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ABSTRACT: Eighteen patients with documented arteriosclerotic heart disease were studied utilizing the isotope Technetium 99m to measure left ventricular ejection fraction before and after the administration of EDTA chelation therapy. A statistically significant improvement in left ventricular ejection fraction occurred in this group of patients. EDTA is known to bind or chelate calcium as well as other minerals in the body. It is thought to remove calcium particles deposited in the arterial wall, plaques and atheromas. In addition, EDTA probably acts by blocking the slow calcium currents in the arterial wall, resulting in arterial vasodilation. Thus EDTA must be added to the other new drugs popularly referred to as calcium blocking agents which have been shown to be potent coronary vasodilator.

During the past year we have conducted studies to evaluate, by objective measurement, the efficacy of chelation therapy. This study deals with the evaluation of patients with documented arteriosclerotic heart disease by measuring the ejection fraction of the left ventricle before and after twenty intravenous infusions of EDTA.

This report is particularly timely in view of the intense interest which has developed during the past year in the United States and Europe concerning evaluation of drugs which antagonize the effect of calcium in the arterial wall1-7.

The calcium ion antagonists which are widely used, particularly in Europe, include Diltiazem, Nifedipine, Veraparnil, Triaparnil, Fendiline, Prenylamine, and D600. There are probably multiple modes of action of these drugs which appear to protect the structure of heart muscle fibers by reducing calcium influx and preventing the exhaustion of ATP and creatine phosphate. Physiologically they increase coronary artery blood flow and decrease myocardial oxygen requirement.

Additionally the calcium blocking agents have increased our knowledge of the events which take place when myocardial ischemia occurs. Under the circumstances of ischemia the muscle fiber becomes overloaded with intracellular calcium ions because of depletion of ATP and creatine phosphate. Mitochondria become impaired by this influx of calcium and are unable to generate enough ATP to maintain ionic hemostasis. When cells of the myocardium become reoxygenated there is a further increase of intracellular calcium under which circumstances cells of the myocardium may die8.

HISTORY OF EDTA CHELATION THERAPY

EDTA (ethylene diamine tetraacetic acid) was initially used in the 1940s to treat heavy metal poisoning. One of the earliest clinical uses of EDTA was in the treatment of lead poisoning'°. Elderly patients with atherosclerosis being treated primarily for chronic lead poisoning showed a dramatic improvement in their atherosclerotic disease following chelation therapy.

Initial work on the chelation process or the bonding of metals was performed by the Swiss Nobel Laureate, Alfred Warner, who propounded his theory of metal-ligand bonding in 1893 and thus provided the foundation of modern coordination chemistry.

Much of the early work on clinical applications of chelation therapy was performed by Norman Clarke, M.D., director of research at the Providence Hospital in Detroit, where EDTA had been found effective in removing metastatic calcium deposits from the human body.11 Subsequently Dr. Clarke reported remarkable benefits and improvement in patients suffering from angina pectoris when treated with EDTA chelation therapy.12

In Dr. Clark's paper the authors report case studies of twenty patients with documented angina pectoris treated with EDTA. They reported consistent decrease or disappearance in anginal symptoms and in some cases the disappearance of abnormalities on electrocardiograms which had been consistently present during two years preceding the onset of EDTA therapy. The authors reported experience with more than 4,000 infusions of EDTA and indicated mild gastrointestinal symptoms to be common. They felt that the incidence of gastrointestinal symptoms were reduced by giving 25-75 mg. of pyridoxine daily.

A word of caution was inserted inasmuch as case number three died suddenly following a convulsion. They also reported the experience of another investigator, Dr. A.J. Boyle, Professor of Chemistry at Wayne University, who treated a patient for calcified mitral stenosis by using EDTA chelation therapy. There was striking clinical improvement following this therapy, but later sudden death occurred from a cerebrovascular accident. The necropsy disclosed multiple areas of embolism that originated from the honeycombed friable residual calcium on the mitral valve. Such experience with the calcium dissolving action of this drug called for caution in the presence of large areas of metastatic calcium involving the internal wall of the heart of large arteries. They thought that this danger could be minimized by allowing more days between infusions and longer rest periods, but they commented that the hazard was minimal compared to the hazard of the occluding arterial disease.

