This inquiry into cardiovascular issues in CFS was prompted by Dr. Cheney’s startling assertion that a paper published in 2003 was the “best, most important publication in 20 years”. Since that encompasses the modern era of CFS research this means he believes it is the most important paper ever done on CFS!
You can find transcripts of Cheney’s talks with two patients edited by Carol Sieverling here. The paper before you focuses on what studies into cardiovascular functioning in CFS have found.
In this section findings from studies on cardiovascular functioning in CFS are examined. First findings on cardiac tests other than stroke volume are presented and then stroke volume and similar tests are. Like most test results in CFS, they display some heterogeneity but are illuminating.
Testing the cardiac response
Exercise – One would think tests involving exercise – surely the most intense stressor of the heart – would readily reveal any cardiac abnormalities present in CFS. Test of cardiac responsiveness to exercise have had, however, mixed results.
Reduced heart rate during exercise was seen several times prior to 1996, but when a 1996 study that included only CFS patients who engaged in maximum effort did not find reduced heart rates in CFS, it appeared the reduced heart rates seen earlier were probably a function of reduced effort not impaired cardiac functioning (Sisto et. al. 1996).
Reduced heart rate and very high heart rate reserves (HRR) during exercise were, however, found in a 2001 study where CFS patients did engage in maximum effort (Inbar et. al. 2001). (HRR is the difference between the maximum heart rate and the resting heart rate.)
The authors explained high HRR’s could be due to low blood supply to the muscles (due to heart dysfunction or low fitness levels) or to reduced SNS activity (Inbar et. al. 2001). Heart rate and blood pressure were, however, normal directly and 24 hours after exercise in another 2001 study (La Manca et. al. 2001).
Resting heart rate was normal but heart rates and systolic BP was blunted during exercise in a 2003 study (Van Ness et. al. 2003).
Cognitive stress – One might not immediately associate a thinking task with increased heart activity but just as with the muscles the brain needs more oxygen when it is called upon to work. CFS patients have consistently displayed reduced cardiac responsiveness to cognitive stress tests.
Heart rates were significantly lower in CFS patients during math tests (Soetekouw 1999). Systolic BP was inhibited in CFS patients during a speech task (La Manca et. al. 2001). Gulf war vets with idiopathic chronic fatigue or CFS had reduced systolic and diastolic BP to cognitive tests (Perkerman et. al. 2000, 2003a). Systolic BP was inhibited in CFS patients during a speech task (Peckerman et. al. 2003b)
(Layman’s speculation: Because the brain is situated above the heart and thus is especially vulnerable to reduced blood flows in orthostatically challenged individuals, is it possible the more consistent findings of reduced cardiac responsiveness to cognitive stressors reflect problems people with CFS have when upright?)
At rest – Twenty-four ambulatory ECG’s were normal and heart rates were reduced significantly in one study(p <. .0001) (Montague et. al. 1989, resting heart rate was increased in another (LaManca e.t al. 1999), and heart rate did not differ significantly from controls in two more (Peckerman et. al. 2003, Van Ness et. al. 2003).
T-waves measure the electrical pulses beginning at the end of the contraction phase and then continuing as the ventricles dilate to receive blood. Several studies by Lerner that have found T-wave abnormalities in a substantial amount of controls but in virtually all CFS patients suggest negative T-wave tests could contraindicate CFS. A twin study, however, did not find T-wave abnormalities in either healthy twins or twins with CFS.
While there is little consensus regarding cardiovascular responsiveness (heart rate, BP) to exercise, there is ample evidence thus far of impaired cardiovascular responsiveness to thinking tasks in CFS. No heart rate or BP abnormalities have consistently been seen during rest in CFS.
Impedance cardiography is a non-invasive means of testing heart functioning that uses electrical impedance – the interference of electrical signals by liquids – to measure blood flow through the heart. A number of confounding variables (i.e. sex, chest size, percentage of fat, etc.) reduced impedance cardiography’s reliability at one time. A recent study, however, indicated that impedance cardiography generated impressively precise figures.
Impedance cardiography tests indicated that reduced stroke volume in response to tilt was significantly different in CFS.patients who’d had a negative TILT test (i.e. fainted or almost fainted) (La Manca 1999) and only in the more severely ill CFS patients in another (Peckerman 2003).
Tilt tests involve strapping patients to a board and tilting them upwards.They are used to analyze problems that arise when one stands upright -a common complaint in CFS. An abstract of a study indicated that Schondorf found no differences in stroke volume between CFS patients and controls using impedance cardiography (Schondorf et .al 1999). Using finger arterial pressure waveform analysis stroke volume was lower in CFS patients with negative (but not positive) tilt tests.
