Research topics: General Articles and Research Overviews, Immune System Research, Viral Research, Cardiac Research, Exercise Research, Muscle Research, Metabolic Research, Neurological and Cognitive Research, Genetic Research, Neuroendocrine Research, and Miscellaneous Research.
Article topics: The Definitions of M.E., On 'fatigue', CBT, GET and the unscientific 'behavioural' paradigm of M.E., On 'stress', M.E. Outbreaks, On the Name Myalgic Encephalomyelitis, M.E. and Other Illnesses, Children with M.E., The Severity of M.E., M.E. Fatalities, Activism Articles, Articles sorted by Author, Articles sorted by Country and Historical, Political and Medical Overviews.
Topic on this page: Cardiac and Cardiovascular Research - page 2 of 3
*O* Lay Summaries of Published Peer-Reviewed Studies from Dr Martin Lerners Website: http://www.cfsviraltreatment.com/publications.html
Repetitively negative changing T-waves at 24-h electrocardiographic monitors in patients with the chronic fatigue syndrome (left ventricular dysfunction in a cohort). Lerner AM, Lawrie C, Dworkin HJ. Chest. 1993;104:1417-1421.
Here, we showed that 24 CFS patients have abnormal cardiac electrical conduction by 24-Hr. ECG testing (Holter monitoring) compared to 106 non-fatigued control patients (p<0.03). In 8 of the 24 CFS patients, gross abnormal cardiac wall motion at exercise MUGA testing was seen. Coronary artery disease was excluded by myocardial perfusion imaging in all CFS patients.
This was our first publication in continuing studies of the chronic fatigue syndrome. Here, for the first time, cardiac abnormalities in CFS illness were recognized.
"Cardiac involvement in patients with chronic fatigue syndrome as documented with Holter and biopsy data in Birmingham, Michigan, 1991-1993." Lerner AM, Goldstein J, Chang CH et al. Infectious Diseases in Clinical Practice 1997;6:327-33.
Here, the prevalence of abnormal Holter monitoring in 67 CFS patients and 78 non-CFS patients matched for age, place and time and absence of other confouding medical diseases were compared. Holter monitors in both CFS and control groups were read by two non-involved cardiologists without clinical knowledge about the patient or place in the study. Dr. Lerner was not a reader of Holter monitors in this study. The prevalence of T-wave abnormalities by Holter monitoring was greater in CFS than in non-CFS patients (p<0.01). The presence of abnormal T-waves at Holter monitoring was "a sensitive indicator of the presence of CFS." The "absence" of these abnormal T-waves made the diagnosis of CFS unlikely (statistical sensitivity 0.96). Light and electron micrographic studies of right ventricular endomyocardial biopsies in these CFS patients showed cardiomyopathic changes. We do not recommend further right ventricular cardiac biopsies in CFS patients since the hearts of CFS patients may be friable and may have an increased likelihood of post-biopsy bleeding.
Summary of Publications 1-3 (Cardiac Involvement in CFS)
This work shows that rapid heart rates at rest, and in some cases, abnormal cardiac wall motion contribute to the light-headedness that many CFS patients experience. Uniformly, abnormal Holter monitoring is present in CFS patients. This additional criterion for diagnosis of CFS illness, namely abnormal Holter monitoring, to the CDC criteria for the diagnosis of CFS does not exclude any CFS patients included in the original CDC definition. The absence of abnormal Holter ECG testing excludes fatigued patients who do not have CFS.A unified theory of the cause of chronic fatigue syndrome. Lerner AM, Zervos M, Dworkin HJ, Chang, CH and O'Neill W. Infectious Diseases in Clinical Practice 1997;6:230-243.
Here, we hypothesize that CFS is a prolonged infectious mononucleosis syndrome in previously healthy (immunocompetent) persons. We further speculate in this early study that prime candidates for cause of CFS are two herpesviruses which cause infectious mononucleosis, Epstein-Barr virus (EBV) and cytomegalovirus (HCMV). We further suggest that studies seeking a single virus cause of CFS, even those studies searching for single-virus EBV or single virus HCMV would conclude in a result of "no cause". Indeed, such negative studies have been done. We suggest that (1997) there may be three causes of CFS, 1) single virus, EBV CFS; 2) single virus HCMV CFS; and 3) EBV-HCMV co-infection CFS. We outline research studies to prove or disprove this new paradigm.\
Editorial response: microbial persistence and idiopathic dilated cardiomyopathy. Lerner AM. Clinical Infectious Diseases. 1999;29:526-7.
Here, Dr. Lerner discusses the possible relationship between long-standing cardiomyopathy, heart muscle disease not associated with coronary artery disease, and CFS.
