Mitochondrial disease in man: report of a probable case with successful therapy
Mitochondrial disease in man:
report of a probable case with successful therapy
Freeman W. Cope, M.D.
238 West Court Street, Doylestown, Pennsylvania 18901
Probable mitochondrial damage in brain and possibly in other tissues of an elderly woman after open heart surgery was treated by therapy aimed at providing the cell with materials necessary to synthesize new mitochondria to replace those damaged by imperfect perfusion of body issues with blood by the artificial heart-lung machine. Large quantities of B-complex vitamins for Krebs cycle enzyme cofactors, vitamin C for protein synthesis, and ribonucleic acid for templates for Protein synthesis were provided. With this therapy started 5 days postoperatively, marked acceleration of clinical recovery from a previously static state of presumed mitochondrial damage occurred. On the basis of animal experiments, a diagnosis of mitochondrial damage is suggested to be reasonable in appropriate human patients. On the basis of the successful result reported here, specific mitochondrial therapy is suggested and feasible and probably beneficial for patients with a diagnosis of mitochondrial damage.
Mitochondria are delicate chemical factories, visible as granules, in all known animal and plant cells. Mitochondria are easily damaged by physical, chemical, and viral agents, which results in disruptions of physiological functions, notably the synthesis of adenosine triphosphate (ATP). In the test tube and in living animals, apparently damage to mitochondria can be prevented and/or repaired by a chemical agent, PGBx as commented on below. However, PGBx is not available for administration to human subjects.
I report here a case in which a presumptive diagnosis was made of cerebral and possibly generalized mitochondrial damage in a human patient following open heart surgery. Vigorous therapy aimed at correction of mitochondrial damage was followed by rapid acceleration of the patient’s recovery. It is suggested that physicians consider mitochondrial damage as a treatable diagnosis in appropriate patients.
Reports of mitochondrial disease in man and animals. Reye’s syndrome, a rare disease of children characterized by liver and brain damage, possibly of viral origin, has shown evidence of mitochondrial damage on electron microscopy.(1-3) Although mitochondrial damage may be an important mechanism behind the symptomatology of Reye’s syndrome, no therapeutic attempts specifically aimed at repair of the presumed mitochondrial damage are known to me. Presumed viral disease of mitochondria has also been reported in snakes.(4-6) Mitochondrial damage in various other diseases of man and animals has been reviewed bv Nass.(7)
Following open heart surgery in man, tetanic contraction of myocardium (called “stone heart”) occasionally occurs and is usually fatal .(8-12) Electron microscopy of stone hearts at autopsy has shown mitochondrial damage. (8-12) It has been surmised that the myocardial contraction of stone heart resulted from inadequate cardiac concentrations of ATP due to damage to cardiac mitochondria occurring in the period of perfusion of the heart by the artificial heart-lung machine during surgery. This hypothesis is consistent with the concept of Szent-Györgyi (l3) that high-energy phosphate produced by mitochondria is necessary for relaxation as well as for contraction of muscle.
Experiments in the test tube and in animals with mitochondrial damage: a promising therapy. The discovery by Polis (14-17) of a polymeric prostaglandin (PGBx) that prevents damage to isolated mitochondria in the test tube (l4,15) and repairs mitochondrial damage in animals (18,19) has stimulated moderate experimental experience relevant to both diagnosis and therapy of mitochondrial disease. Mitochondrial damage manifested by failure to synthesize ATP has been produced experimentally in vitro by various chemical agents and by warming in the absence of substrate. Such damage is prevented by PGBx.(14,15) Ischemic damage to myocardium in monkeys(18) and to brain in rabbits (19) is corrected in large measure by injection of PGBx indicating that it probably restores function of mitochondria damaged by ischemia in tissues of living animals.
As a physician who had worked in the laboratory alongside those performing the cited mitochondrial damage and therapy experiments, I was in a unique position to use that experience to diagnose and treat successfully the above-mentioned patient.
