart rate of 28 beats per minute (bpm) OR a pulse of more than 110-120 bpm. Also known as POTS for postural orthostatic tachycardia syndrome, this was a very common finding even among patients with other severe deviations. * Orthostatic narrowing of pulse pressure A fall in pulse pressure -- the difference between systolic and diastolic -- to 18 mmHg or lower (vs. the 40-point difference in a "normal" BP of 120/80, for example). Dr. Bell explains, "Usually, when the pulse pressure falls much below 20, you can't even read the person's pulse. When it falls this low, the patient is in a state of circulatory shock." In the most recent edition of his publication, The Lyndonville News, Bell wrote briefly about a woman with systolic hypotension: "One patient had a normal BP lying down (100/60) but it fell to 60/0 on standing. No wonder she was unable to remain upright -- a blood pressure that low is really unable to circulate blood. In any ICU they would panic seeing a blood pressure like that. And yet she was turned down for disability because she was considered a hypochondriac." Her case was not unusual in Bell's study or in his clinical practice. Fight, Flight, or Lie Down Among the chemicals released by the ANS are cortisol, dopamine, epinephrine (adrenaline), and norepinephrine (very similar to epinephrine but with somewhat less effect on the heart). Dr. Bell suggested that most of these chemicals are probably involved in CFIDS -- especially when released inappropriately, causing further vasoconstriction in those furnace pipes. He cited a recent article regarding norepinephrine (released by the adrenal gland), which noted a relationship between orthostatic intolerance and "norepinephrine transport." Bell suggested that "a physiological mishandling of norepinephrine" may play a role in CFIDS. Monitoring "hyperadrenergic" (norepinephrine-related) orthostatic problems, Bell predicted, is likely to prove a helpful measure in the future. "Norepinephrine is the best method the body has for getting blood to the brain, to get that mental clarity of the fight-or-flight response," he noted. "But in CFS it seems to get kicked in inappropriately. Half the patients I've tested have an abnormality on testing. I think we'll soon see testing of such things as plasma norepinephrine when patients are experiencing orthostatic symptoms. "[Norepinephrine is] good for getting blood to the brain but it's counterproductive in CFIDS -- it probably causes further vasoconstriction, it raises pulse, it causes panicky symptoms and makes you feel tremulous, it causes exhaustion and forgetfulness, and it can cause poor sleep later." Many CFIDS patients can relate to that frazzled, revving-on-empty feeling. Turning Toward a Treatment? While Bell and Streeten have yielded further insights into the body's different responses to low circulating blood volume, there are no answers yet about how best to treat the five subgroups they identified. Perhaps one group will turn out to comprise the "Florinef responders"; in the past Bell has seemed bedeviled by the fact that the drug has worked so well for some PWCs but not others (relatively few of his own patients have shown improvement on it). While there is still nothing as simple as a swab strep-throat culture for diagnosing CFIDS, the subgrouping may be a step in that direction, as well as toward determining the optimum treatment for each subgroup. "The reason I'm excited about this [most recent study] is that it provides a method to subgroup patients and perhaps to find the different mechanisms behind each abnormality," Bell said. With these mechanisms more fully understood, advances in therapies should follow. Before falling ill with CFIDS in 1988, Joan S. Livingston was executive editor of a nationally award-winning magazine, an editor and writer for The Harvard Business Review, a freelancer for magazines, newspapers, and corporations, and a published artist and poet who ran 7 miles daily. Currently she is on the board of directors of the Massachusetts CFIDS Association, for whose quarterly newsletter, "The Update," she is an editor and writer. This article is drawn from a related piece in the current Summer "Update"; her article on the other Dr. Bell study referred to -- on circulating blood volume -- appeared in the Winter '97-98 edition of the newsletter. [This feature is reprinted with permission from About.com and any support group wishing to reprint this article in their own newsletter can easily obtain approval by contacting Lisa Lorden by e-mail at chronicfatigue.guide@about.com.] Hi Linda, Thanks for writing. The article is still on my site at http://chronicfatigue.about.com/library/weekly/aa072600a.htm. You're welcome to post it, and I'd appreciate it if you'd include a link to my site at http://chronicfatigue.about.com. All the best to you, Lisa -- Lisa Lorden About's Guide to Chronic Fatigue Syndrome/Fibromyalgia CFS, Heart Problems, and a Risky Procedure: A Warning from Dr. Cheney by Carol Sieverling, reviewed and edited by Paul R. Cheney, M.D., Ph.D. I had a relatively brief appointment with Dr. Cheney at the end of June. He is very concerned that the CFS community will hear that he has detected a heart problem