Circulatory Impairment in Myalgic Encephalomyelitis: A Preliminary Thesis

Dr. A Martin Lerner died on Oct. 5, 2015. This is my article from 2001 explaining his work, and the evolving hypothesis of ME and infectious cardiomyopathy. I've known since the 1980's that ME involved the heart. Noone believed me. But as my (ex) husband used to say, with a combination of facetious humor and dead seriousness, "Maryann is always right." Lerner was the first to study the connection. There have been many since. I discovered Lerner's work in 2001 In an obscure medical journal, plucked it out of obscurity, wrote on it and disseminated it all over the internet on the ME sites & mailed it to other ME researchers. I did it because I was sure that he was on to something, although personally when we spoke by phone we didn't get along. There have been many refinements, improvements and work by others on the cardiomyopathy thesis since, by ME researchers Natleson, Peckerman, and Cheney. The rest is history. Here is what I wrote, more or less, but revised for current nomenclature and to point out technical advances in knowledge of the pathophysiology.

The most acutely perceptive and pioneering work on ME these days is happening in a quiet corner of the country, out of the research limelight. The work is being conducted by A. Martin Lerner, M.D., an infectious-disease specialist at Wayne State University, along with his colleagues in cardiology. The basic thesis of their research is that the disease is an infectious cardiomyopathy of single or multiple viral etiology -- a cardiomyopathy that is progressive and degenerative.

According to the theory, ME results when an initial infection with a virus, or a reactivation of a latent virus – for example, EBV, CMV, enteroviruses, coxsakie viruses, or others -- attacks cardiac tissue, producing exercise intolerance, the hallmark of the disease. The human cardiac myofiber becomes the site of persistent viral infection. The infection flares up when the infected person physically exerts him or herself. This theory is especially noteworthy because it explains what no one has been able to explain and what has baffled researchers for years: why some EBV-infected are healthy while other EBV-infected are ill. In those EBV-infected who develop ME, cardiac tissue is affected, while in those EBV-infected who do not develop ME(they either recover from an acute infection or have latent subclinical infection), the heart was never involved (this holds for CMV as well for Lerner). According to this hypothesis, then, EBV or CMV seropositive non-ME patients will not show EBV or CMV nucleic acids in cardiac myofibers, whereas these viral nucleic acids are theorized to be present in the cardiac myofibers of ME patients.

Lerner's focus was on these two viruses, but enteroviruses & coxsakie viruses also attack the heart. Lerner and his associates have observed that patients with acute EBV mononucleosis who recover have normal 24-hour electrocardiographic Holter monitoring throughout their illness. Conversely, patients with prolonged illnesses of EBV mononucleosis consistently have abnormal 24-hour Holter monitor results. Lerner's work also accounts for why no single viral etiology has been found for ME, since a number of different viruses, among them coxsackie virus, can cause a cardiomyopathy. Lerner's work cites studies showing that EBV and CMV are especially cardiotropic for the human myocyte. Lerner and his associates have backed up their theories with an impressive amount of data. Having performed biopsies on the cardiac tissue of ME patients, they have found myocardial fiber hypertrophy, myofiber disarray, interstitial fibrosis, fat infiltration, and increases in mitochondria in cardiac tissue, findings indicative of a cardiomyopathy. They have also found T-wave inversions and/or T-wave flattenings on 24-hour EKG Holter monitoring in 100% of ME patients.

Because of this consistent finding, they suggest that the Holter results should be included as part of the CDC case definition because it can distinguish "ME" (CDC term) patients from fibromyalgia patients and others with pain syndromes who do not relapse with exertion, as well as from those with fatigue associated with depression, a group that also does not suffer relapse with exertion. The work offers hard evidence to back up patients' much-disbelieved claim that exercise is harmful and causes disease progression in ME.

On Lerner's model, a virus infecting the heart becomes more active following the patient's physical exertion, thus causing disease progression and accounting for the post-exertional sickness so common in this disease -- including flu symptoms, chills, fevers, weakness. Indeed, the cardiac connection is what is so groundbreaking about this research. With a mouse model, Lerner has shown that raised myocardial viral titers accompany physical exertion in the host. He shows that when an infectious cardiomyopathy is present, overactivity causes cardiac ischemia and disease progression.

