Introduction

This article is going to look at the use of EDTA Chelation Therapy in the management of cardiovascular disease and other degenerative conditions associated with the accumulation of calcium in sites outside of the bony tissue where its presence has been implicated as one source of the dysfunctional state, e.g. in rheumatoid and osteoarthritis, scleroderma.

Definitions

Chelation is derived from the Greek word "Chele" which refers to the claw of the crab or lobster and implies the firm pincher-like binding action of an organic compound to a metal ion.

Ions are charged particles in solution. There are two types and they are cations which are positively charged particles and anions where are negatively charged particles.

Metal ions are positively charged particles or cations. These have centers of activity known as reactive sites. These sites are occupied by water molecules when the metal ions are in a solution of water. These water molecules can be displaced by substances that compete more strongly for the reactive sites of the metal ion.

Morgan and Drew in 1920 defined chelation as the incorporation of a metal cation into a heterocyclic structure. Hetero is derived from the Greek language and means "other, different". Cyclic means "a ring" and so heterocyclic pertains to a closed chain or ring of atoms which includes atoms of different elements, e.g. nitrogen and hydrogen. This binding process provides the basis for Chelation Therapy. The heterocyclic ring structure is vital for chelation to occur.

The maximum number of bonds that can be formed by the cation is called the coordination number. The number of anions that can coordinate or complex with a cation is usually 4, 5 or 6 for the most common metals.

The chelating agent EDTA contains a total of six electron-binding sites or groups which can occupy either 4, 5, or 6 coordination positions which surround a central metal ion.

Thus Chelation is defined as an equilibrium reaction between a metal ion and a complexing agent characterized by the formation of up to six bonds between the complexing agent and the cation resulting a ringed structure with the metal ion in its centre. Thus when this occurs the metal is said to be chelated and the complexing compound is the chelating agent.

It is this encompassing or wrapping around of the chelating agent that sequestrates the metal ion and prevents it binding to enzyme sites where it does its damage in cellular systems.

A Ligand is defined as any atom or molecule which binds to a central atom, having at least one pair of electrons it can donate to a metal ion. An example of such is ammonia which can bind to a cation. A chelating agent is a special form of ligand and it always possesses a ring structure to work by definition.

Therefore all chelating agents are ligands but not all ligands are chelating agents.

A ligand has a point or points of contact which bind to the cation, these points of contact are called Dentates or teeth. A ligand is characterized by its number of teeth.

EDTA has six pairs of electrons that it can donate and is therefore called a hexadentate or sexadentate (has 6 teeth) ligand.

Chelating processes are essential to life and occur naturally in our bodies. Naturally occurring chelates include chlorophyll which is a chelate of magnesium, haemoglobin which is a chelate of iron and vitamin B12 which is a chelate of cobalt.

Some drugs work by chelating minerals. For instance, the antibiotic tetracycline is a chelator of zinc and prevents the bacteria from getting the zinc it requires for its reproduction. This makes the bacteria weaker and more susceptible to being engulfed and destroyed by the patient's own white blood cells.

What is EDTA?

EDTA is Ethylene Diamine Tetra Acetic Acid.

The Ethylene portion looks like this:

	H	H
-		-	-
	C-
-		C	-
	H	H

It has two carbon toms to which are attached:

• The Diamine portion composed of two nitrogens or amine groups, so you get:

-- N - C - C - N -



• The tetra acetic acid is composed of 4 acetic acid groups with two being attached to each nitrogen group like so:

HOOC - CH2		CH2 - COOH
	N - C - C - N
HOOC - CH2		CH2 - COOH

This gives Ethylene Diamine Tetra Acetic Acid (EDTA).

Since disodium EDTA is more soluble in water than EDTA, it is the former compound which is used in clinical practice and this compound looks like so:

NaOOC - CH2		CH2 - COONa
	N - C - C - N
HOOC - CH2		CH2 - COOH

It is the disodium EDTA that is preferable as it has an impact on calcium balance which is the effect needed.