called Patent Foramen Ovale (PFO) in a significant number of his patients, and that as a result, many CFS patients will pursue a corrective procedure that is potentially very dangerous. He asked me to write an article informing CFS patients about the risks of undergoing a catheterization procedure to close a PFO or Atrial Septal Defect (ASD). Background - Virtually All CFS Patients Have Diastolic Dysfunction As most are already aware, Dr. Cheney has found that the cellular energy deficit at the core of CFS results in diastolic heart dysfunction. This heart condition does not trigger CFS. However, the heart is affected as CFS progresses and cellular energy disturbances mount. About 100 of his patients have been tested in his clinic via echocardiography (a sonogram of the heart) and all but one were positive by one or more parameters indicative of diastolic dysfunction. The exception is a 21-year-old patient and her age may have been a factor. For those who want more technical details on testing for diastolic dysfunction, all patients (except the 21-year-old) evidenced diastolic dysfunction by their pulmonary vein D/S ratio. In addition, Dr. Cheney is finding that his older patients, typically over 50, manifest diastolic dysfunction by the classical reversal of the mitral in-flow E/A ratio. This E/A reversal accounts for 40% of all the patients he's tested so far. This ratio jumps to 60% if the TDI e'/a' reversal is also used as either/or criteria for diastolic dysfunction. Younger patients manifest diastolic dysfunction primarily as left atrial cavitation during 70-degree head-up tilt. (The tilt is part of his echo protocol). Seventy percent of his patients are in this category. Except for a small group of middle-aged patients, the E/A or e'/a' reversal as compared to atrial cavitation is usually mutually exclusive. However, both aberrations can exist together in the middle-aged patient. There have been other online postings that discuss Dr. Cheney's understanding of diastolic dysfunction in CFS (Co-Cure.org), as well as the three-hour video of Dr. Cheney's presentation to our support group just over a year ago. A few of those videos are still available from dfwcfids.org. (A new Cheney video and/or DVD should be available this fall). What is a PFO? In most people, the right and left sides of the heart have no opening between them. Circulated blood flows into the right side of the heart. It then goes to the lungs to pick up oxygen, dump carbon dioxide, and has mini-clots filtered out as well as potential portal vein toxins and toxic gases produced by fermentation in the gut. From the lungs it goes to the left side of the heart, which sends it on to the brain and body. When the fetus is in the womb, however, it relies on its mother for clean, oxygenated blood from the umbilical cord blood and does not use its lungs. As a result, the fetal heart has an opening known as the Patent Foramen Ovale (PFO). This opening allows blood to take a short cut from the right atrium (upper chamber of the right heart) to the left atrium, which sends it on its usual path through the left ventricle and out the aorta to the rest of the body. The PFO is formed by two overlapping tissues or septi, the septum primum and the septum secundum. Typically, when the lungs kick into action at birth, pressure in the right heart substantially decreases relative to the left side and the PFO slams shut and the two tissues grow together, forming a permanent seal. But in up to 20 to 30 percent of the general population, the flaps of both tissues press together but never fuse. This can potentially allow unfiltered blood to escape into the left side of the heart from the right, depending on the difference in pressure between the right and left sides. However, the normal pressures in a healthy heart (left side greater than right) keep the flap valve from opening, so the vast majority of people with a PFO experience no problems. A PFO opens when more pressure is created in the right side of the heart. This can be produced acutely by a Valsalva maneuver, and can occur when people cough, sneeze, lift something heavy, or strain at stool. If the pressure is enough to open the PFO, blood can flow from the right atrium to the left. Dr. Cheney demonstrates the basics of a PFO visually with his hands. Hold your hands as if in prayer against your chest. Tilt your hands down and point them away from you, but keep them against your chest. (They represent the wall separating your atria, the two upper chambers of your heart.) Slide the left one down so that your left index finger is aligned with your right ring finger. Your right hand stays stationary. Your left hand is the "valve" that moves. Keep your little finger still - it's the hinge - while tilting your left hand away from your right. This is a rudimentary representation of a PFO. With your hands in this position, you should be able to feel why higher pressure on the left keeps the PFO shut. (Your left hand pushes against your right.) Conversely, higher pressures on the right cause the valve of the PFO to open. (Your left hand tilts away from your right.) For excellent diagrams and a good description of the development of a PFO in