Report of a case of presumed mitochondrial damage after open heart surgery
This is a classic case of pure aortic stenosis in a 72-year-old woman who had suffered several debilitating episodes of severe left heart failure immediately before open heart surgery (successful installation of an artificial aortic valve). Postoperatively the cardiac function was essentially normal, but the patient showed extreme generalized muscular weakness and considerable mental confusion, both much more severe and prolonged than usual in chest surgery patients even of this advanced age. These clinical findings were consistent with a diagnosis of mitochondrial damage in brain, and perhaps also in muscles, resulting from imperfect circulation during the period of open heart surgery. PGBx, the most obvious therapy, was not obtainable for this purpose. Therefore alternative therapy aimed at rebuilding damaged mitochondria was improvised at bedside. This therapy consisted of providing components necessary to the cells for constructing replacement mitochondria. Initiation of the therapy was followed by immediate and marked improvement of recovery rate of the patient, who at 4 years post-operation is still in good health. Case details are given below.
(1) Family history included a sister who had died in infancy with probable congenital heart disease. A grandmother had developed diabetes late in life.
(2) Personal history was that of a 72-year-old white woman of moderate habits, moderate athletic activities, and general good health prior to the present illness. A cardiac murmur without cardiac symptoms had been present since childhood, probably systolic, because various physicians had told the patient to disregard it. The patient had completed three pregnancies without complications. No history of rheumatic fever or venereal disease.
(3) Present illness began two years prior to operation, with repeated episodes of lightheartedness and dyspnea on exertion. Two months prior to operation, episodes of severe dyspnea required repeated hospitalizations with diagnosis of left heart failure, occasional bigeminal rhythm and premature beats. Therapy was digitalization, diuretics, and low salt diet, by which the patient was maintained in a marginally ambulatory state. A diagnosis of severe calcific aortic stenosis was made, confirmed on X-ray visualization of the calcified valve. Quinidine therapy was attempted but had to be discontinued because of side effects. An expected survival of 18 months was estimated by the attending cardiologist. Cardiac catheterization showed marked calcific aortic stenosis with mild aortic regurgitation and moderate narrowing of the proximal right coronary artery.
(4) Operation was performed by one of the world’s most experienced cardiac surgeons, with temporary cadiopulmonary bypass and partial hypothermia. Calcific stenosis of a tricusped aortic valve was found. The aortic valve was resected and replaced with an aortic valve prosthesis.
During 3 days in intensive care immediately after operation, the patient underwent several episodes of runs of premature beats, treated successfully with injections of local anesthetic agents.
Upon discharge from intensive care, only occasional premature beats occurred. Blood pressure was normal. The patient was maintained on digitalis, and coumadin anticoagulant therapy was begun.
At 3 days post-operative, the patient’s cardiovascular function was essentially normal. Nevertheless, she showed extreme generalized muscular weakness and flaccidity to the extent that she could barely raise her head off the pillow. Her mind was intermittently cloudy. This state continued for 2 more days.
(5) At this point, as the primary and referring physician, I concluded that the symptoms were markedly in excess of those usually experienced by patients following chest surgery. On the basis of my experience with mitochondrial damage in animals, I concluded that the patient had probably suffered mitochondrial damage of brain and perhaps of muscles due to imperfections of perfusion during surgery. The obvious therapeutic agent, PGBx, was not available for use in humans at that time. In lieu of PGBx, the best alternative evident to this investigator was to provide all available building blocks needed by the patient to synthesize new mitochondria.This therapeutic strategy was begun cautiously on the fifth post operative day with administration of B-complex vitamin capsules and vitamin C, 100 t.i.d. Within 2 days, significant acceleration of recovery from the previously static condition of the patient was observed. Therapy was then increased in vigor by addition of 15 grains of brewers yeast, t.i.d. Over the next 3 days, rapid improvement in muscular strength and mental state was observed, so that intensity of therapy was increased further to a total of 30 grains of brewers yeast 4 times per day. [Note: 6.43 grams = 1 Tbsp. Q.i.d.] Recovery of muscular strength continued at a rate that appeared even more rapid, so that within a few more days the patient was able to get out of bed and walk with little or no assistance.