"New cardiomyopathy: a pilot study of intravenous gancyclovir in a subset of the chronic fatigue syndrome." Lerner AM, Zervos M and Dworkin HJ et al. Infectious Diseases In Clinical Practice 1997;6:110-117.
Here, we emphasize the need of subset classification in the diagnosis and treatment of CFS illness. CFS patients in this study had significant IgG serum antibody titers to cytomegalovirus, but little to no evidence of EBV infection by blood tests. In this study 13 of 18 CFS patients were remarkably improved after 30 days of intravenous ganciclovir (p<0.05). Single virus HCMV CFS in this pilot study was improved by antiviral treatment. There were no side effects from this carefully monitored trial.
A six-month trial of valacyclovir in the Epstein-Barr virus subset of chronic fatigue syndrome: improvement in left ventricular function. Lerner AM, Beqaj SH, and Deeter RG et al. Drugs of Today. 2002;38:549-561.Drugs of Today. 2002;38:549-561.
Twenty-five patients with CFS illness were treated orally for 6 months with pharmacokinetic doses of valacyclovir (valtrex) in a formulation to give continuous anti-EBV effective blood levels throughout the day. This is the first time such valacyclovir dosing was given. The trial was approved by the U.S. Food and Drug Administration. Patients were carefully monitored for safety by repeated appropriate blood tests. There were no adverse side effects. Sixteen patients with single virus EBV infection were benefitted, but 9 clinically similar CFS patients with EBV-HCMV co-infection were not benefitted. Valacyclovir (valtrex) in the laboratory is effective versus EBV, but it is NOT effective (active) versus HCMV. Therefore, the results strengthen the need for subset classification and appropriate subset-directed antiviral treatment for CFS illness. This, to our knowledge, is the first successful report of valacyclovir treatment for EBV infection.
A small, randomized, placebo-controlled trial of the use of antiviral therapy for patients with chronic fatigue syndrome. Lerner AM, Zervos M and Chang CH et al. Clinical Infectious Diseases. 2001;32:1657-58.
Eleven CFS patients with EBV-HCMV co-infections were appropriately treated according to their prior subset classification over an 18-month period with antiviral drug treatments. All patients were carefully monitored for safety every 4-6 weeks. Valacyclovir for EBV infection and ganciclovir for HCMV infection were used. There were no significant side effects in CFS patients. All 11 CFS patients in this study were significantly improved.
Summation of Publications 4, 6-8 (Treatment of CFS Illness with Anti-viral Drugs According to Subset Classification)
In these studies, 40 CFS patients were safely treated with antiviral drugs. They were remarkably improved.
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. Lerner AM, Beqaj SH, Deeter RG and Fitzgerald JT. In Vivo. 2002;16:153-160.
This is an especially enlightening study. In many CFS patients in whom our work implies an A) EBV; B) HCMV; or C) EBV-HCMV (co-infection) cause for CFS illness, normal means for diagnosis by blood tests or virus isolation (including those using polymerase chain reactions) are negative, both in our work, reviewed here, and in the careful work of others. In this study, we show a definitive new means of HCMV multiplication in this HCMV subset of CFS patients. The p52 and CM2 HCMV IgM antibodies were present in 16 CFS patients, but were not present in 77 various control patients. In these CFS patients, portions of the HCMV genetic material are synthesized, but remain unassembled into complete virus. These data provide strong evidence for a virus etiology for CFS illness and provide a strong rational for antiviral treatment of CFS patients.
"Cardiac and virologic issues" pp 304-330 from Handbook of Chronic Fatigue Syndrome. Lerner AM, Deeter RG, O’Neill W, Dworkin HJ, Zervos M, Beqaj SH, Chang CH, and Fitzgerald JT. Jason LA, Fennell PA, and Taylor RR. John Wiley & Sons, Inc. 2003.
We present the evolution of data describing studies over greater than a decade which support the paradigm that CFS is a prolonged infectious mononucleosis due to Epstein-Barr virus, cytomegalovirus or the two viruses in co-infection undergoing incomplete virus multiplication. The paradigm suggests that the immunocompetent (otherwise healthy) CFS patients' immune defenses do not allow complete virus formation, but only parts of the virus(es) genetic material is expressed. Cardiac involvement of this newly hypothesized method of virus infection leads to rapid heart pumping at rest (tachycardia) and eventually cardiac muscle pump weakening. Specific antiviral treatment has led to remarkable sustained improvement in patient well being so that criteria for the diagnosis of CFS are no longer present. Medical testing by Holter monitoring, MUGA, nuclear stress testing, cardiac biopsy, virus serologic tests and disappearance of symptoms of CFS support this theory.