utero and after birth see www.oucom.ohiou.edu/dbms-witmer/Downloads/Witmer%2008-21-02%20Heart%20defects.pdf. (See pages 7-9, Atrial Partitioning II-IV). Most (Perhaps All?) CFS Patients Have a PFO In late April Dr. Cheney began looking for PFOs in his patients based on evidence of high right-sided pressures and low left-sided pressures in CFS patients. To date he has administered contrast echos to 24 patients. Seventy-eight percent of those not on the treatment protocol for his current research study were positive - a PFO opened and visibly shunted blood from one atrium to the other. A Valsalva maneuver is used to induce the PFO to open while the contrast IV saline with micro-bubbles of air flow through the heart. This is called a saline bubble test. (Actual echo photos of a positive test result will be posted on dfwcfids.org in our "Cheney section".) One published study found that when contrast IV saline was administered in the arm as opposed to the groin area during this test, a false negative rate of 30% occurred. Since the groin area cannot be used for the IV in the setting of Dr. Cheney's clinic, and the arm is typically used by most physicians, it's possible that virtually all of his patients have (or had) PFOs that shunt blood from one atrium to the other. This obviously assumes that those who tested negative actually have PFOs that went undetected (i.e. false negatives). Dr. Cheney suspects that the PFOs of most CFS patients open only transiently, not chronically. In other words, the flap valve only opens occasionally. However, the size of the PFO and how often it opens varies from patient to patient. During the contrast echo, some patients clearly had a large opening, allowing more bubbles to cross into the left atrium. Others only had a very few bubbles moving across, indicating a much smaller opening or less pressure difference between the right and left atria. Consequences of a PFO In adults, this two-flap valve (PFO) between the right and left atrium allows blood to flow either way, though it tends to flow predominantly in one direction in any one person. A right to left shunt (flow) increases the risk of a stroke, since the lungs have not filtered out mini-clots. (Taking low-dose aspirin three times a week along with a daily supplement of Nattokinase or Lumbrokinase, is not a bad idea. For a comparison of the latter two, see www.allergyresearchgroup.com/faq/index.php?article=3D182.) Dr. Cheney suspects that these mini-clots explain why so many CFS patients (up to 50%) have punctate lesions or Unidentified Bright Objects (UBOs) on their MRI brain scans. Each UBO may actually be a very tiny area damaged by a mini clot. Migraines have also been linked to PFOs that shunt right to left. Clinical trials are underway to close PFOs in patients with severe migraines that are non-responsive to medication. Dr. Cheney pointed out that carbon dioxide levels in the blood rise with a right to left shunt since unoxygenated blood from the right side gets dumped into the left arterial circulation. Since carbon dioxide is a vasodilator it would cause arteries in the brain to dilate, which could trigger a migraine. The increased carbon dioxide could also cause slight brain swelling, which could be mistaken for Chiari I Malformation. Many will remember all the publicity that this defect received a few years ago as it mimics CFS, and the brain surgery that some underwent with mixed results. Higher levels of carbon dioxide would also explain some patients Dr. Cheney has seen through the years whose symptoms seemed to mimic carbon monoxide poisoning. There are different risks if the PFO primarily shunts from left to right, sending blood from the left atrium to the right atrium. From there it's pumped through the right ventricle into the pulmonary artery and into the lungs. Increasing the amount of blood in the right atrium can increase the pressure of the blood moving into the lungs. If the pressure on the right side of the heart is high enough, pulmonary hypertension can develop and eventually become life threatening if it rises too high. (Pulmonary hypertension is a disorder in which the blood pressure in the pulmonary artery rises far above normal levels.) A left to right shunt also reduces the efficiency of the heart as oxygenated blood is returned to the right heart, going in the wrong direction. The heart has to work harder to overcome this inefficiency. Cause of PFOs and ASDs in CFS Patients Researchers state that between 20% and 30% of the general population has a PFO, yet Dr. Cheney's findings as of July 19th indicate that 78% of his "non-study" CFS patients have one. Are people with PFOs at risk for CFS, or does CFS create PFOs? Though there is no definite answer as yet, Dr. Cheney strongly suspects the latter. There is evidence in CFS patients that right-sided pressures are higher than normal and left-sided pressures are lower than normal. There's a complex explanation for this that I'm not sure I fully understand - see the note at the end for my attempt at an explanation (thankfully heavily edited by Dr. Cheney). The bottom line is that when the pressure on the right side of the heart rises high enough in relation to the pressure on the