EDTA has an octahedral or eight sided structure and binds the minerals by donating up to six electron groups, at the two amines (nitrogen) and the 4 carboxyl groups (oxygen). It can occupy 4, 5, or 6 coordination positions around a central cation. With this binding the mineral is surrounded by the EDTA molecule to form an octahedral structure. EDTA can bind many minerals and metal cations but only one for each molecule of EDTA.

The commercial forms of EDTA are Disodium EDTA or Calcium Disodium EDTA. These preparations are approved for the treatment of hypercalcaemia (too much calcium in the blood) and ventricular arrythmias caused by digitalis toxicity (the disodium form) and for removal of lead and other heavy metals (the calcium disodium form). However, for vascular and degenerative disease, physicians make Magnesium Disodium EDTA.

EDTA does not pass through cell membranes nor does it effectively penetrate the blood brain barrier.

To understand what EDTA does in the body and how it works one has to know about the relative affinity EDTA has to individual metal cations. This brings forward the subject of what are called stability constants.

Stability Constants

Any mineral cation which complexes with a chelating agent has a certain attraction or affinity to that agent which is expressed mathematically by an equilibrium or stability constant (Ks). The higher the constant, the greater the affinity of the mineral to the chelating agent and the more it is complexed. Stability constants are expressed as the logarithm or Log K value. The higher the number of Log K for a mineral, the higher the affinity it has to the chelating agent.

The stability constant Long K values of minerals for EDTA are as follows:

Reduced iron 25.1, Mercury 21.8, Copper 18.8, Lead 18.5, Nickel 18.0, Zinc 16.5, Cadmium 16.5, Cobalt 16.3, Aluminum 16.1, oxidized Iron 14.3, Calcium 10.7, Magnesium 8.7.

So when magnesium EDTA is administered in Chelation Therapy for the cardiovascular patient, as soon as it hits the blood stream, it will drop the magnesium and grab onto calcium, as calcium is present in plentiful amounts. But as EDTA circulates, if it comes across an oxidized iron cation, it will drop the calcium and grab the iron; then if it comes across cadmium or zinc, the EDTA will loose the iron and grab the cadmium or zinc. As it circulates more and comes across a lead ion, it can drop the cadmium or zinc and grab the lead.

The only exception to this rule is the toxic metal mercury. Even though mercury has a very high Log K stability constant, it is so firmly complexed to sulfhydryl groups and bound, EDTA can't extract it and as a result EDTA is a very poor chelator of mercury in clinical practice. Only if mercury is free and available will EDTA complex the mercury. However, there is very little free mercury available in the circulation available to be complexed.

Also the trace mineral chromium (which is not on the list) will bind so tightly to EDTA that it never comes loose. Thus chromium EDTA has been used in assessing glomerular filtration of the kidney because what goes in will go out unchanged.

There are a number of factors that will alter the affinity of metal ions to EDTA. These are:

• The acidity (or pH) of the solution the EDTA is in. As pH increases, so does the binding strength of EDTA to the metal ion, so EDTA chelates more efficiently in a slightly alkaline solution. However there are physiological buffers in the blood which keep the blood in a very narrow range of PH, so this factor of pH is not an important one in clinical practice.



• The binding strength of the chelating agent to metal cations each of which have specific binding affinities to any one chelator. What this means is that if there are equal concentrations of two cations in solution, the one with the greater affinity will be complexed to a greater extent with the chelating agent. An example would be if there was a lot of lead and calcium present. EDTA would bind more of the lead because of the former's greater affinity.



• The relative metal concentrations, so that a high concentration of a lower affinity cation can partially displace metals of greater affinity which are present in low concentrations through the law of simple mass action. An example of this is for calcium which has a low stability constant but since it is present in relatively high concentrations in the blood, EDTA will complex a great deal of it. In fact if one gave 3 grams of EDTA as a very fast infusion, every free molecule of calcium would be complexed. This would cause acutely low calcium levels, tetany and the death of the recipient. This is why EDTA is infused in a controlled amount over a given time to ensure the levels of calcium are reduced in a slower manner. When EDTA is given over time, it allows the body to pull calcium out of storage sites to make-up enough for the loss in the blood.