(6) At 3 weeks post-operative, the patient was discharged from the hospital and was able to make the long airline flight back home with minimal assistance. At 3 months post operative, she was strong enough to carry on most household activities. Her vitamin and yeast therapy were maintained during this time. Digitalization and anticoagulation were also maintained.
At 4 years post-operative . the patient shows good general health and strength and is able to maintain household and outdoor activities appropriate for an elderly woman. Her cardiac function remains normal except for occasional premature beats. Vitamin therapy has been decreased to 15 grains yeast and 300 mg of vitamin C per day, together with low sodium, high potassium diet. Anti-coagulation and digitalization have been continued, although the latter is probably unnecessary. The patient developed a benign endometrial tumor that was removed by curettage without complication. Also developed was a mild diabetes mellitus, regulated by 10 units of NPH insulin per day.
My clinical impression of this case was that the patient (a) showed little or no improvement from a clinical picture consistent with mitochondrial damage up to the fifth post-operative day, (b) promptly began recovery when mitochondrial therapy was begun, and (c) exhibited accelerated rate of recovery when the intensity of mitochondrial therapy was increased. Moreover, recovery was not marginal or partial but virtually complete. My conclusion, therefore, was that moderate mitochondrial damage in brain and perhaps in muscles during the open heart surgery had indeed occurred. The patient’s advanced age and previous tissue damage from episodes of severe cardiac failure may have tendered the mitochondria abnormally susceptible to damage from imperfections of tissue perfusion during surgery.
The results with one patient, lacking even a control patient, do not constitute verification of the above impression. Nevertheless, the case is reported as a necessary first suggestion to other physicians that a diagnosis of mitochondrial damage is sometimes reasonable-and that the patient may be given appropriate therapy in a logical manner with reasonable hope of benefit.
With regard to choice of therapy for mitochondrial damage, the most obvious choice would be ATP to replace the ATP that the damaged mitochondria fail to produce in adequate quantities. But this choice is impractical because of side effects from intravascular ATP administration .20 PGBx seems the next best choice because of its specific beneficial effect on mitochondrial damage in both test tube and animal experiments..(14-19) Unfortunately, because of legal restrictions, PGBx is not yet available for clinical trial in man.
The remaining alternative therapy, used in this case, is aimed at maximizing the ability of the cells to synthesize new mitochondria to replace those that had been damaged. Vitamin C was administered because it is well known to be necessary for synthesis of proteins, a major component of all mitochondrial enzymes. Various B vitamins are cofactors of the various Krebs cycle and oxidative enzymes in mitochondria, and were therefore administered in excess to provide these components for construction of the mitochondrial enzymes. To construct any protein, the cell uses templates of ribonucleic acid (RNA), so that brewer’s yeast was administered to provide plenty of RNA to aid in the synthesis of mitochondrial protein while also providing more B-complex vitamins needed as cofactors for the protein enzymes in mitochondria.
Of general interest in relation to this case is the review by Nass,,- which describes the mechanism of growth of new mitochondria. This occurs by growth and fission- of preexisting mitochondria, controlled (-at least partly) by DNA and RNA contained within the mitochondria.
A high potassium, low sodium diet to facilitate recovery of proteins from a damaged to an undamaged state (21) Might also have been used for therapy of this case, but I was not aware of that possibility at the time of treatment.
Predisposing to mitochondrial damage in this case may have been the age of the patient (72 years) and the fact that the tissues had been subjected to several episodes of reduced blood flow during periods of severe cardiac failure within a few months prior to operation. Most patients going into cardiac surgery do not have these predisposing factors. Worthy of note, however, are the experimental observations on perfused animal limbs to the effect that perfusion at a constant pressure does not seem to maintain the health of the tissue as well as perfusion with a pulsating pressure, even though average perfusion pressure is the same. (22) The pumps used in open heart surgery usually maintain a steady pressure, which perhaps is not as suitable for tissue health as the pulsating pressure produced by the biological heart.
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22. C.F. Hazlewood. Private communication.
Received November 21, 1980.