left side, it's possible that a PFO sealed after birth could pop open. Thus CFS could conceivably create PFOs. Once a PFO exists, whether it never sealed after birth or was later blown open by the pressure differential of the two sides of the heart, CFS can enlarge it through the following process: (1) The cellular energy deficit of CFS leads to diastolic dysfunction of the heart. (2) Textbooks state that diastolic dysfunction leads to dilation (enlargement) of the left atrium and increased right ventricular systolic force. (3) Referring to the diagrams on the website given above or to the arrangement of your hands described above, imagine the two opposing flaps that make up the PFO being pulled farther and farther apart by the left atrial enlargement. (The lower hand being pulled down). The flap that moves and is considered to be the valve is the lower one and is structurally part of the left atrium. The combination of left atrial enlargement and a high right to left pressure difference could explain why nearly 80% of CFS patients have tested positive for PFOs, and why their primary shunting is typically from right to left. As the left atrium expands over time, the PFO may gradually transition from a flap valve to an actual hole. Cardiologists then call it an ASD and usually insist that it has existed since birth, which may or may not be the case in CFS patients. In the context of CFS, with left atrial enlargement and a high right to left pressure differential, the difference between a PFO and an ASD is simply a matter of degree - a distinction without a difference. When the flaps can no longer oppose each other, the PFO becomes an ASD. There is precedent for a disorder in which left atrial enlargement can lead to the formation of an ASD. It's called Lutembacher Syndrome. This disorder is defined as a combination of mitral stenosis and an ASD shunting left-to-right and even bi-directionally. (Mitral stenosis is a narrowing of the valve that lies between the left atrium and left ventricle.) Classic Lutembacher Syndrome is usually described as a congenital mitral stenosis and an acquired ASD. Recently, several variants have been described. Dr. Cheney's research into this subject revealed that left atrial enlargement is part of Lutembacher Syndrome and that left atrial enlargement could produce an ASD by enlarging a PFO or enlarging a pre-existing small ASD. It's worth noting that less than one percent of the general population has an ASD, but that people with mitral stenosis have a much higher incidence rate of ASDs, suggesting that something (such as left atrial enlargement) is actually creating the ASD. Why Not Close the PFO or ASD? Until a few years ago, all PFO and ASD closures involved open-heart surgery and the use of a heart-lung bypass machine. In 2000 the FDA approved a device called CardioSeal. In 2002 the Amplatzer device was approved. CardioSeal contains a nickel-cobalt-chromium-molybdenum alloy. Amplatzer contains nickel and titanium. Both devices are collapsible discs that are threaded though the femoral vein into the heart. Once in place, they open up like umbrellas and anchor to the wall of the atrium with hooks. The ASD or PFO is sandwiched between the two connected metallic mesh discs. Approximately a year ago a patient of Dr. Cheney's with a 15-year history of CFS had a device implanted in his atrial wall via a catheter threaded up the femoral vein. His story is very enlightening. He had several echos done from 2001 to 2004 that showed pulmonary hypertension, but there was no mention of a PFO or ASD in the echo reports. (After recently examining some of those earlier echos, Dr. Cheney noted the classic E/A reversal that denotes diastolic dysfunction.) During that same period the patient was also having brief, unsustained bouts of atrial fibrillation that were gradually becoming worse. In the spring of 2005 the patient had another echo done in his hometown that revealed a 50% ejection fraction (above 55% is normal), mild regurgitation in the tricuspid and mitral valves, a slightly enlarged left atrium, pulmonary hypertension of about 50 mm Hg (normal is 16 mm Hg, primary pulmonary hypertension is anything above 25 mm Hg at rest), and most disconcertingly a very large ASD. The cardiologist emphasized the size of the hole in the atrial wall and told him he'd probably had it since birth. The patient isn't sure he's had the ASD since birth, given his previous health history and the large size of the ASD. It's highly unlikely such a large hole in the heart would go undetected for nearly 60 years. A procedure to close it was done about a year ago. He is the first and only patient of Dr. Cheney to undergo this procedure - at least so far. After a short bout of atrial fibrillation immediately after the procedure, he experienced three weeks during which he felt as if he had been cured. In the last 20 years he'd never felt that good. Then his atrial fibrillation recurred, soon becoming chronic and unresponsive to therapy. Months went by and nothing could control it. His left atrium further enlarged and he deteriorated clinically. Atrial fibrillation is very poorly tolerated when one also has diastolic dysfunction. In February of