IgM serum antibodies to Epstein-Barr Virus are uniquely present in a subset of patients with the chronic fatigue syndrome. Lerner AM, Beqaj S, Deeter RG, and Fitzgerald JT. In Vivo. 2004;18:101-106.
A first unique subset of patients with chronic fatigue syndrome (CFS) and specific diagnostic serum antibodies to cytomegalovirus (HCMV) non-structural gene products p 52 and CM2 (UL 44 and UL 57) indicates incomplete HCMV persistent multiplication in these specific patients with CFS. The results suggest that specific antiviral (HCMV) treatment in these patients may be beneficial. A second Epstein-Barr Virus (EBV) distinct subset of CFS is now defined. Fifty-eight CFS patients and 68 non-CFS matched controls were studied. Serum antibodies to EBV viral capsid antigen (VCA) IgM and EBV Early Antigen, diffuse (EA, D) as well as HCMV (V), IgM and IgG; VP (sucrose density purified V); p 52 and CM2, IgM serum antibodies were assayed. Serum EBV VCA IgM positive antibody titers were identified in 33 CFS patients (Group A subset EBV VCA IgM 62.3 ± 8.3, neg < 20), but were not present in other CFS patients (Group B subset EBV VCA IgM 6.8 ± 0.7) or controls (p < 0.0001). EBV VCA IgM titers remained positive in CFS patients from Group A for 24-42 months. Anti-viral medicines effective in HCMV and EBV infections are different, and preliminary studies suggest that this patient-specific pharmacokinetically directed antiviral therapy should be continued for 6-12 months. Trials of antiviral therapy must be individually monitored by complete blood counts, creatinine and tests of liver function (AST, ALT) every 4-6 weeks for safety. (reference publication #7)
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. Lerner AM, Dworkin HJ, Sayyed T, Chang CH, Fitzgerald JT, Beqaj S, Deeter RG, Goldstein J, Gottipolu P and O'Neill W. In Vivo. 2004;18:417-424.
Here, we report a prospective consecutive case control study from 1987-1999 of cardiac dynamics as measured by radionuclide, ventriculography in 98 CFS patients. Controls were 191 patients with various malignancies who were evaluated in protocols requiring radionuclide ventriculography before initiation of cardiotoxic chemotherapeutic agents. The prevalence of abnormal cardiac wall motion (ACWM) at rest in CFS patients was 10 of 87 patients (11.5%). With stress exercise, 21 CFS patients (24.1%) demonstrated ACWM. Cardiac biopsies in 3 CFS patients with ACWM showed a cardiomyopathy. Among the controls, ACWM at rest was present in 4 of 191 patients (2%) (p=0.0018). A progressive cardiomyopathy often associated with EBV and/or HCMV incomplete virus multiplication is present in CFS patients.
Nondiscocytic erythrocytes in myalgic encephalomyelitis.
Simpson LO. New Zealand Medical Journal 1989; 102: 126-7.Abstract:
Blood samples from 102 volunteers who believed they suffered from myalgic encephalomyelitis were photographed in a scanning electron microscope at 500x. All identifiable cells were counted and classified on the basis of their shape. The frequency of each cell shape was expressed as a percentage of the total number of cells counted in the sample. The resulting data were compared with that from 52 healthy controls and 99 cases of multiple sclerosis which had been selected randomly by a computer from a panel of 229 cases in a concurrent study. Samples from subjects with myalgic encephalomyelitis had the lowest percentages of normal red cells and the highest incidence of cup forms. The results provide evidence that myalgic encephalomyelitis has an organic cause. Quantitative analysis of red cell shape may assist in the diagnosis of myalgic encephalomyelitis.MYCOPLASMA
Extracted from Nexus Magazine, Volume 8, Number 5 (August-September 2001)
PO Box 30, Mapleton Qld 4560 Australia. editor@nexusmagazine.com
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© by Donald W. Scott, MA, MSc © 2001
You can also ask your doctor for a blood volume test. Every human being requires a certain amount of blood per pound of body weight, and it has been observed that people with fibromyalgia, chronic fatigue syndrome, multiple sclerosis and other illnesses do not have the normal blood volume their body needs to function properly. Doctors aren't normally aware of this.
This test measures the amount of blood in the human body by taking out 5 cc, putting a tracer in it and then putting it back into the body. One hour later, take out 5 cc again and look for the tracer. The thicker the blood and the lower the blood volume, the more tracer you will find.
The analysis of one of my clients stated: "This patient was referred for red cell mass study. The red cell volume is 16.9 ml per kg of body weight. The normal range is 25 to 35 ml per kg. This guy has 36% less blood in his body than the body needs to function." And the doctor hadn't even known the test existed.