• In-vivo versus in-vitro. "In-vivo" means how a substance reacts in a living person whereas "in-vitro" measures how a chemical responds in a test tube out of the body. All stability constants were determined in vitro. When EDTA and metal cations interact in the blood, they are involved with the body's buffering systems. This is an entirely different situation and the stability constants do not apply as they do in vitro.

The metallo enzymes in the body are not affected by EDTA whose action is only to complex unbound ionic metals which are in small concentrations as compared to the total amount of minerals in the body which are often bound to naturally occurring ligands, metallo enzymes or transport proteins. Also EDTA can strip away those metal cations which are loosely bound to ligands in the body as it has the ability to bind them more tightly. So how are the stability constants used in clinical application?

When the ingredients of a chelation treatment are added to a 500cc bottle of water, one is dealing with "in-vitro" characteristics. The EDTA is put in and then magnesium is added. From this, magnesium EDTA is made, with the release of hydrogen ions. This makes the solution more acidic, i.e. the pH of the solution is lowered. If this solution is administered to a patient, the infusion would be painful. Therefore sodium bicarbonate is added in-vitro into the bottle before it is administered into the patient to ensure the pH of the solution is increased to a neutral level.

Now the solution is prepared, it is infused and one has magnesium-EDTA going in and when it comes across calcium the magnesium is released into the blood and calcium-EDTA is formed. The net result is the delivery of magnesium to the cells, because it is released by the EDTA for calcium ions which the EDTA complexes as the stability constant for calcium is greater than the stability constant of magnesium. This is "in-vivo".

The combining of EDTA with magnesium in the infusion bottle prior to administration releases 8 K calories of heat in what is called an exothermic reaction. This reduces the discomfort of infusion by releasing the heat in the bottle and not in the patient. The combining of magnesium EDTA with calcium ³in vivo² releases only 2 K calories of heat which is much less than would occur if Disodium EDTA and magnesium were added separately in the body at the same time.

So to sum up there is Disodium EDTA in the bottle to which is added magnesium and this instantly makes Magnesium EDTA with the release of some protons. This increases the acidity of the bottle which is corrected by the addition of bicarbonate. When that is put in the bloodstream, calcium is complexed making calcium EDTA and magnesium is released. The use of Magnesium EDTA in the management of hypertension (high blood pressure) is efficacious as Magnesium EDTA is an excellent way of delivering magnesium to the cells of the vascular wall and other tissues.

Blood pressure is lowered by two actions.

When Magnesium EDTA is infused, it quickly becomes calcium EDTA and magnesium is released. The EDTA will also complex lead and cadmium. This gives a two-pronged attack on hypertension. Magnesium relaxes arterioles (small arteries) which lowers blood pressure and it is known that cadmium and lead are causative agents in hypertension and so in reducing the body burden of these two minerals, there is the positive result of normalizing hypertension.

Effects of EDTA on Other Metals

Mercury
Although mercury has a relatively high affinity for EDTA in vitro, it is not effectively complexed by EDTA in vivo. This is because mercury is so tightly bound to ligands, such as sulfhydryl groups, in the tissues.

Mercury accumulates insidiously over time from mercury amalgams, from food (especially in large fish) and from industrial leakage into our water and air. Toxic metals can be expelled into the air and their molecules can persist for many months to be carried over whole continents. Mercury selectively destroys brain cells irreversibly and can be a factor in many neurological problems. Other detoxification methods have to be employed for the removal of mercury from the body but by removing other toxic metals with EDTA, mercury becomes more available for freeing up by other chelating agents.

Zinc
Although the stability constant for zinc is intermediate, great quantities of zinc are removed by EDTA because of its relatively high concentration in the body and its relative loose binding to tissue ligands in vivo. Zinc must be replaced when a patient undergoes a course of Chelation Therapy.

Reduced Iron (Ferric Iron)
This mineral has a high stability constant and is therefore removed with ease by EDTA. This is useful when a patient is overloaded with iron since it reduces the generation of reactive, unstable molecules, called free radicals. These free radicals are more readily produced in the presence of iron. However care is necessary not to induce significant iron deficiency if iron stores are already depleted prior to chelation with EDTA. As an important aside, the hearts of patients with cardiomyopathy are often heavily burdened by toxic metals and the latter could well contribute to this often fatal condition. Hence Chelation Therapy might offer definite benefits in patients with cardiomyopathy.