this year, he went to a nationally renowned clinic for a consultation about his chronic atrial fibrillation. This national clinic is well known for its expertise in a laser procedure called a Mini-Maze used to cure atrial fibrillation. They did an echo and discovered that his heart had nearly been destroyed. Both atrio-ventricular valves were now severely leaking and his ejection fraction was down to 30%. They told him he would die without urgent open-heart surgery. His diagnosis was changed from "chronic atrial fibrillation following ASD closure" alone to now include "valvular heart disease", a diagnosis he'd never had before. He had both valves repaired and the Mini-Maze laser procedure was ultimately successful at stopping the atrial fibrillation. Dr. Cheney credits the surgeon and clinic with saving the patient's life. They told him that with the fibrillation halted, his left atrium would reduce in size. They also told him that the ASD closure device appeared to have "traumatized" tissue growing over its metallic mesh surfaces. (It's normal for endothelial cells to gradually cover the implanted device, though it's not normal for them to become "traumatized".) In May, the patient made several trips to the ER, most for tachycardia (rapid beating of the heart). His fourth trip was prompted by trouble breathing and feeling faint. They found he was experiencing cardiac tamponade - the heart was being compressed by fluid accumulating in the space between his heart muscle and the outer covering of the heart, known as the pericardial sac. That day and the next they used a syringe to draw out a total of over 3 liters of fluid from that space. (That's over 3 quarts!). The patient stabilized enough to finally see Dr. Cheney the last week of June. (I saw Dr. Cheney two days later, after he'd had time to start processing all that he had learned from this patient.) Dr. Cheney noted that the echo done at the patient's June visit looked "pretty good", except that his left atrium was larger than ever, and he still had a significant pericardial effusion (fluid gathering in the pericardial sac) and continued evidence of diastolic dysfunction. His ejection fraction was normal and his heart valves were no longer leaking. In many ways, his situation was pretty stable considering all that had happened. Conclusions Dr. Cheney spent much time describing this case to me, and in turn I have devoted much space to it here because it illuminates some very important points. While it's very likely that some elements of his story are unique to this patient, there is much that suggests that implanting these devices in a CFS patient carries significant risks of which cardiologists may be unaware. His shunting before the closure was likely in both directions. Now, without the ability to shunt blood over to the left side, too much pressure might build up in the right side. He no longer has the safety of the pop-off or release valve effect of the ASD. Some cardiologists are hesitant to close some ASDs for this very reason. The problem is a conundrum because failure to close a large ASD could also result in increased right-sided pressure if the shunt is predominantly left to right under high pressure. The traumatized tissue on the implanted device is what concerns Dr. Cheney the most. The device used for this procedure contains nickel, a heavy metal, and Dr. Cheney believes that the tissue could be reacting to it. (A friend of mine with CFS once mentioned that some of her earrings caused her ear lobes to swell and turn red. She finally figured out that this only happened when the earrings contained nickel.) Nickel poisoning could set in motion Fenton chemistry that could increase his diastolic dysfunction, which would further enlarge his left atrium. Therefore, the use of nickel could be contributing to the very disease process that made its use seem necessary in the first place. (Nickel testing may reveal if he is, in fact, reacting to it). The diastolic dysfunction itself most likely started the enlargement of his left atrium, which may have widened an existing PFO or smaller ASD, and even contributed to the development of atrial fibrillation. Dr. Cheney is convinced that CFS created or interacted with the patient's ASD, especially in light of the new data on CFS and PFOs. His cognitive complaints were slowly developing after CFS onset and may have been connected to or even caused by the evolving ASD and increased right to left shunting. Dr. Cheney's major concerns: [1] If the left atrium is enlarging due to CFS associated diastolic dysfunction, should you even consider implanting a device into it? The continued enlargement expected in untreated diastolic dysfunction might simply cause the tissue growing over the device to stretch and tear. The resulting damage and inflammation might cause the heart to react by building up fluid around it that may result in tamponade (compression of the heart with fluid) or evoke chronic atrial fibrillation. Needless to say, Dr. Cheney has serious reservations about implanting a device to close a PFO in a CFS patient if the left atrium has not yet been stabilized by treating the underlying diastolic dysfunction. [2] Dr. Cheney is also