The 1999 cardiac impedance study done by Natelson’s group was interesting because it examined three potential reasons for reduced stroke volume; preload, afterload and myocardial contractility. So far as I understand it, preload measures the tension in the wall of the left ventricle at the end of the diastolic (filling) phase just prior to contraction.
This apparently occurs when the ventricle is stretched to its maximum amount by inflows of blood. Afterload was formerly known as the amount of blood pressure the heart must overcome to eject the blood but is now measured by the amount of tension the ventricles must produce in order to eject sufficient amounts of blood; people with high blood pressure have a higher afterload.
Myocardial contractility simply appears to measure the contractility of the heart muscle fibers. This study found wall stress and contractility were normal but that the heart walls of CFS patients with positive TILT tests didn’t stretch enough to receive normal amounts of blood. This would presumably be caused by insufficient amounts of blood flowing into the ventricle or because the heart muscle was unable to stretch enough because it had been damaged.
It is important, given impedance cardiography’s somewhat checkered past, that its findings be validated by other tests of cardiac function. In his 2003 paper Peckerman noted that ‘given the level of uncertainty still existing in impedance cardiography, the study findings would need to be confirmed using other methods of cardiography’.
Nuclear ventriculography (MUGA) tests cardiac function by radiating red blood cells and then measuring their passage through the left ventricle as it opens and closes. The ratio between two measures (relaxation volume/contraction volume), called the ejection fraction, measures the degree of ventricular contraction occurring.
Since the heart should display greater contraction under stress the ejection fraction should go up during exercise; i.e. the heart should eject more of the blood available to it.
A large study (n=87) found abnormal wall cardiac motion (AWCM) in 11% and 21% of CFS patients with positive EBV tests at rest and under stress respectively. Cardiac biopsies showed a cardiomyopathy in 3 patients (Lerner et. al. 2004). Lerner indicated this meant a progressive cardiomyopathy was present in some CFS patients.
In another study mild left ventricular dysfunction occurred in 13% of CFS patients. MUGA tests were abnormal in about 13% of CFS patients (Lerner et. al. 1993).
In the most dramatic evidence of cardiac dysfunction yet uncovered Peckerman announced at a conference in 2003 that ejection fractions in CFS patients were normal at rest but in 80% of the CFS patients tested they decreased during exercise (ImmuneSupport 2003).
Ejection fraction – the percentage of blood in the left ventricle ejected – should rise by as much as 50% during exercise. Just as in Peckerman’s 2003 study the more severely ill CFS patients had greater declines in heart performance, but this study appears to indicate higher functioning CFS patients showed cardiac impairment as well.
As of April, 2007, however, his study has still not been published. Lerner found normal resting ejection fraction in CFS but that ‘gross ventricular dysfunction’ occurred with increasing workload. Interestingly abnormal ejection fraction is usually a sign of systolic not diastolic dysfunction. Lerner suggested the fatigue in CFS might be related to a ‘subtle’ cardiac dysfunction (Lerner et. al. 1993)
Most published studies of cardiac functioning have found cardiac abnormalities in a subset (ranging from 11 to 50%) of CFS patients. Cardiac functioning may or may not appear normal during rest but abnormalities of one sort or another are commonly found during exercise and, in particular, cognitive tests.
Tests of cardiac output (stroke volume, ejection fraction) have mostly found reduced cardiac output in subset of CFS patients. An important study verifying cardiac impairment in a large proportion of CFS patients has not yet been published.
Severity of the damage
How severe is the reduced cardiac output in the more severely ill CFS patients found in Peckerman’s study? Statistically the difference in stroke volume between the severe CFS and other groups in the 2003 Peckerman study, while significant, was hardly impressive. Even after subtracting out the less severe from the more severe CFS patients the finding of cardiac insufficiency just exceeded the conditions for statistical significance (p<.03).
In his presentation Cheney overstates the degree of cardiac inhibition the ‘disabled’ CFS patients display when he states that when standing their Q drops ‘to 3.7 liters a minute, a 50% drop from the normal of 7.’ The controls and less severely disabled CFS patients have an average ‘Q’ of 7 when supine and of 4.8 when upright. Thus the more severe CFS patients actually pumped about 20% not 50% less blood (@1 liter/minute) than the healthy but ‘exercised challenged’ controls did.
In the Sieverling paper Cheney states the more severely ill patients Peckerman used in his study have ‘heart failure’ and are on the edge of ‘organ failure’. (Cheney takes some pains to explain that the kind of ‘heart failure’ CFS patients display is not associated with heart attack).