Note that the dose of EDTA used in the early studies (5 grams per infusion) is nearly twice the dose (3 grams) that is commonly used today. Additionally, in these early days of chelation therapy it was common practice to give infusions daily for five days with a rest period of two days, whereas this frequency of administration is rarely used today and was not used as a part of this study protocol.

ATHEROGENESIS

A possible sequence of events as postulated by Clarke, et al. in the atherosclerotic process is that the reparative processes go awry because of changes in the mucoid ground substance. This material, with its content of highly polar polysaccharides and chondroitin sulfate, is capable of fixing large quantities of calcium and cholesterol. The affinity for calcium is well known since calcium chloride solution is a standard extractant for removing chondroitin sulfate from tissue. There appears to be some special relationship between the polyuronides with cholesterol and the relationship between chondroitin sulfate, metachromatic tissue and the deposition of cholesterol. Please note that metachromatic tissue is present in the intirna and luminal part of the media of human aorta and other arteries, such as coronary arteries. It is always found in locations where cholesterol deposits are typically located. The polyuronides appear to be bound more firmly to protein than is lipid material, causing a displacement of lipid from lipoprotein and its consequent deposition in the metachromatic tissue13.

Calcium is apparently displaced from serum transudates by a similar mechanism. Subsequent to this, phosphate begins to be deposited and the calcified area takes on a Ca:P ratio much like that of normal bone.

Although cholesterol reducing agents are a standard part of the treatment of atherosclerosis, their administration has not uniformly brought about a reduction in coronary events, as was reported by the Coronary Drug Project.14

With the above format firmly in mind, it is not too surprising that the administration of agents which remove calcium from the arterial wall do bring about dramatic relief of signs of arterial insufficiency and angina pectoris. This presumably takes place because of removal of metastatic calcification in the arterial wall as well as interference with slow calcium currents which were recently described.15 A relationship between calcium and cholesterol metabolism was shown by Gabel16, who described infusions of calcium in dogs which produced a prompt decline of up to 39% in blood cholesterol levels.

Undoubtedly, the complex process of atherogenesis is multifactoral, including a change in the ground substance of arterial walls, alteration in enzyme chemistry, as well as trace mineral deposition and/or change. Another factor is alteration in lipid metabolism, including increased deposition of lipids in the arterial wall secondary to elevation of the blood lipid levels, particularly hypercholesteremia (type II hyperlipoproteinernia).

PLAN OF STUDY AND METHOD

The purpose of this study was to observe not only clinical response to the administration of chelation therapy but to record objective measurements of some parameter of cardiac function before and at the end of twenty infusions of the drug. EDTA was administered as a dose of 3 gm. disodium ethylene diamine tetraacetic acid in 25Occ of Ringers lactate solution. 200 mg. of lidocaine were added to the solution in order to control local pain. Since EDTA is an amino acid it may produce local pain when administered intravenously.

All patients had a complete physical and cardiac evaluation prior to the onset of therapy and all had documented evidence of arteriosclerotic heart disease. In addition to the usual studies, particular emphasis was placed on renal function inasmuch as this is the primary mode of excretion of EDTA. The biologic half life in the body following intravenous administration is approximately one hour and nearly all of the drug is recoverable in the urine. Unless otherwise indicated the infusions were given once per week and were administered over a period of three hours in an office setting. During the course of chelation therapy, vitamin and mineral supplements were administered orally, otherwise there was no change in their usual program of therapy.

