Great Summary of Cardiac Issues/CFS

[Guest guest]

This is a superb summary of cardiac issues in CFS

looking at the data Cheney has been citing in his new

theory. Don't you love it when someone digs deeper to

give some real context to the assertions which get

floated about causes and cures?

Jim

http://phoenix-cfs.org/Cardiovascular%20Studies.htm

CFS PHOENIX

A Laymen’s Guide to Cardiovascular Issues in CFS:

Part I - Testing the Heart, Stroke Volume, Future

Research

By Cort

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 by clicking here. The paper

before you focuses on what studies into cardiovascular

functioning in CFS have found.

Please note that as the title indicates I am a laymen

trying to make my way through some very complex

subjects. Please send any clarifications, potential

changes or comments to me at phoenixcfs@....

Thanks.

THE STUDIES

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.

While the ANS modifies heartbeat rate the basic

frequency of the heartbeat (@105 x’s a minute) is

determined by the cardiac pacemaker cells.

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 normal

directly and 24 hours after exercise (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)

(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 was reduced significantly (p <. .0001)

(Montague et. al. 1989, resting heart rate was

increased (LaManca e.t al. 1999), and heart rate did

not differ significantly from controls (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 ventricules 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.

Summary: 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.

STROKE VOLUME

The Tests – 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.

Using impedance cardiography reduced stroke volume in

response to tilt was significantly different only in

CFS.patients with 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). Judging from an abstract only, 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

reasons for reduced stroke volume; preload, afterload

and myocardiac contractility. So far as I understand

it, preload measures the tension in the wall of the

left ventricule at the end of the diastolic (filling)

phase just prior to contraction. This is apparently

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 ventricules must produce in order to

eject sufficient amounts of blood. Obviously someone

with high blood pressure would have a higher afterload

requirement. Myocardial contractility simply appears

to measure the contractility of the heart muscle

fibers. This study found wall stress and contractility

were normal but that, in crude terms, it sounds like

the heart walls of CFS patients with positive TILT

tests didn’t stretch enough to receive normal amounts

of blood. This could presumably be because there

wasn’t enough blood flowing into the ventricle to

force to it to stretch or because due to heart disease

it couldn’t stretch enough. The reduced preload found

is apparently the reason for the title of Cheney’s

June 2005 seminar in Dallas; CFS and Diastolic

Cardiomyopathy.

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. (Not all the

blood is ejected from the left ventricle at rest).

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).

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. This study has not, however, yet been published.

Lerner also found normal resting ejection fractions

but that ‘gross ventricular dysfunction’ occurred with

increasing workload. Interestingly ejection fraction

is usually a sign of systolic not diastolic

dysfunction. He suggested the fatigue in CFS might be

related to a ‘subtle’ cardiac dysfunction (Lerner et.

al. 1993)

Summary: 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).

The severe CFS patients pumped about 20% less blood

(@1 liter/minute) than the healthy but ‘exercised

challenged’ controls did. 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 the kind

of ‘heart failure’ CFS patients display is not

associated with heart attack).

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’ Thus he indicated CFS patients could have a

‘subtle’ form of heart failure that was unrecognized

but could still conceivably account for many of the

symptoms seen in CFS. Whether CFS patients have ‘heart

failure’ was pure conjecture at this point, however,

he stated his group ‘could not make a statement about

heart failure with any certainty based on these

preliminary findings.’

After announcing the preliminary results of a study

measuring ejection fractions Peckerman was quoted as

saying, however, " Basically we are talking about heart

failure, " Another cardiologist ph I. , of

Emory University said reduced ejection fractions are

typically seen in " people with three-vessel heart

disease, " tells 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.

(Speculation - It may be that when researchers talk

about heart problems they do so against the background

of overt heart failure and heart attack; 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.)

It is still difficult, however, to reconcile Cheney’s

statement that Peckerman’s paper is the ‘best, most

important publication’ ever 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. Similarly Dr. Cheney must account for the

fact that 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. Cheney, in fact,

never says this study applies to less disabled CFS

patients; he appears to be always careful to note he

is talking about the 'more disabled' CFS patients.

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, if he chooses

to release the information, what his findings will say

about the range of CFS patients that he sees.

Hopefully during his seminar in June in Dallas he will

address how the less disabled but nevertheless still

very hampered CFS patients fit into his new equation.

(A videotape will be available). 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 two years after its initial

findings were announced, 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 of Peckerman’s CFS patients didn’t change

upon standing, it invariably falls when his patients

stand. The heart rates of his patients are also

usually lower than normal. But not lower stroke volume

or ‘Q’???. (Since he is clinician of great renown one

might think he would have a larger pool of patients

who, because they can fly great distances to see him,

are probably in less severe shape than others??)