In his paper, however, Peckerman stated the reduced heart output in CFS patients was ‘not likely to fall within the range that would be considered abnormal’. When asked whether the more severe CFS patients were in ‘heart failure’ Peckerman stated ‘Any such conclusion is really beyond the scope of this study.
But what we may be seeing here is a more subtle form’. Lerner also characterized the heart problems in some CFS as ‘subtle’ but did note they had the potential to disrupt everyday activities (so much for subtlety!). Peckerman stated that ‘Present medicine is slowly realizing that there are many people with heart failure that is not clinically evident but which may be progressing in that direction. They walk around with an unrecognized disease that is not being treated’ Peckerman stated his group ‘could not make a statement about heart failure with any certainty based on these preliminary findings.’
However, in a later interview, after announcing the preliminary results of a study measuring ejection fractions Peckerman was quoted as saying “Basically we are talking about heart failure,” Another cardiologist Joseph I. Miller, of Emory University said the reduced ejection fractions found in CFS patients were typically seen in “people with three-vessel heart disease,” Miller told WebMD. “A drop in [blood pumped by the heart] during exercise is not a typical response. It is actually a marker of significant coronary artery obstruction.” (De Noon). Nevertheless Peckerman was also quoted as saying the cardiac dysfunctions seen in CFS were ‘minor’ since they did not show up at rest.
(Layman’s speculation – It may be that when researchers talk about heart problems they do so against the background of overt heart failure and heart attack and that relative to those life-threatening problems the cardiac problems in CFS may seem ‘subtle’ or ‘minor’ even if they potentially present CFS patients with severe difficulties in their day to day lives. There is also always the spectre of patient ‘hysteria’ when talking about such hot-button issues as heart failure and the need to carefully moderate one’s speaking)
It is still difficult, however, to reconcile Cheney’s reported statement that Peckerman’s paper is the ‘best, most important publication’ in the history of CFS with Peckerman’s inability to find any abnormalities in stroke volume or ‘Q’ in over half the CFS patients he examined. No studies – even those using impedance cardiography – have been able to provide statistical proof of reduced stroke volume in CFS patients without breaking them up into subgroups.
Dr. Cheney apparently received a grant for a impedance cardiography machine and is employing it in his practice. Since he should rather quickly gather more information on stroke volume and ‘Q’ and other cardiac issues on CFS patients than any other researchers studies it will be interesting to see what his findings are.
Hopefully during his seminar in June 2005 in Dallas he will address how the less disabled but nevertheless still very hampered CFS patients fit into his new equation. Peckerman’s study on ejection fractions in CFS may be the key to resolving the issue of the less severely affected CFS patients, but it has not, some four years after its initial findings were announced in 2003, been published.
It is possible the less severe CFS patients are not a subject of great concern for Cheney since he doesn’t see that many of them. He has stated the ‘severe’ patients in Peckerman’s study would be mild or moderately ill patients in his practice. As evidence for this; he noted that while the mean arterial pressure (MAP) of Peckerman’s CFS patients didn’t change upon standing, it invariably falls when his patients stand.
(The formula he gives for mean arterial pressure (SBP + DBP/2= MAP) is wrong, however. The real formula for mean arterial pressure (Diastolic BP + 1/3 pulse pressure = MAP) emphasizes diastolic pressure or systolic pressure.) He also states that the heart rates of his patients are also usually lower than normal.
Cheney is also incorrect when he states that since “Natelson requires, as a rule…that you consider coming off all medications …or he may not (have you in his study) that patients from the ‘truly severe end of the spectrum of CFS’ would not participate in his study because they could not tolerate coming off their medications.
It may very well be that the ‘truly severe’ CFS patients do not participate in these kinds of studies as Cheney states but not because they have to come off their medications. At the end of the Peckerman paper Peckerman stated that “many of our patients were on medications…(including) SSRI’s…which may have influenced our results’.
Correlating laboratory abnormalities with symptom expression is an important aspect of validating the importance of a given test. If laboratory abnormalities do not correlate with symptom expression doubt is cast on the centrality of the findings.It has been difficult to find laboratory tests that rise or fall depending on the severity of CFS.
That three studies have found that the sicker CFS patients have more significantly impaired cardiac output bodes well for the idea it play a major role in CFS (Peckerman et. al. 2000, Van Ness et. al. 2003, Peckerman et.al. 2003).
That exercise intolerance – which many CFS patients consider to be a hallmark symptom of their illness – was one of two symptoms correlated with stroke volume, was encouraging as well. It is interesting given the infectious component of some types of heart disease that fever/chills were the other symptoms correlated with stroke volume
In the Sieverling paper Cheney stated that “’Q” in CFIDS patients correlated – with great precision – ‘with the level of disability as judged by validated clinical questionnaires that asked about activities of daily living….(bathing, dressing, etc.).’