HEART STUDY

Radioactive studies were performed in the Nuclear Medicine Department of Long Beach Community Hospital. The studies described below were performed using a scintillation camera, manufactured by Searle Radiographics. The scintillation camera was attached to a microprocessor and the data were recorded on floppy discs. Cardiac nuclear scintigraphy was performed by the usual technique using technetium 99m.

In this study each patient serves as his own control, being studied before and at the end of the prescribed course of chelation therapy. Unless indicated, no other change in cardiac event or drugs affecting the heart occurred during the course of therapy. The resting ejection fraction was measured before and at the end of therapy and is taken as an objective measure of the apparent benefit of chelation therapy.

All eighteen patients had well documented arteriosclerotic heart disease. Patients numbers 1 RH. 4 MW, 14 CA, and 16 RP had previously undergone open heart surgery with coronary artery bypass grafting. Patient 16 RP had additionally undergone heart surgery with a Vineberg procedure several years antedating coronary artery bypass grafting. These patients continued to have evidence of coronary ischemia, even following coronary artery bypass grafts, prior to being treated with chelation therapy.

Patient ages ranged from +8-72; the mean change in the ejection fraction was +5.77%, with a range of -2 to -16%, as shown in Table 1.

All patients improved clinically and in all but two there was a complete subsidence of angina during the course of chelation therapy. One patient who did not have complete relief of chest pains was number 16 RP who had had two previous open heart surgical procedures as described above. Even so, during the course of chelation therapy her cardiac symptoms were markedly ameliorated. A second patient, number 6 SW, who also did not achieve complete relief of anginal symptoms, was subsequently studied by coronary angiogram. Three vessel coronary artery disease was found on the angiograms and he elected to proceed with heart surgery and coronary artery bypass grafting. Even so, during the course of chelation therapy his anginal symptoms decreased by about 50% and his ejection fraction increased by 12%.

RESULTS

EJECTION FRACTION MEASURED BY TECHNETIUM 99m BEFORE AND AFTER CHELATION THERAPY*

TABLE I

MEAN CHANGE +5.77% RANGE-2 T0+16% (P<0.0005)

*STUDIES PERFORMED AT NUCLEAR MEDICINE DEPARTMENT LONG BEACH COMMUNITY HOSPITAL USING 20 MILLICURIES TECHNETIUM 99m GLUCOHEPTONATE. UNLESS OTHERWISE INDICATED, TREATMENT CONSISTED OF 20 IV INFUSIONS CF 3gr EDTA.

Patient 13 ND, a 67 year-old white male, had sustained an acute anterior myocardial infarction. He was thereafter studied by coronary angiograms, which indicated three vessel coronary artery disease and the patient was advised by his physician to have open heart surgery with coronary artery bypass grafting. The patient declined the invitation to surgery and elected to have chelation therapy instead, Chelation therapy brought about a marked clinical improvement as well as a rise in his ejection fraction. Not shown here are the results of his exercise test which indicated a significant improvement in physical performance following chelation therapy. STATISTICAL EVALUATION *

The data show a statistically significant increase in the mean ejection fraction after the use of the drug (P

The Standard Deviation		= 5.15%
The t distribution table		= 4,75%
The probability of error is quite low:	p	= 0.0005.

SIDE EFFECTS

There were no serious side effects encountered and kidney function remained stable throughout the course of chelation therapy- Local pain at the site of injection was easily controlled by reducing the rate of administration of the IV solution.

Mild nausea and dry mouth sensation were occasionally encountered if the rate of infusion was too rapid. Also, pins and needles paresthesias were occasionally encountered with inadvertent rapid infusion of the drug. This likewise was easily corrected by slowing the rate of IV drip.

One 72 year old female diabetic with coronary artery disease experienced nausea and vomiting for several hours after each of two IV infusions of EDTA. Subsequent to this she and her family moved out of state and were lost to follow-up.