very concerned about the interaction of nickel and the pathophysiology of CFS. Implantation of the closure device containing nickel puts CFS patients at risk for the induction of Fenton chemistry, which will exacerbate the underlying CFS pathophysiology and further enlarge the left atrium. [3] Dr. Cheney suspects that we do not really understand the implications of the presence of the PFO/ASD in the setting of such a complex disorder as CFS, and all the interrelationships that exist. The pop-off valve effect of a PFO/ASD that releases pressure is an example. He is concerned that if the PFO/ASD is closed, a lot of physiology could be changed abruptly, and because it is so complex and interrelated the patient could get worse. Signs of Hope I have saved this final point for last because it's hopeful. Dr. Cheney is very intrigued that the patient described above, who clearly has CFS associated diastolic dysfunction, felt cured for three weeks after his ASD was closed. Obviously, there were problems that would have surfaced eventually, given the state of the tissue over the device and the development of chronic atrial fibrillation. But his "three-week cure" raises the possibility that if it were possible to restore normal pressures to the heart and keep PFOs from opening, or to stabilize the left atrium and keep PFOs from developing into larger PFOs or ASDs, a significant positive clinical transformation might be possible. Dr. Cheney wonders how many of our symptoms are totally, or at least partly, derived from a PFO. He doesn't yet know for sure, but the possibilities are intriguing. Other than open-heart surgery or the implantation of a device containing nickel through a femoral vein, cardiologists have little to offer. However, Dr. Cheney's current study protocol is yielding very interesting early results. And it is early - the study will not be fully completed until late this year or early next year. There are two distinct stages of treatment, and the second has two different dosage groups. There are about 20 participants and they are at different points on the study timeline. Many are just starting the second phase of treatment, so the full benefits of the study protocol have yet to be seen. Two early hopeful indications from the study relate to PFOs and suggest that the treatment protocol is leading to an improvement that is normalizing pressures in the heart and keeping PFOs closed. First, the numbers change as more patients are tested, but currently 67% of study patients test positive for a shunting PFO versus 78% of those not on the study treatment protocol. And it's possible many study patients who are testing positive now will test negative after they've been treated for a longer time. The hope is that those study patients who tested negative are not false negative (i.e. actually have a shunting PFO that was not detected), but have been on the treatment protocol long enough to have improved their cardiac function to the point of keeping a PFO shut. Unfortunately at the time the study began, PFOs were not even on the radar thus making a true baseline for a shunting PFO impossible to determine for many study patients. If this data holds true over time and with larger numbers, this could represent an alternative to open-heart surgery or having a device implanted, at least for many CFS patients. Second, my own experience suggests that the treatment does indeed normalize heart pressures and may keep a PFO closed. I am in the study and have been on the second phase, the porcine heart cell signaling factors, since May 24th. While it was not possible to test me early enough to get a true baseline for a shunting PFO, there is evidence that I have a PFO that was shunting, albeit perhaps only to a mild degree, until just recently. I was negative on the contrast echo at my June 30th appointment, indicating that no shunting was taking place, which is great news and matches my overall improvement. Indications that I may have a PFO that was shunting right to left and is now likely staying closed are: *Increased pressure on the right side of the heart (TRmaxPG on the echo). A high pressure in September of 2005 dropped 35% into the normal range on both my 2006 April and June echos. *Venous blood gas testing showed low PO2 levels in March (possible shunting), but normal levels in May (no shunting). *The echo sonographer described the area of my left atrium where a PFO would be located as "very thin". Dr. Cheney said that's how a PFO typically looks, though this is far from definitive. *I have a history of migraines that do not respond to medication, but have not had any recently. *I had "punctate lesions" or UBOs on an MRI done several years ago. *While wearing a pulse-oximeter clipped to my finger in Dr. Cheney's office in April of this year, my oxygen saturation suddenly and inexplicably dropped to 81% and then rose back to normal (98%). I have been monitoring it since May, and it has not dropped into the 80's (except during intentional breath holding) at any time that I have been aware of. With few study participants even at the halfway point yet, Dr. Cheney is not comfortable giving out treatment protocol information. And even if adjustments