Chemical Measurements during EDTA Infusions

A study was started at the Walter Reed Hospital in the United States on EDTA Chelation Therapy. Unfortunately this research was interrupted before completion by the Gulf War in 1990 and was never restarted as the funding for this research was withdrawn.

However, important observations and discoveries were found and below is a short review of these results.

Three groups of patients were evaluated. One group received 3 grams of Magnesium EDTA, one group received 1 grams of Magnesium EDTA and one group Magnesium Chloride only. All groups received the infusion over 3 hours.

The following chemical parameters were assessed:

Total serum calcium, serum ionized calcium, serum parathyroid hormone* (it's C terminal) serum parathyroid hormone (it's N terminal), serum magnesium and urinary calcium, zinc, iron, copper, manganese and aluminum excretions.

So what was found with some of these parameters?

Total Serum Calcium

• With infusion of magnesium alone, there was no change.
  
  
• With infusion of 1 gm of Magnesium EDTA, there was a very slight lowering between the 6th and 9th hours after the infusion's start.
  
  
• With infusion of 3 gm of Magnesium EDTA, there was a lowering of serum calcium from the 4th hour to the 9th hour.
  

Serum Ionized Calcium

• With magnesium alone, ionized calcium stayed in the normal range.



• With 1 gm of Magnesium EDTA, there was a small drop.



• With 3 gm of Magnesium EDTA, at 3 hours serum ionized calcium dropped quite low and this level did not get back to baseline after 9 hours.
  

Serum Parathyroid Hormone

C Terminal
With magnesium and 1 gm of Magnesium EDTA there was no effect. With 3 gm of Magnesium EDTA, there was a peak outside the normal range within the hour. At 2 hours the level fell but at the 3rd hour it came up again and stayed there for up to 9 hours.

N Terminal
With 3 gm of Magnesium EDTA, there was a huge peak by 1 hour, at 2 hours it fell but by 3 hours it was up again and stayed there for another 3 hours before falling back into the normal range. This did not occur with the other two infusions.

So why do the C and N terminals peak, drop and go back up? It is thought that the parathyroid gland has a reservoir of hormones and it's the EDTA that affects this reservoir by a release of the hormones already formed. However the reservoir runs dry and so the parathyroid has to quickly regroup, manufacture more parathyroid hormone de-novo and does it as needed.

Serum Magnesium

With the infusion of magnesium alone, serum levels peak at 3 hours outside the normal range. There is a similar occurrence with 1 gm of Magnesium EDTA. But with 3 grams of Magnesium EDTA given at a uniform rate over 3 hours, serum magnesium remains in the normal range. This is because available calcium is being stripped from cell membranes and magnesium is being delivered intra-cellularly. Magnesium EDTA is a very effective intra-cellular magnesium delivery system and this mechanism accounts for one of its many beneficial effects in the management of cardiovascular patients.

Urinary Calcium Excretion

With 3 gm of Magnesium EDTA, large amounts of calcium are excreted (at twice the amount one would excrete on a daily basis), but not with the other two infusions. As a result, patients receiving Chelation Therapy need to take adequate calcium supplementation or extra dietary calcium to replete this loss on the days they are not being chelated. This is very important.

Other Urinary Mineral Excretions

Zinc
Although the stability constant of zinc is intermediate, 3 gm of Magnesium EDTA removed large quantities and this can lead to zinc deficiency. This pull out is due to the relatively high concentrations of zinc present in the body and it is not tightly bound to ligands in vivo. Therefore zinc must be replaced when a patient undergoes Chelation Therapy.

Copper and Manganese
These minerals were also excreted into the urine with 3 gm of EDTA in high amounts.

Aluminum
Aluminum was removed at much higher levels with 1 gm of Magnesium EDTA compared to 3 gm of Magnesium EDTA.Aluminum has been implicated in Alzheimer's Disease because this mineral is found in the nerve tangles associated with established disease.