Government researchers, in contrast, routinely state that it is a disease of underactivity and that a couch-potato lifestyle is the cause of symptoms. While government researchers and others who propose a behavioral/ volitional hypothesis advocate exercise, Lerner advises resting the heart in order to "do no harm" and to prevent necrosis of cardiac tissue. Lerner and colleagues have also discovered abnormal ejection fractions in some of their "ME" patients. An ejection fraction is the fraction of blood within the left ventricle that is ejected with the heart's contraction -- when it goes down, the blood is not dispelling. While not all patients showed this, because in diastolic dysfunction [see Dr. Paul Cheney's more recent work] ejection.fraction is preserved, some ME patients had reduced ejection fractions at rest while others had an ejection fraction that decreased during exercise from 51% to 36%. In a normal subject, an ejection fraction will rise during exercise. They note that a stationary or falling ejection fraction is abnormal. Lerner's work cites studies showing that declining ejection fractions are not seen in normal persons leading a sedentary life. In diastolic cardiomyopathy and diastolic heart failure, ejection fraction is preserved, and often even higher than normal to compensate for inadequate filling.

This work on diastolic cardiomyopathy was pioneered by Dr. Cheney and Lerner's team did not study it. Deconditioning and a sedentary lifestyle in normal subjects are not causes of the decreasing left ventricular ejection fractions that Lerner found in some patients. On the contrary, these cardiac abnormalities are likely virally induced: in some of the CMV patients, ejection fractions reverted to normal after anti-viral therapy with ganciclovir. Interestingly, these researchers offer an alternative theoretical framework for the Johns Hopkins finding of Peter Rowe et al., that "ME" patients have an abnormal response to upright tilt. Lerner and colleagues deny that the basis of this abnormal response is an abnormal neural reflex (as Rowe argued), arguing instead that the abnormal cardiac response to upright tilt is induced by the cardiomyopathy itself.

According to cardiology textbooks, reduced cerebral blood flow and faintness can be caused by diminished left ventricular contractile power. In 2002, I had many long talks with the late, world-renowned endocrinologist Dr. David Streeten, who was brought into ME research by ME clinician Dr. David Bell. Dr. Streeten also disagreed with Peter Rowe on the cause of orthostatic intolerance in ME patients, yet he also disagreed with Lerner. According to Streeten, neither the heart nor NMH were the cause of orthostatic intolerance in ME: instead, Streeten showed that low blood volume was the cause in this patient population. Streeten and I had long talks on blood-volume-induced O.I. and he explained the role of the kidneys in causing it (which I now can't remember). I came to agree with Streeten that low blood volume was the primary cause of O.I. in ME, with the others possibly playing a contributing role in some cases, not all.

In the end Dr. Paul Cheney's cardiac research on ME nailed the problem, in a way that encompassed both Streeten's work and his own: Low blood volume COUPLED with diastolic dysfunction play a huge role in the disease, and the one aggravates the other, making the disease insidious. When a theory comes along that explains more of the data than others have, the research community needs to take a serious look at that theory -- the thesis of Lerner and colleagues explains a myriad of phenomena that others, and other theories, failed to explain. For example, if ME is indeed an infectious cardiomyopathy in which raised myocardial viral titers follow physical exertion, then we can nderstand more fully not only why patients relapse with exertion, but also why only physically active persons acquire the disease to begin with (and why bedridden patients in one hospital outbreak completely escaped contracting the disease).

As I mentioned above, the thesis also explains why some EBV or CMV seropositive individuals are healthy while others are sick. The infectious cardiomyopathy thesis is also consistent with Suhadolnik's finding that ME entails an abnormality in an antiviral lymphocyte enzyme system, the 2-5A pathway, which suggests the presence of chronic viral infection. And elevated interferon, associated with viral infections, has been shown to lower the HPA axis -- hormonal deficits could themselves be a result of viral pathology. In short, Lerner and colleagues are doing real research and making real discoveries, instead of wasting taxpayer money on pseudo-research after the fashion of Straus, Demitrack, Komaroff, Wessely and others in the behavioral & shrink lobby.