There is, however, no information on disability in the 2003 Peckerman/Natelson paper or in the preceding 1999 paper by the same group. The 2003 paper discusses CFS patients in terms of ‘severity’, not disability. The conditions for severity are not strict; “to meet the criteria for severe CFS the participant had to meet the more stringent 1988 CDC case definition of CFS…..In addition at least seven of those symptoms had to be rated as substantial or worse in severity”.
Later Cheney stated “the correlation coefficient of .46 with P value of 0.0002 suggests that the disability levels of those that were disabled was exactly proportional to the severity of their “Q” defect-without exception, and with scientific precision by virtue of their most disabling symptom, post-exertional fatigue. WOW! …”He goes on to say that the results are so “profound because no paper that I know of has been published in 20 years that …so precisely correlates with disability”
But is post-exertional fatigue an analogue for disability? A questionnaire (Activation-Deactivation-Adjective Checklist) taken before and after the study found that the more severe CFS patients did have much greater measures of ‘tiredness’. The results section of the paper, indicated, however, that the more severe CFS group did not have a significantly reduced activity levels compared to less severe CFS group.
A self assessed measurement of ‘energy’ (Activation-Deactivation-Adjective Checklist) also did not find any significant differences in ‘energy’ between the more severe and less severe CFS patients. It is unclear, then, how disabled they were.
Cheney is also incorrect when he states that it was post-exertional fatigue alone that accounted for so much of the variance. The Peckerman paper stated that ‘the proportion of variance in the mean cardiac output values explained by the linear combination of thethree symptoms (R2=0.46, p<.00002)…..’ (post-exertional fatigue, fever-chills and improved memory/concentration (?)), i.e., the severe CFS patients were distinguished from the less severe CFS patients because they had worse post-exertional fatigue and fever/chills and better cognition.
Thus while exercise intolerance is the hallmark symptom for many people with CFS, the fact that many of the symptoms associated with CFS; (‘weakness’, sore throat, swollen lymph nodes, memory/concentration problems, headache, joint pain) were not correlated with stroke volume suggests it may not play a role in exacerbating them.
Since reduced stroke volume should result in reduced brain blood flows one might have expected these patients to have more problems with cognition yet the patients with more severe CFS appeared to have better memory/concentration scores than the less severe CFS patients.
Thus while it was encouraging that exercise intolerance was correlated with ‘Q’, it was discouraging that it was only negatively correlated with two of the symptoms found in CFS. These tests are very subjective and their results can be quite variable.
Peckerman’s and Cheney’s statements regarding the same finding differ dramatically in emphasis. Taking a conservative approach it appears that one can safely say based that a cardiac dysfunction sufficient to produce some of the symptoms of CFS but not to cause heart attack appears to occur in a set of CFS patients.
Since Dr. Cheney, by his own account, has a more severely ill patient population than normal, his findings may not necessarily reflect those of the typical CFS patient. This summary is complicated by Peckerman’s missing study which appears to suggest that even less severe CFS patients have impaired heart function.
Reduced stroke volume was correlated with one of the hallmarks of CFS, reduced exercise intolerance but not with many of the other symptoms associated with CFS. How important reduced stroke volume plays in producing the symptoms of CFS is unclear.
Causes of low stroke volume
Both LaManca et. al. (1999) and Peckerman et. al. (2003) note several possible reasons for the reduced stroke volumes seen in a subset of CFS patients. These include heart damage, low blood volume, autonomic nervous system dysfunction, hypothyroidism and deconditioning.
In the Sieverling paper Cheney appears convinced that heart damage, probably caused by a nexus of factors that include pathogens and toxins, is responsible for the cardiac insufficiency shown in some studies.
The Frustaci Paper – An important facet of Cheney’s theory is provided by a 1999 Italian study that found, during an analysis of the trace elements (TE’s) in muscles and hearts of idiopathic (origin unknown) cardiomyopathy (IC) patients and other heart disease patients, astoundingly high levels of mercury (22,000 x’s) and antimony (12,000 x’s normal) and elevated levels of other metals (gold – 11 x’s, chromium – 13 x’s, cobalt – 4 x’s) only in the hearts (not the muscles) of patients with idiopathic cardiomyopathy (Frustaci et. al.. 1999).
The authors speculated that virally induced cell membrane damage could result either in increased ingress of TE’s into the cell or reduced transport of TE’s out of the heart cell. They suggested mitochondrial damage occurred when free radicals from the increased heavy metal loads inhibited the sodium pump and other ion channel transporters.