A research study on the effect of trivalent chelating agents was being done in Toronto, Canada in the 1980's. Trivalent chelating agents are effective for removing ferric (reduced iron) ion and aluminum. The agent being used was Deferoxamine on a select group of patients with Alzheimer's with an age matched control group. After 2 years of treatment, the treated group had better cognitive parameters, compared to the control group with Alzheimer's who deteriorated in the expected way. This research suddenly came to a stop and has not been continued for political reasons.

Pharmcacology of EDTA

EDTA is not metabolized in the body nor is it reabsorbed by the kidney collecting tubules. It therefore carries its bound metal/mineral out of the body through the urine. The biological half-life of EDTA in humans is about one hour and only 1-2% remains in the body after 24 hours and consequently one hour after a 3 hour infusion of EDTA has finished, there is very little EDTA remaining in the body. However because of its effects on parathyroid hormone, a cascade of events is initiated which continue on well after the EDTA has been excreted.

The calcium and other minerals bound to the EDTA pass through the blood stream and are excreted through the kidneys and out of the body by the urine. About 5% of the total dose of EDTA passes through the liver and is excreted through the gastrointestinal tract.

All the mechanisms of EDTA have not been elucidated but all of its pharmacological effects are the result of its metal binding properties.

In summary, what are the chemical and clinical effects of EDTA Chelation Therapy?

• It removes harmful minerals such as lead, cadmium, and aluminum from the body. It mobilizes and removes calcium from soft tissues, blood vessel walls, joint spaces and eyes.
  
  
• There is calcium in a diseased artery as well as cholesterol. This arterial wall calcium deposit is much like the calcium present in bone. Therefore parathyroid hormone will also work on soft tissue calcium as well as bone calcium. So EDTA helps to reduce plaque build up in the arteries by its effect on parathyroid hormone levels.
  
  
• It reduces iron and copper in the body. These minerals are known to drive free radical formation and damage leading to the harmful inflammation.
  
  
• It makes red blood cells more flexible and thus improves blood flow in the micro-circulation. Red blood cells get a little bit stiff when there is too much calcium present and are less able to bend and go from a doughnut shape into a bullet shape as they slide through the capillaries. Thus stiff red blood cells are less able to release oxygen to the cells and collect carbon dioxide from the cells because there is less surface area available. Thus EDTA Chelation Therapy helps to restore the normal flexibility of red blood cells and improve blood flow in the microcirculation and oxygenation of the tissues of the body.
  
  

Long term Effects of EDTA Chelation Therapy

Chelation Therapy will

• Reduce tissue calcification



• Reduce plaque size



• Reverse hardened arteries over time. Chelation is not a quick fix so repeated treatments are necessary.
  
  
• Increase bone density.
  
  
• Improve cellular metabolism and function as it betters the enzymatic activity of cells by removal of toxic metals from enzyme systems. <
  
  
• Reduce inflammation by lessening free radical damage
  
  
• Reduce platelet aggregability (stickiness).
  
  
• Reduce thickening of the blood.
  
  
• IMPROVE QUALITY OF LIFE. Patients generally experience better energy, improved well-being, increased physical activity with less claudication, less angina and improved cardiac function.
  
  
• It can reduce the number of patients needing coronary by-pass surgery and leg amputations by 60%. Thus chelation saves money and saves lives. EDTA is a drug, it is not "alternative", but should be considered standard medicine and when given correctly and by the correct protocol is effective in the management of cardiovascular disease especially when used with proper dietary modification, exercise, nutrient supplementation and appropriate medical therapy. The drug management of cardiovascular disease when used alone may well produce an improved prognosis but not necessarily improved quality of life. When the chelation equation is added in the combination of both therapies it can produce patients who have regained their future and well-being and who can look to their future once again in a positive manner.
  

Paul Jaconello
M.D. Diplomate American Board of Chelation Therapy

Note: the majority of this article's information was culled from lecture notes of Ted Rozema, M.D., secretary of the American Board of Chelation Therapy.

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