If you lost 36% of your blood in an accident, do you think your doctor would tell you that you are alright and should just take up line dancing and get over it? They would rush you to the nearest hospital and start transfusing you with blood. These tragic people with these awful diseases are functioning with anywhere from 7% to 50% less blood than their body needs to function.
*O* Red Blood Cells and Chronic Fatigue Syndrome By Jule Klotter (Townsend Letter, issue: November 2001)
According to an article by Maryann Spurgin, Ph.D., New Zealand researcher Dr. L.O. Simpson has theorized that myalgic encephalomyelitis (ME), also known as Chronic Fatigue Immune Deficiency Syndrome (CFIDS), results from "insufficient oxygen availability due to impaired capillary blood flow."
Simpson attributes the impaired capillary blood flow to smaller-than-usual capillaries and to the presence of abnormal red blood cells (nondiscocytes).
In healthy people, most red blood cells are smooth-surfaced and concave-shaped with a donut-like appearance. These discocytes have extra membranes in the concave area that give them the flexibility needed to move through capillary beds, delivering oxygen, nutrients, and chemical messengers to tissue and removing metabolic waste, such as carbon dioxide and lactic acid
"The Role of Red Blood Cell Morphology in the Pathogenesis of ME/CFIDS" by Maryann Spurgin, Ph.D., The CFIDS Chronicle, Summer 1995 discocytes have extra membranes in the concave area that give them the flexibility needed to move through capillary, beds, delivering oxygen, nutrients, and chemical messengers to tissue and removing metabolic waste, such as carbon dioxide and lactic acid. Abnormal red blood cells lack flexibility that allow them to enter tiny capillaries. These nondiscocytes are characterized by a variety of irregularities, including surface bumps or ridges, a cup or basin shape, and altered margins instead of the round shape found in discocytes.
Simpson found that people with ME/CFIDS have higher percentages of nondiscocytes than people' with other chronic illnesses, such as Lupus, multiple sclerosis, Huntington's disease, malaria, and diabetes. In addition, the percentages of cup-shaped somatocytes in ME/CFIDS patients can remain high for months, inhibiting blood flow.
Simpson believes that, in ME/CFIDS, either the mechanism whereby red blood cells revert to the discocyte form is hampered for some reason or that whatever triggered the red blood cells to transform into nondiscocytes remains in effect, albeit unidentified.
*O* Dr. Les Simpson – Rethinking the Pathogenesis of CFIDS By Craig Maupin at http:///www.cfidsreport.com
Simpson continues, "I found that ME blood filtered poorly - implying that they had a problem with blood flow, particularly at capillary level. In a paper published by New Jersey Medicine, I suggested that ME people might have the anatomical feature of smaller than usual capillary diameters. Such a proposal would help to explain the great variety and variation in distribution of the symptoms reported by ME people."
Other models for the illness have struggled to fit the distinct features of CFIDS, such as exertion intolerance and circulatory dysfunction. Simpson feels impaired blood flow offers a unifying thesis that can explain many of these distinct symptoms. He vividly recalls the unique response to exercise of a patient referred to him. "Two scans were done [SPECT scans] -- pre and post exercise. While the pre-exercise scan showed reduced cerebral blood flow, this was much worse in the post-exercise scan. At that time, the effects of physical activity on red cell shape had not been reported. This shows the extent of ignoring blood rheology factors as determinants of blood flow."
On the pathophysiology of ME/CFS by Les Simpson, MD
The significance of the concept of 'mean capillary diameter' is that it explains why individuals with similar values for altered red cell shapes do or do not evince symptoms. While the effects on red cell shape of a change in the environment is the same, only those with small capillaries will develop symptoms. As overexertion changes red cell shape in an additive fashion, there will be an accompanying exacerbation of symptoms. It is worth noting that in a CFS patient with SPECT-demonstrated reduced cerebral blood flow in a pre-exercise sample, the cerebral blood flow was further reduced in a post-exercise SPECT scan.
Pathogenesis and management of delayed orthostatic hypotension in patients with chronic fatigue syndrome. De Lorenzo F, Hargreaves J, Kakkar VV. Clinical Autonomic Research 1997; 7(4): 185-90.