Cheney is incorrect, by the way, 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’.

Symptom correlation - 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

a given abnormality. It has been difficult to find

laboratory tests that rise or fall depending on the

severity of CFS. Although immune tests generally have

not, the degree of RNase L fragmentation does as do

indices of oxidative damage.

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

Cheney stated as well 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.).’ It is unclear,

however, where Dr. Cheney got this information from.

There is 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 that 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 "

Cheney is obviously referring to something as he goes

into quite some detail but he is not referring to any

study done by the Natelson group on cardiovascular

functioning.

Later he 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! ... " Thus he indicates

that for him the degree of post-exertional fatigue

experienced is an appropriate analogue for disability.

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? In the results section of the paper

Peckerman stated that the more severe CFS group did

not have a significantly reduced activity levels

compared to less severe CFS group, a finding that puts

into question how ‘disabled’ this group was. They felt

worse, their symptoms were worse but they did not

indicate that their activity levels were reduced more

because of CFS than the ‘less severe’ CFS patients.

Cheney is also incorrect in stating that it was

post-exertional fatigue alone that accounted for so

much of the variance. Actually " the proportion of

variance in the mean cardiac output values explained

by the linear combination of the three symptoms

(R2=0.46, p<.00002)…..’ (post-exertional fatigue,

fever-chills and improved memory/concentration). 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 does not play a role in

exacerbating them. One might have thought, in

particular, that reduced blood flows to the brain due

to reduced stroke volume would have been the source of

the memory/concentration problems but the more severe

CFS patients with reduced 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.

(Question: How did exercise intolerance get to be one

of the ‘minor’ symptoms? Since exercise intolerance is

one of my key symptoms it makes me wonder about the

definition of the disease and the makeup of these

study groups. This study indicates reduced cardiac

output appears to be an important feature of those CFS

patients with increased exercise intolerance and

fever/chills.)

Summary – Peckerman’s and Cheney’s statements

regarding the same finding differ dramatically in

emphasis. Taking a conservative route, it appears that

one can safely say based on the evidence presented

thus far, 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.

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.

Heart damage - 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 substance 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? A

section of the Frustaci paper is devoted to noting

several factors that have skewed TE analysis of

tissues in the past that were presumably 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; 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

importantly, did not increase heart tissue mercury

levels.)

No follow up studies have been published in the six

years following the publication of the Frustaci paper.

The lack of follow up to this study is one of those

conundrums that just chafe at patients. 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 this year.

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. This is

apparently not a paper that rocked the cardiac

research world! 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. It is a ‘fringe topic’. 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 that indicated

increased RNase L fragmentation impairs mercury

clearance from cells provides another mechanism for

increased cell mercury levels in CFS. Since RNase L is

one of the chief cellular antiviral agents, RNase L

fragmentation in suggests impaired antiviral defenses

in CFS as well. While I don’t know of any published

evidence of increased mercury levels in CFS Cheney

regularly tests for mercury levels and presumably has

ample evidence for increased mercury levels in CFS.

Cheney’s theory certainly has its 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.

If heart damage has occurred perhaps the most likely

culprit is a virus.

Viruses – There is no question regarding the role

viruses play in heart disease. Note that several of

the pathogens listed as possible contributing factors

to heart disease in the chart below appear to occur

with some frequency in CFS.

*from Stedman’s Online Medical Dictionary

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. Efforts to link a specific

virus to CFS, however, have had mixed results. Lerner

points out that these studies rarely test for

non-structural viral epitopes that can be released

during incomplete viral replication. He asserts these

epitopes may be responsible for the cardiac damage

seen in some CFS patients.

Completely replicated viruses (virions) consist of a

capsid (containing DNA) that is surrounded by a viral

tegument (containing the factors necessary for viral

synthesis), which in turn, is surrounded by a lipid

bilayer. The lipid bilayer contains the epitopes that

are typically recognized by the immune system. If

viral replication is not complete, however, then

non-structural viral epitopes can be exposed an immune

system that is poorly adapted to deal with them.

Lerner has found two subsets of CFS patients who

contain antibodies to either non- structural EBV or

HCMV epitopes. (Lerner et. al. 2002, Lerner et al.

2004b). Their findings regarding incomplete virus

replication have been buttressed by a recent study

finding antibodies to non-structural EBV enzyme

epitopes in some CFS patients (Glaser et. al. 2005).

As mentioned earlier the Lerner group has found

evidence of heart damage in CFS patient with high

antibody titers. While cardiac biopsies of 15 CFS

patients with high titers for the HCMV antibody were

negative for HCMV, a morphological examination of

their heart tissues revealed heart fiber disarray,

dissolution, ‘dropout’ and occasional hypertrophy.