In a recent article in JAMA, for example, about a 56-year-old "ME" patient, Komaroff misrepresented the facts: he stated that the disease was not progressive, and he favorably cited articles by Sharpe and Wessely stating that exercise was an effective treatment. Komaroff failed to note, however, that the exercised patients were selected according to the Sharpe-defined Oxford criteria and the CDC Fukuda case definition, and that the study selected patients with fatigue, not patients with the disease ME. Komaroff admitted that "ME" may be a heterologous disorder but then failed to treat it as such: he used effective results on one group as evidence of effectiveness on an entirely different. group. There are parts of Lerner's cardiomyopathy thesis which stand in need of clarification, elaboration, and even correction.

I wanted to see Lerner and colleagues clarify a number of points in their future publications. I expressed this to Lerner, but he was a bit dogmatic & didn't want to or couldn't explain it. First, why were only EBV and CMV named in the theory? Other viruses have been implicated as well. Second, why do they believe that the heart is the only organ involved in the chronic viral state? That doesn't make sense to me at all. The liver and other organs are clearly infected. What happens to the kidneys that causes them to play a role in O.I., something he never acknowledged?

Lerner and his cardiology associates should have explained both to physicians and to the public why he believed that the heart can trigger much of the secondary phenomena seen in the disease. I believe that the infected heart is central, but many other systems are involved as well. Nevertheless, Lerner was a pioneer for standing in opposition to much of the writings by government researchers and the shrink lobby.

Straus's work seeks to refute viral etiology, whereas Lerner's work argues in favor of it. Straus's work argues for pre-morbid psychiatric disorder; Lerner's published work argues that the disease strikes "previously healthy, vigorous young adults." Lerner, Cheney, Bell, Streeten and other pioneers refute that the disease is a psychiatrically mediated behavioral problem of patients who refuse to exercise. Lerner argued that exercise avoidance is mediated by a cardiomyopathy. Exercise causes myocardial viral titers to increase and suggests resting the infected heart in order to "do no harm," the very opposite of what is recommended by government researchers.

The infectious cardiomyopahty thesis is a truly insightful thesis, and following his heart transplant, Dr. Cheney read some of the articles by Peckerman and began to study ME cardiomyopathy. Cheney vastly improved upon the cardiomyopathy theory, and I believe Cheney to be correct in that diastolic cardiomyopathy (cardiomyopathy with preserved ejection fraction) is central to the disease. Thanks to my friend Carol Seiverling for helping to bring Cheney's theory to light, both by the brilliant articles that she wrote, and by hosting talks by Cheney that were published in DVD format, some of which are on. youtube.

Those who are researching the disease today are far too unaware of these pioneers and their work, who understood and understand the pathophysiology of ME disease far better than many newer researchers.

REFERENCES

1. Lerner, A. Martin. Viral myocarditis as an incidental discovery. Hospital Practice , October 15, 1990; pp. 81-90.

2. Lerner, A. Martin, Goldstein, J., Chang, C., et al. Cardiac involvement in patients with chronic fatigue syndrome as do***ented with Holter and biopsy data in Birmingham, Michigan, 1991-1993. Infectious Diseases in Clinical Practice , 1997; 6:327-333.

3. Lerner, A. Martin, Zervos, M., Dworkin, HJ. New cardiomyopathy: pilot study of intravenous ganciclovir in a subset of the chronic fatigue syndrome. Infectious Diseases in Clinical Practice , 1997; 6:110-117.

4. Lerner, A. Martin, Zervos, M., Dworkin, HJ. A unified theory of the cause of ME Infectious Diseases in Clinical Practice , 1997; 6:239-243.

5. Lerner, A. Martin, et al. Repeatedly negative changing T-waves at 24-h electrocardiographic monitors in patients with the chronic fatigue syndrome: left ventricular dysfunction in a cohort. Chest , 1993; 104:1417-1421.

6. Dworkin, Howard J., Lerner, A. Martin, et al. Abnormal left ventricular myocardial dynamics in eleven patients with chronic fatigue syndrome. Clinical Nuclear Medicine , 1994; 19(8):675-677.

7. Suhadolnik, Robert J., et al. Biochemical evidence for a novel low molecular weight 2-5A-dependent RNaseL in chronic fatigue syndrome. Journal of Interferon and Cytokine Research , 1997; 17:377-385.