Electron microscopy of the heart cells indicated various degenerative changes including fragmentation of the internal membranes found in the mitochondria. Alternately the authors suggested that by ‘antagonizing’ CA++ at the actin-myosin junction, heavy metals could induce declining heart muscle contraction and thus heart cell functioning.
Changes in calcium levels at the actin-myosin junction induce muscle contraction. Actin-myosin make up the essential contractile element of muscle fiber.
(The findings of such unexpectedly huge elevations of mercury in the heart cells of IC automatically raises a red flag. Could a laboratory error have been made? The Frustaci paper stated, however, that several factors that have skewed TE analysis of tissues in the past that were avoided in this study. Cheney noted the great precision of the instrument used to measure the TE loads. He also noted that a professor he admires stated it was impossible for heart tissue to contain that much mercury because there simply aren’t enough sites for mercury to bind to. This means, he believes, a pathogen must have brought it in. One of the few studies on this subject found that feeding mice methyl mercury increased rates of viral infection in their heart tissues but did not, not interestingly increase heart tissue mercury levels.)
No follow up studies have been published in the six years following the publication of the Frustaci paper. Heart disease is one of the major killers of our times and a great deal of research devoted to it; just last year the NIH allocated 2.4 BILLION dollars in research grants for cardiovascular research.
A PubMed search of ‘heart disease’ brought up over 1200 papers that had been published in the first five months of 2005 alone. Another search using ‘arteriosclerosis’ brought up almost 500 papers.
Yet this study – which provided a startling finding that one would think might shed some light on this major health concern – has had no follow up studies in the five years since it has been published. Mercury contamination of the heart tissues, rightly or wrongly, does not appear to be considered a major cause of heart damage by the research community.
The relative lack of interest in this area can be seen in the references in Frustaci’s paper; almost half of which are at least 10 years old and a good portion of which date back to the seventies.Cheney states ‘a great deal of evidence’ implicates heavy metals in heart disease but that research is almost totally devoted to iron and copper, not the heavy metals Frustaci found. Frustaci is, however, not a one-shot wonder. His publication record on heart research is impressive.
A report from the 2005 AACFS conference indicating increased RNase L fragmentation impairs mercury clearance from the cells provides a potential mechanism for increased cell mercury levels in CFS. No studies have examined mercury levels in CFS patients but Dr. Cheney regularly tests for them.
Cheney’s theory certainly has some logical underpinnings. But is there any direct evidence to date of heart damage in CFS?
Only Lerner has directly examined the hearts of CFS patients. He found heart tissue damage in CFS patients with high titers of antibodies to the HCMV virus which is able to cause heart damage (see below). Since most CFS patients do not display similar antibody levels his findings, however, may apply to only a subset of CFS patients. Dr. Cheney’s continuing studies on diastolic dysfunction have continued to find abnormalities but have yet to find strong evidence of heart damage damaged; i.e. heart enlargement.
If heart damage has occurred the most likely culprit is probably a virus.
There is no question regarding the role viruses play in heart disease. Several of the pathogens listed as possible contributing factors to heart disease occur with some frequency in CFS.
The Lerner group in Michigan has been investigating viral induced cardiac dysfunction in CFS for over 10 years. In 1993 Lerner found abnormal T-wave oscillations that appeared to indicate left ventricular dysfunction in CFS.
Ultimately Lerner and his group developed a theory that posited immune system breakdowns lead to incomplete/complete herpesvirus (EBV/HCMV/HHV6) multiplication in the hearts of CFS patients. He asserts these epitopes may be responsible for the cardiac damage seen in some CFS patients.
Low blood volume
Since large quantities of blood pool in the pelvic area and abdomen upon standing, people with low blood volume experience particularly low cardiac blood volumes when they stand.
Several studies have indicated a subset of CFS patients have reduced blood volume. Cheney has included ‘volume loaders’ in his treatment protocol for several years. The renin-aldosterone-angiotensin system – the main regulator of blood volume – is disturbed in CFS. Studies have found that CFS patients with low blood volume exhibit reduced levels of the substances (renin/aldosterone) that are usually elevated during low blood volume. Several studies are examining low blood volume in CFS (see below).
Peckerman found, however, that relative to controls, stroke volume in CFS patients was inhibited more when they were laying down than when they stood up. Because blood flows to the heart decrease upon standing people with low blood volume should show an even greater relative reduction in stroke volume when they stand. the opposite, however, occurred – the greatest relative difference in stroke volume between CFS patients and controls occurred when they were lying down; the hearts of CFS patients pumped out about .8 liters less a minute than the sedentary controls when standing and about 1.3 liters a minute less when supine.