in the protocol are not made at the conclusion of the study, his primary concern is that no treatment protocol is ever one-size-fits-all. It's always individualized for each patient. So the treatment protocol needs to be presented in a setting that allows him to provide a context and go into more detail. Dr. Cheney is light years ahead of where he was a year ago when he spoke to our support group here in the Dallas - Fort Worth area. He wants to come speak again and we are working to arrange a date in late August or September. A DVD of the presentation should be available some time after the seminar. Watch for online announcements on the Co-Cure.org announcement list or see our website, dfwcfids.org, for details as they become available. In the meantime, if you are a CFIDS patient and discover you have a PFO or ASD, please think twice before allowing the implantation of a device containing nickel into an atrial wall that is, or will likely be, expanding. Please wait until more is known about these complex issues and until we see what benefit Dr. Cheney's current research study protocol has to offer. Note from the section on the cause of PFOs and ASDs in CFS patients: The increased pressure on the right side of the heart may in part be a result of a left shift on the oxygen-hemoglobin dissociation curve observed in most CFS patients. Interestingly, babies in the womb are left-shifted due to fetal hemoglobin and therefore have higher pressure on the right side of the heart, and of course they have a PFO. All of this is normal, even necessary, for fetuses - but not for adults. In a sense, the left shift and higher right-sided pressures the left shift produces are telling our bodies that we are back in the womb and therefore a PFO is necessary for life - a fact that is not true for adults. The left shift on the oxygen-hemoglobin dissociation curve and the resulting reduction in oxygen transfer into the cells of the body is actually a defense against the redox (reduction-oxidation) problem described in my 2004 article on the heart which can be found on our website, dfwcfids.org. It describes Martin Pall's work, particularly the production of energy (ATP) which generates superoxide in the mitochondria, which under normal circumstances is safely reduced to water by enzymes embedded in the mitochondria and just outside the mitochondria. However, in CFS the enzymes do not seem to function effectively due to a variety of reasons, most of which are the subject of speculation. This allows superoxide to leak out of the mitochondria where it can combine with nitric oxide to form peroxynitrite, a very deadly free radical. Because it takes one superoxide molecule combining with one nitric oxide molecule to produce one molecule of peroxynitrite, the levels of peroxynitrite in the body can be significantly reduced if there isn't much superoxide available to combine with nitric oxide. And in CFS that's exactly how the body defends itself against terrible damage from peroxynitrite - it cuts back on energy production which in turn lowers the production of superoxide. Note: Increasing the energy of a CFS patient is extremely dangerous unless you first restore the enzymes in the mitochondria and the supporting co-factors they need to work well. If superoxide cannot be safely broken down into water and/or peroxynitrite neutralized, inducing energy in a CFS patient will likely result in a major relapse, perhaps worse than any state previously experienced. Be very cautious with any product on the market designed to increase cellular energy in CFS if you haven't first restored the function of the enzymes needed to handle the by-products of such energy production. Of course Dr. Cheney's current study protocols are intended to address this very problem. The push-crash phenomenon, whether on the small day-to-day scale or on a much broader scale, is actually part of the CFS case definition and the principle cause of CFS disability. In effect, the fatigue of CFS is a defense mechanism, and push-crash is simply a way to enforce this mechanism and protect the patient. To summarize, the redox problem in CFS causes the body to actually put mechanisms in place to lower the amount of oxygen getting into cells. This is a protective, compensatory measure. This acute reduction in oxygen to the cells is caused by a left shift on the oxygen-hemoglobin dissociation curve. This results in increased right-sided pressures in the heart. When these pressures are high enough, they can pop open a PFO that was previously sealed at birth. The diastolic dysfunction of CFS also plays into this picture by causing left atrial dilatation and by increasing the right ventricular systolic squeeze. Unfortunately, a PFO with a right to left shunt forces a shift to the right on the oxygen-hemoglobin dissociation curve and can therefore cause serious redox problems by driving oxygen into the cells. PFOs in a CFS patient are therefore a serious menace as they effectively evoke oxygen toxicity throughout the body. In a curious way, CFS and newborns are both supersensitive to oxygen toxicity and for similar reasons. Edited by Paul R. Cheney MD, PhD  
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