CONCLUSIONS

The intravenous administration of ethylene diamine tetraacetic acid (EDTA), popularly known as chelation therapy, has been shown to bring about clinical as well as objective improvement in patients with documented arteriosclerotic heart disease. A statistically significant improvement in left ventricular ejection fraction occurred in this group of patients to whom the drug was administered.

EDTA is known to bind or chelate calcium as well as other minerals in the body. It is thought to remove calcium particles deposited in the arterial wall and in the plaques and atheromas on the arterial surface.

Additionally, EDTA probably acts by blocking the slow calcium currents in the arterial wall. Since these calcium ions are necessary for arterial muscular contraction and spasm of the arteries, the net effect of blocking these calcium currents is arterial vasodilation. Thus EDTA must be added to the other new drugs popularly referred to as calcium blocking agents which have been shown to be potent coronary vasodilators.

*Statistical analysis performed by Victor D'Agostino, PhD. of California State University, Long Beach, II. Richard Casdorph is currently Assistant Clinical Professor of Medicine at the University of California Medical School, Irvine, California. He practices in internal medicine and cardiovascular disease at Long Beach, California. He received his, training in cardiovascular diseases at the Mayo Clinic and received his Ph.D. degree in Medicine from the University of Minnesota. More recently he has taught at U.C.L.A. Medical School and has been Chief of Medicine at Long Beach Community Hospital.

REFERENCES

1. Bigger JT: A Primer in Calcium Ion Antatoxists. Whippany, New Jersey, Knoll Pharmaceutical Co, 1980.

2. Bonow RO, Leon MB. Rosing DR, Kent K,M, Lipson LC, Green MV, Epstein SE: Effect of propanolol and verapamil on left ventricular diastolic filling in patients with coronary artery disease, Circulation 1980 Oct:62:III-85. (Abstr).

3. Honrath P. Krememr P. Mathey D. Bleifeld W: Effect of nifedipime on left ventricular performance at rest and during exercise on patients with artery disease. Circulation 1980 Oct;62:III.8S(Abstr).

4. Allen JW: Deltriarem in patients unresponsive to conventional anti-anginal therapy, Circulation 1980 Oct;62:III-28 (Abstr),

5. Zelis, R. Schroeder JS, (Editors of Symposium) Calcium, calcium antagonists, and cardiovascular disease. Chest 1980 (supplement); 78:121-247.

6. Constricting arteries expand views of ischemic heart disease (Medical News). JAMA 1980;243:309-316.

7. Nowak FG. Cocco G. Chu D. Gasser DF: Antiarrhythmic effect of the calcium antagonist triapamil (RO 11.1781) by intravenous administration in patients with coronary heart disease. Clinical Cardiology 1980:3:371-376

8. Calcium antagonists value in cardiomyopathy shown. Internal Medicine News 1980 Oct 1;1.

9. Bessman ST. Doorembos NJ: Editorial Chelation. Ann Intern Med 1957;47;1036-1041.

10. Halstead BW: Scientific Basis of EDTA Chelation Therapy, Coltron, Calif, Golden Quill Publishers, 1979.

11. Clarke NE. Clarke CN. Mosherre: The in vivo disolution of metastatic calcium, an approach to atherosclerosis, Am J Med Sci 1955; 229:142-149.

12. Clarke NE. Clarke CN, Mosherre, Treatment of angina pectoris with disodium ethylene diamine tetraacetic acid. Am J Sci 1956;232:654-666.

13. Faber M: Arch Pathol Lab Med 1949;48:342.

14. The Coronary Drug Project Research Group. Clofibrate and niacin in coronary heart disease. JAMA 1975;231:360.

15. Loreil BH, Paulus WJ. Grossman W. Wynn H. Kohn PF. Braunwald E: Improved diastolic function and systolic performance in hyperrophic cardiomyopathy after nifedipine. N Engl J Med 1980;303:801.803.

16. Gabel FJ: de Phyriol et de Path Gen 1932:30:340.

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