Abstract: The relationship between orthostatic hypotension and chronic fatigue syndrome (CFS) has been reported previously. To study the pathogenesis and management of delayed orthostatic hypotension in patients with CFS, a case comparison study with follow-up of 8 weeks has been designed. A group of 78 patients with CFS (mean age 40 years; 49% men and 51% women), who fulfilled the Centre for Disease Control and Prevention criteria were studied. There were 38 healthy controls (mean age 43 years; 47% men and 53% women). At entry to the study each subject underwent an upright tilt-table test, and clinical and laboratory evaluation. Patients with orthostatic hypotension were offered therapy with sodium chloride (1200 mg) in a sustained-release formulation for 3 weeks, prior to resubmission to the tilt-table testing, and clinical and laboratory evaluation. An abnormal response to upright tilt was observed in 22 of 78 patients with CFS. After sodium chloride therapy for 8 weeks, tilt-table testing was repeated on the 22 patients with an abnormal response at baseline. Of these 22 patients, 10 redeveloped orthostatic hypotension, while 11 did not show an abnormal response to the test and reported an improvement of CFS symptoms. However, those CFS patients who again developed an abnormal response to tilt-test had a significantly reduced plasma renin activity (0.79 pmol/ml per h) compared both with healthy controls (1.29 pmol/ml per h) and with those 11 chronic fatigue patients (1.0 pmol/ml per h) who improved after sodium chloride therapy (p = 0.04). In conclusion, in our study CFS patients who did not respond to sodium chloride therapy were found to have low plasma renin activity. In these patients an abnormal renin-angiotensin-aldosterone system could explain the pathogenesis of orthostatic hypotension and the abnormal response to treatment.
The relationship between neurally mediated hypotension and the chronic fatigue syndrome. Bou-Holaigah I, Rowe PC, Kan J, Calkins H. Journal of the American Medical Association 1995; 274(12): 961-7.
Abstract: OBJECTIVE-To compare the clinical symptoms and response evoked by upright tilt-table testing in healthy individuals and in a sample of those satisfying strict criteria for chronic fatigue syndrome. DESIGN-Case-comparison study with mean (SD) follow-up of 24 (5) weeks. SETTING-Tertiary care hospital. PATIENTS AND OTHER PARTICIPANTS-A sample of 23 patients with chronic fatigue syndrome (five men and 18 women; mean age, 34 years), each of whom fulfilled the strict diagnostic criteria of the Centers for Disease Control and Prevention, was recruited from regional chronic fatigue support groups and from the investigators' clinical practices. There were 14 healthy controls (four men and 10 women; mean age, 36 years). INTERVENTIONS-Each subject completed a symptom questionnaire and underwent a three-stage upright tilt-table test (stage 1, 45 minutes at 70 degrees tilt; stage 2, 15 minutes at 70 degrees tilt with 1 to 2 micrograms/min of isoproterenol; and stage 3, 10 minutes at 70 degrees with 3 to 4 micrograms/min of isoproterenol). Patients were offered therapy with fludrocortisone, beta-adrenergic blocking agents, and disopyramide, alone or in combination, directed at neurally mediated hypotension. MAIN OUTCOME MEASURES-Response to upright tilt and scores on symptom questionnaires prior to and during follow-up. RESULTS-An abnormal response to upright tilt was observed in 22 of 23 patients with chronic fatigue syndrome vs four of 14 controls (P < .001). Seventy percent of chronic fatigue syndrome patients, but no controls, had an abnormal response during stage 1 (P < .001). Nine patients reported complete or nearly complete resolution of chronic fatigue syndrome symptoms after therapy directed at neurally mediated hypotension. CONCLUSIONS-We conclude that chronic fatigue syndrome is associated with neurally mediated hypotension and that its symptoms may be improved in a subset of patients by therapy directed at this abnormal cardiovascular reflex.
Exercise capacity and immune function in male and female patients with chronic fatigue syndrome (CFS). Snell CR, Vanness JM, Strayer DR, Stevens SR. University of the Pacific, Department of Sport Sciences, Stockton, CA 95211-0197, USA. snells@juno.com
Hyperactivition of an unwanted cellular cascade by the immune-related protein RNase L has been linked to reduced exercise capacity in persons with chronic fatigue syndrome (CFS). This investigation compares exercise capacities of CFS patients with deregulation of the RNase L pathway and CFS patients with normal regulation, while controlling for potentially confounding gender effects. Thirty-five male and seventy-one female CFS patients performed graded exercise tests to voluntary exhaustion. Measures of peak VO2, peak heart rate, body mass index, perceived exertion, and respiratory quotient were entered into a two-way factorial analysis with gender and immune status as independent variables. A significant multivariate main effect was found for immune status (p < 0.01), with no gender effect or interaction. Follow-up analyses identified VO2(peak) as contributing most to the difference. These results implicate abnormal immune activity in the pathology of exercise intolerance in CFS and are consistent with a channelopathy involving oxidative stress and nitric oxide-related toxicity.