Cardiac biopsies had to be stopped, however, after

some patients developed extensive bleeding.

A antiviral therapy trial finding much decreased

symptom scores and increased energy index point scores

and ventricular functioning for about 2/3rds of CFS

patients at 18 months suggests viral cardiomyopathy is

a central feature of CFS in some patients (Lerner et.

al. 2002a). Other antiviral trials are currently in

progress. (See EYE ON…..The Researchers). These trials

are specifically directed at patients with high titers

of the relevant antibodies and thus are likely to be

relevant only for a subset of 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; paradoxically 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.

Peckerman indicated the increased cardiac

insufficiency while supine suggested the heart

functioned less well when in an environment in which

it is exposed to greater flows of blood. Patients with

heart failure exhibit the same pattern. Judging from

the charts in Peckerman’s paper when standing the

hearts of CFS patients pumped out about .8 liters less

a minute than the sedentary controls; when supine the

CFS hearts pumped about 1.3 liters less a minute. 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) does so when we

are supine. Peckerman suggests that vagal with drawl

while we are supine could result in the greater

relative decrease in stroke volume seen in CFS; when

we are erect the SNS jumps in to at least partially

ameliorate the problem. CFS patients display

indications of both reduced PNS and increased SNS

activity.

Cardiac - 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) in CFS. CFS patients

also displayed reduced vagal ‘power’ during and after

walking (Sisto et. al. 1995, Cordero et. al. 1996).

has found evidence of increased vasomotor tone

(sympathetic activity) in CFS and complete vagal

withdrawl ( 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 capillary filtration will

reduced blood volume and heart output. Both Cheney and

Peckerman have suggested reduced circulation resulting

from reduced cardiac output is a key problem for the

more severely effected CFS patients.

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 II,

Orthostatic Intoleranc III).

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 (

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

’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 then to 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 II).

In another subset of POTS and CFS patients reduced

arteriole vasoconstriction results, this time in

contrast to Cheney’s theory, in increased 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 ( 2004). Interestingly

there is a potential viral tie-in here; (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 with 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.

Spence and Khan also note a possible viral tie-in;

decreased AChE activity occurs in herpes simplex virus

infection (See Orthostatic Intolerance IV).

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 a brain

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.

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.

Deconditioning - 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 but the area has varied according to the study.

Future research

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,

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 (See EYE ON….the

Researchers).

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 ((See EYE ON….the Researchers)

Klimas received grants in 2001/2002 from the National

Institute of Allergy and Infectious Research to study

the causes of low blood volume in CFS. She mentions

the possible connection low blood volume may have to

reduced stroke volumes in her abstract. (See EYE

ON….The Researchers). Unfortunately Dr. Klimas did not

return queries regarding her current research projects

and the status of this project is unknown.

Hurwitz is currently engaged in a large study on RBC

mass that should characterize the extent and effects

of low blood volume in CFS (yes, see EYE ON….The

Researchers).

Just as cardiac research into CFS seemed on the brink

of success it has apparently lost its funding. Despite

his pro-activeness in the clinical area Cheney is not

a researcher, per se; although he was once fairly

prolific he has not co-authored a paper in eight

years. His influence, therefore, while large within

the patient and clinical community, is 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.

That does not appear to be happening.

The Future – Cheney has some suggestions that may help

cardiac functioning – most of which are not new and

none of which sound particularly promising. A report

from one of Cheney’s patients indicates there is no

quick fix for the kind of heart damage Cheney

speculates may have occurred. Indeed, in contrast to

diseases in other organs, heart disease is rarely

cured. As we have seen, however, reduced stroke volume

can be caused by several factors, not all of which

involve heart damage. Nor, according to one of

Cheney’s patients, do all Cheney patients have reduced

stroke volume.

Cardiac problems sound scary and appear to cast a

rather ominous gloom over CFS. Who after all wants

heart problems? If heart problems do exist in CFS,

however, this is not necessarily terrible news. 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 they may ultimately become the beneficiary of

a very active research field.

Summary: 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 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. This is highlighted by inability of the

Peckerman study to find abnormalities in less than

half the CFS.. 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 however, 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.

Thus several studies into cardiovascular functioning

in CFS have lead us into some very familiar territory;

the results lack consistency but are intriguing. There

are still no easy answers in CFS. 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 found. The role heart

damage, low blood volume, autonomic nervous system

functioning and deconditioning play in the low cardiac

function 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 functioning

in CFS is encouraging.