This indicated the heart functioned less well when when it was exposed to greater flows of blood and strongly suggested it was not blood volume but problems with the heart muscle that were causing the stroke volume problems.
This appears to the best evidence yet of heart damage in CFS. Peckerman noted, however, one study that found reduced supine cardiac output in patients with low blood volume (!). It is interesting, as well, that decreased blood volume appears to decrease preload – the abnormality that typically appears to be found in CFS.
The extent and effects of low blood volume in CFS clearly needs more study – which it is getting (see below).
Autonomic nervous system dysfunction: Since the ANS is the main regulator of cardiovascular activity, ANS dysfunction could effect both cardiac and vascular activity. The sympathetic branch of the nervous system (SNS) regulates heart activity when we are upright and parasympathetic nervous system (PNS – vagus system) does so when we are supine.
Peckerman suggests that vagal withdrawl while we are supine could result in the greater relative decrease in stroke volume seen in CFS; when CFS patients are are erect, on the other hand, SNS jumps in to at least partially ameliorate the problem. CFS patients display indications of both reduced PNS and increased SNS activity.
The reduced heart rate variability (HRV) (with an increased low frequency peaks) during tilt that CFS patients consistently display suggests increased sympathetic tone (activity) and decreased parasympathetic tone (activity) do occur in CFS. CFS patients also displayed reduced vagal ‘power’ during and after walking (Sisto et. al. 1995, Cordero et. al. 1996). Stewart has found evidence of increased vasomotor tone (sympathetic activity) in CFS and complete vagal withdrawl (Stewart 2000). The vagus nerve is the nexus of the PNS.
Vascular – The vascular response involving the constriction and dilation of the veins and arteries is the other side of the cardiovascular response. Mostly controlled by the ANS proper vascular resistance is critical to maintaining blood pressure. If the veins and arterioles do not constrict when we stand blood pooling in the veins and capillaries will reduce blood volume and heart output.
Peckerman’s theory that normal BP in severe CFS patients is achieved at the cost of reduced circulation suggests an at least adequate and perhaps overactive sympathetic response. Among the several indications of overactive sympathetic activity in CFS are increased circulatory NE levels and reduced NE re-uptake. It is intriguing that an overactive sympathetic response can cause low blood volume, which of course can lead to reduced stroke volume.
Vascular problems in CFS have been best studied by researchers engaged in examining orthostatic intolerance and postural tachycardia syndrome (POTS). They have found certain subsets of POTS and CFS patients display vascular problems that could inhibit the circulation (see Orthostatic Intolerance I: The Evidence, Orthostatic Intolerance in CFS II – Types and Orthostatic Intolerance in CFS Pt. III – Possible Causes).
In particular one subset of postural tachycardia syndrome (POTS) and CFS patients called ‘low-flow’ POTS patients exhibit defective local blood flow regulation, decreased venous peripheral capacity and probably reduced blood volume of some degree (Stewart and Montgomery 2004).
They appear to have undergone ‘venous remodeling’ with a subsequent reduction in vein area in the lower extremities. This could be due to a persistent vasoconstriction or to reduced blood volume. These patients appear to fit well with Peterson’s and Cheney’s suggestions that blood pressure is maintained at the expense of circulation.
If the arterioles vasoconstrict in order to decrease blood vessel area and thus increase blood pressure then blood flows to the capillaries and the veins will be reduced. This could result in the veins ‘remodeling’ themselves to accommodate the reduced blood flows.
While Cheney posits the reduced blood flows are due to heart problems the researchers concentrating on orthostatic intolerance believe they are due to problems in the local vasculature (see Orthostatic Intolerance in CFS II – Types).
In another subset of POTS and CFS patients reduced arteriole vasoconstriction results, this time in contrast to Cheney’s theory, inincreased blood volume in the capillaries. These patients are designated ‘hi-flow’ because they exhibit higher than normal flows of blood in their lower extremities.
The current theory regarding these patients posits they have a ‘long axon’ neuropathy that interferes with norepinephrine (the chief vasoconstrictor) production in the lower extremities (Stewart 2004). Interestingly there is a potential viral tie-in here; Stewart (2004) reports that as with CFS patients, hi-flow POTS patients often experience infectious events just prior to getting POTS.
These patients appear most amenable to treatment; they tend to have very positive responses to alpha adrenergic receptor enhancers such as Midrodine that cause the blood vessels to vasoconstrict.
A research group allied with MERGE has also – in contrast to Cheney’s theory – found increased skin blood flows in CFS (Khan et. al. 2003, Spence et. al. 2004). Preliminary findings suggest decreased acetylcholinesterase (AChE) levels result in prolonged blood flows in the capillaries of the skin of CFS patients.
Various cholinergic abnormalities including increased brain choline levels and antibodies to cholinergic receptors appear to occur in CFS. It is interesting given these findings that acetylcholine is the chief agent of cardiac parasympathetic activity.
Could the increased PNS activity seen in heart rate readings be associated with the increased acetylcholine activity MERGE found? Spence and Khan also note a possible viral tie-in; decreased AChE activity occurs in herpes simplex virus infection (See Orthostatic Intolerance in Chronic Fatigue Syndrome (ME/CFS) IV: A Biomarker?).
Total peripheral response (TPR) is one measure of vascular resistance. Reduced TPR in Gulf War veterans with either idiopathic CF or CFS appeared to be the cause of reduced cardiovascular responsiveness to cognitive tests (Peckerman et. al. 2000).
A normal TPR response to a test of local SNS function (a cold pressor test) in this same group suggested that the central dysregulation appeared to originate in areas of the brain regulating cognitive and autonomic activities. They noted that low BP responses to cognitive stressors can be a symptom of abrain disease that interferes with the brains ability to regulate sympathetic activity.
A follow up study found, interestingly enough, that fatigued vets without post traumatic stress disorder (PTSD) had diminished peripheral resistance during cognitive tests but that only vets with PTSD had reduced cardiac output (Peckerman et. al. 2003a).
Interestingly fatigued vets were able to achieve normal BP readings because they, in contrast to PTSD/CF vets, were able to increase their cardiac output (Q) enough to overcome their poor TPR levels. Thus these vets – obviously an unusual subset of CFS patients – were able to increase their heart output in order to make up for a dysfunction found elsewhere.
In summary, there is evidence for both decreased and increased blood flows to the microvasculature. While Cheney believes decreased microcirculatory blood flows are due to heart damage, other research groups believe altered microcirculatory flows are either due to nerve damage in the legs, low blood volume, or dysfunctional blood vessel functioning. Some evidence suggests a small subset of CFS patients (Gulf War vets) are able to increase their cardiac output to make up for reductions of peripheral resistance that are likely tied to ANS dysfunction.
Thus there is evidence to support Peckerman’s suggestion that increased SNS and decreased PNS activity in CFS could be responsible for the low ‘Q’ seen in CFS patients.
The physical limitations CFS poses on many place them as risk of deconditioning; a state in which reduced physical activity adds a layer of disease onto the original illness. Many illnesses can result in temporary but still prolonged periods of bed rest but in almost none has the specter of deconditioning been so prominently raised.
Adherents of the deconditioning paradigm believe that CFS patient’s fear of activity leads them into vicious cycle of fear induced bed rest and symptom exacerbation that leaves the CFS patient terminally bed bound. Thus exercise intolerance – one of the key symptoms of CFS – ultimately sets the stage for a somewhat logical but ultimately devastating regimen of more and more bed rest.
Since constant bed rest can result in impaired cardiovascular functioning it must be accounted for in CFS. Reduced heart rates, stroke volume and reduced blood volume (as well as orthostatic intolerance) can all be caused by constant bed rest. There doesn’t seem to be any doubt that constant bed rest will impair cardiac functioning in CFS or any other kind of patient; the question is how much of the reduced stroke volume found is due to deconditioning and how much is inherent to CFS?
Deconditioning was suggested to account for the increased heart rates and reduced left ventricular wall thicknesses (De Lorenzo 1998). A 2002 study, however, found reduced blood volume more likely played a role in the reduced V02 max levels seen in CFS than reduced activity levels.
The only study I have been able to find that explicitly looked at deconditioning in CFS patients did not find evidence for it (Bazelmans et. al. 2001). Other studies, however, have found evidence of it (Fishler et. al. 1997).
CFS – A disease of impaired microcirculation?
One way to test a theory is to examine if what it predicts occurs. Both Peckerman and Cheney suggest the cardiac insufficiency seen could result in impaired circulation. Is there evidence for this in CFS?
Two studies have examined blood flow in the cerebral arteries in the brain. One found blood flow was significantly reduced and the other found a trend towards reduced blood flows. (Due to poor sample selection the second study may have overestimated cerebral blood flows in CFS patients relative to controls.)
Two studies examining blood flows to the muscles have found evidence of both reduced and normal blood flows to the muscles of CFS patients. The most recent study found reduced blood flows (but no effect on oxidative metabolism) (McCully et. al. 2003, 2004). Several studies have found reduced blood perfusion in the brain.