References

Bazelmans E, Bleijenberg G, Van Der Meer JW, Folgering

H. 2001. Is physical deconditioning a perpetuating

factor in chronic fatigue syndrome? A controlled study

on maximal exercise performance and relations with

fatigue, impairment and physical activity. Psychol

Med. 2001 Jan;31(1):107-14.

Cordero DL, Sisto SA, Tapp WN, LaManca JJ, Pareja JG,

Natelson BH. 1996. Decreased vagal power during

treadmill walking in patients with chronic fatigue

syndrome. Clin Auton Res. 1996 Dec;6(6):329-33.

De Noon 2003.

http://my.webmd.com/content/article/63/72082.htm

Fischler B, Dendale P, Michiels V, Cluydts R, Kaufman

L, De Meirleir K. 1997. Physical fatigability and

exercise capacity in chronic fatigue syndrome:

association with disability, somatization and

psychopathology.J Psychosom Res.42(4):369-78.

Guilucci, Mark. Fall 2003. Research Q & A Cardiac Output

Linked to Severe CFS Cases. Research Review. Cfids

Association of America.

Lerner, AM, Beqaj SH, Deeter RG, Dworkin HJ, Zervos M,

Chang CH, Fitzgerald JT, Goldstein J, O'Neill W.

2002a. A six-month trial of valacyclovir in the

Epstein-Barr virus subset of chronic fatigue syndrome:

improvement in left ventricular function.

Drugs Today (Barc). 38(8):549-61.

Lerner AM, Beqaj SH, Deeter RG, Fitzgerald JT. 2002b.

IgM serum antibodies to human cytomegalovirus

nonstructural gene products p52 and CM2(UL44 and UL57)

are uniquely present in a subset of patients with

chronic fatigue syndrome. In Vivo. 2002 16 (3):153-9.

Lerner AM, Dworkin HJ, Sayyed T, Chang CH, Fitzgerald

JT, Beqaj S, Deeter RG, Goldstein J, Gottipolu P,

O'Neill W. 2004a. Prevalence of abnormal cardiac wall

motion in the cardiomyopathy associated with

incomplete multiplication of Epstein-Barr Virus and/or

cytomegalovirus in patients with chronic fatigue

syndrome.In Vivo. 18(4):417-24

Lerner AM, Beqaj SH, Deeter RG, Fitzgerald JT., 2004b.

IgM serum antibodies to Epstein-Barr virus are

uniquely present in a subset of patients with the

chronic fatigue syndrome. In Vivo. 2004

Mar-Apr;18(2):101-6.

Montague, T., Marrie, T., Klassen, G., Bewick, D.,

Horacek, B. 1989. Cardiac function at rest and with

exercise in chronic fatigue syndrome. Chest 95

(779-84).

McCully KK, S, Rajaei S, Leigh JS Jr, Natelson

BH. 2003. Blood flow and muscle metabolism in chronic

fatigue syndrome. Clin Sci (Lond) 104 (6) : 641-7.

McCully KK, S, Rajaei S, Leigh JS Jr, Natelson

BH. 2004. Muscle metabolism with blood flow

restriction in chronic fatigue syndrome. J Appl

Physiol. ;96 (3): 871-8.

Peckerman A, LaManca JJ, Qureishi B, Dahl KA, Golfetti

R, Yamamoto Y, Natelson BH. 2003. Baroreceptor reflex

and integrative stress responses in chronic fatigue

syndrome. Psychosom Med. 2003 Sep-Oct;65(5):889-95.

Schondorf R, Benoit J, Wein T, Phaneuf D. 1999.

Orthostatic intolerance in the chronic fatigue

syndrome. J Auton Nerv Syst 75 (2-3): 192-201.

Sisto SA, Tapp W, Drastal S, Bergen M, DeMasi I,

Cordero D, Natelson B. 1995. Vagal tone is reduced

during paced breathing in patients with the chronic

fatigue syndrome.

Clin Auton Res. 5 (3): 139-43.

Spence VA, Khan F, Kennedy G, Abbot NC, Belch JJ.

2004. Acetylcholine mediated vasodilatation in the

microcirculation of patients with chronic fatigue

syndrome. Prostaglandins Leukot Essent Fatty Acids. 70

(4):403-7.

, J. 2000. Autonomic nervous system dysfunction

in adolescents with postural orthostatic tachycardia

syndrome and chronic fatigue syndrome is characterized

by attenuated baroreflex and potentiated sympathetic

vasomotion. Pediatric Research 48, 218-226.

Timmers, H., Wieling, W., Soetekouw, P., Bleijenberg,

G., Van Der Meer, J.and Lenders, J. 2002. Hemodynamic

and neurohormonal responses to head-up tilt in

patients with chronic fatigue syndrome. Clin Auton

Res. 12: 273-80.