One could almost ask what future? Peckerman co-authored six studies on CFS in 2003 but has not produced any studies since then. Peckerman’s sponsor, Benjamin Natelson, has lost funding for his CFS research center and is not currently engaged in cardiovascular research in CFS. Dr. Peckerman had enough data to present intriguing findings on left ventricular dysfunction on CFS at a conference in 2003 but has never published a paper on it.
Despite the apparent success Peckerman had in differentiating more from less disabled CFS patients – one of the chief reasons his study was sponsored – there was no follow up from the NIH for his 2003 study. No NIH grants for cardiac studies on CFS currently exist.
Aside from ongoing Lerner studies on antiviral treatment in EBV infected CFS patients, only studies examining subjects ancillary to cardiac function appear to be ongoing in CFS
Snell has a grant from the CAA to comprehensively examine the physiological responses CFS patients display to exercise. Since this study will examine central nervous system activity, hormonal and cardiovascular responses it should help to pin down central factors in the exercise intolerance seen in CFS.
Hurwitz is currently engaged in a large study on red blood cell (RBC) mass that should characterize the extent and effects of low blood volume in CFS.
Just as cardiac research into CFS seemed on the brink of success it apparently lost its funding. Despite his pro-activeness in the clinical area Cheney is not a researcher, per se and has not co-authored a paper in eight years. His influence, therefore, while large within the patient and clinical community, is probably somewhat muted in the research world. Thus his theory, while intriguing, needs the attention of a researcher with funding for it to make a difference in the CFS research community.
Cheney has some suggestions that may help cardiac functioning – most of which are not new and only one of which sounds particularly promising. A report from one of Cheney’s patients indicates he believes there is no quick fix for the kind of heart damage he believes has occurred in CFS.
In contrast to almost all other cases of ‘heart failure’, if that is what CFS patients have, CFS patients can take some comfort in the fact that their ‘heart failure’ appears to progress only very slowly, if it progresses at all. We have also seen that reduced stroke volume can be caused by several factors, not all of which involve heart damage. In a recent video Cheney reported that a large percentage of his patients (@80%) show signs of diastolic heart failure.
Cardiac problems sound scary and cast a rather ominous gloom over CFS. Yet the news may not be all bad. First there is no indication at all that CFS patients are in danger of imminent heart failure. Indeed, one reason there has been so little cardiac investigation into CFS, is that even long term CFS patients rarely exhibit signs of overt heart failure.
Second, cardiovascular research in the US is the beneficiary of a huge amount of research money every year ($2.5 billion from the NIH). There may be no field in medicine which has advanced more quickly in the last twenty years. If CFS patients do end up having heart problems it is possible they will ultimately become the beneficiary of a very active research field.
CFS patients generally display normal parameters of cardiac functioning (heart rate, blood pressure) at rest but can exhibit reduced cardiac functioning during exercise and, in particular, appear to do so during TILT and cognitive stress tests. While one researcher has found extensive T-wave abnormalities in CFS patients a follow up study by an independent laboratory found none.
The inability of any study to find reduced stroke volume in CFS patients without breaking them up into subsets suggests it plays a major role in only some patients. Lerner’s studies suggest a subset of CFS patients display a progressive cardiomyopathy that can be ameliorated using antiviral drugs.
Study into the intricacies of heart functioning in CFS , given the complexity of the field, is still in a very preliminary stage. The cause of the reduced stroke volume seen in some CFS patients is unclear; it could be due to heart damage, low blood volume, dysfunctional autonomic nervous system functioning or deconditioning. There is evidence for both increased and decreased microcirculatory flows in CFS.
The studies into cardiovascular functioning in CFS have lead us into some very familiar territory; the results lack consistency but are intriguing. More study – much more study – is needed. Peckerman’s test results need to be verified using other methodologies. Peckerman’s missing study needs to be published. The role heart damage, low blood volume, autonomic nervous system functioning and deconditioning play in the low cardiac functioning seen must be elucidated
Despite the many unanswered questions the amount of work beginning to gather – from several different angles – around the issue of circulatory and cardiovascular dysfunction in CFS is encouraging.
- A Guide to Cardiovascular Issues in Chronic Fatigue Syndrome. Part II: the Cheney Theory – An Inquiry
- Cardiovascular Issues in CFS/ME Part III: Assessing Diastolic Heart Failure
- A Guide to Cardiovascular Issues in Chronic Fatigue Syndrome Part IVa: Superoxide and the Heart
- A Guide to Cardiovascular Issues in CFS IVb: Peroxynitrite and the Heart
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