Zinc as a Natural Angina Pectoris Cure?

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ZINC AS A NATURAL ANGINA PECTORIS, ISCHEMIA OF EFFORT and CARDIAC ARRHYTHMIA CURE?


by George Eby

revision date: December 21, 2007

What is Angina Pectoris?

According to the American Heart Association, angina pectoris is the medical term for chest pain or discomfort due to coronary heart disease. Angina is a symptom of a condition called myocardial ischemia. It occurs when the heart muscle (myocardium) doesn't get as much blood (hence as much oxygen) as it needs. This usually happens because one or more of the heart's arteries (blood vessels that supply blood to the heart muscle) is narrowed or blocked. Insufficient blood supply is called ischemia. Angina also can occur in people with valvular heart disease, hypertrophic cardiomyopathy (this is an enlarged heart due to disease) or uncontrolled high blood pressure. These cases are rare, though. Typical angina is uncomfortable pressure, fullness, squeezing or pain in the center of the chest. The discomfort also may be felt in the neck, jaw, shoulder, back or arm. Many types of chest discomfort aren't related to angina. Acid reflux (heartburn) and lung infection or inflammation are examples.

One needs to go to the Center for Disease Control page to learn that: "Blockages in the arteries in our body is caused by arteriosclerosis (hardening of the arteries) brought on, and/or aggravated, by several health risk factors. The main culprit ingredient is cholesterol, which mostly come from saturated fats that we eat, like red meats (pork, beef, etc.), eggs, butter, lard, dairy products, etc. Ingestion of these foods leads to high level of the bad cholesterol, which thickens the blood consistency, which leads to thick cholesterol "paint" deposits on the inside walls of the tiny coronary arteries, which are only 1 to 3 millimeters in diameter, like the size of a round toothpick. This situation is like using thick paint applied layers after layers, every second, day after day, year after year, onto the inner walls of these tiny pipes. Just like the sewer or drain pipes in our homes, this cholesterol "junk" could clog up our coronary arteries, as small as they are."

Experimental Evidence for Efficacy of Zinc in the Treatment and Prevention of Angina Pectoris.

In 1981 while Dr. William W. Halcomb DO, (currently of Mesa, Arizona) and myself were running our clinical trial of zinc gluconate throat lozenges and common colds, a man in his 60s entered the trial and received zinc gluconate. His cold did not respond to zinc and he used the 23 mg zinc lozenges each 2 hours for seven days. Even though our questionnaire was designed to detect and remove people from the trial who had any disorder other than a cold, he had sneaked in. That man had been on a railroad disability for angina pectoris for 15 years and was only moderately comfortable using nitroglycerin like candy all day long - but only if he did not exert himself physically. His pain was sufficiently intense that he had not worked for 15 years and he was essentially house bound.

The man returned a few days after the trial was over and told us that he wanted to know whether or not he received zinc or placebo, and if it was placebo (as he suspected) what was the placebo. We looked up the record, and told him he had received zinc gluconate. He then told us that after about 5 days on zinc, his angina pectoris pain disappeared for the first time in 15 years. After his zinc, he went snow skiing for the first time in over 15 years and had no trouble. This man obtained a new job and felt fine working hard all day - as long as he took his zinc!

Nearly immediately after that experience in 1981, a 70 year old father of a friend of mine tried zinc tablets, not as lozenges, but as dietary supplements to treat his excruciatingly painful 24/7 angina pectoris. He had no ability to exert himself due to angina pectoris pain. He was heavy, about 300+ pounds (150 kg) and 180 mg of zinc did not help him, but 300 mg of zinc (from zinc gluconate) after 30 days of treatment cured his angina pectoris - so he said. After about a year of freedom from angina pectoris and resumption of an active lifestyle, this man's cardiologist, while remarking his great pleasure with his progress, told my friend's father to discontinue the zinc because zinc would significantly decrease serum high-density lipoprotein concentration but would slightly increase low-density lipoprotein (the harmful type). Although such is true in healthy adults, less is known about changes in cholesterol in aging and/or unhealthy adults due to dietary supplements of zinc. Furthermore, I hypothesize that transient increases in low density serum cholesterol could easily have resulted from release of tissue bound cholesterol. In other words, would a serum increase in low density cholesterol result if zinc removed cholesterol from arteries??? I think such is possible, and offer some evidence. Also, excesses of zinc can lower copper and iron serum levels. Reductions in iron may be beneficial in several ways important in cardiology. Regardless, my friend's father died of congestive heart failure (possibly due to a taurine deficiency) about one month after stopping zinc. See this page for the role of taurine in cardiology.

In 1981, Dr. Halcomb nearly immediately incorporated these observations into his daily clinical practice. Since 1981 he found that control of angina pectoris with as little as 60-mg zinc tablets 3 times a day along with dietary changes and smoking cessation occurred in most of patients in clinical practice allowing either termination or substantial reduction in nitroglycerin intake. He said that more patients might respond to higher oral dosages, as long as zinc serum concentrations remain in the high part of the normal zinc serum range (about 140 micrograms zinc per deciliter).

How Can Zinc Cure Angina Pectoris?

How can zinc cure angina pectoris? Possibilities include: Zinc stabilizes cell membranes of the cardiovascular system. Zinc depletes excess stores of iron and cadmium (cadmium greatly worsens cardiovascular disease). Zinc competes with iron for gut absorption sites and blood transport proteins. Zinc prevents arterial scarring from viral infections of the arteries. Zinc ion is also anti inflammatory. Clearly, variations in normal zinc status (un-supplemented) as determined using zinc content of fingernails is not correlated with incidence of acute myocardial infarction.

I asked this same question to Dr. Ananda S. Prasad, M.D., PhD, of Wayne State University. Dr. Prasad is the foremost authority on zinc biochemistry on Earth and a distinguished professor of medicine. Dr. Prasad discovered zinc to be an essential human nutrient many years ago and has published extensively for more than 50 years on the role of zinc in biochemistry. Here are most of his papers, and here is a Google search for Dr. Ananda S. Prasad. Dr. Prasad's answer was very interesting. He said:


"Dear George,

Many thanks for your letter. I am indeed very excited about the Cardio-vascular events and zinc. The present day concept is that elderly subjects produce increased amounts of cytotoxic cytokines such as TNF-alpha , IL-beta and IL-8 and these cytokines affect the vascular endothelium and they generate activated endothelial cell molecules such as ICAM, VCAM and E- Selectin etc. These molecules trap platelets, red cells, neutrophil, monocytes etc. and plug up the blood vessels (thus angina and Sickle Cell Pain Crisis). Furthermore the monocytes-macrophages get activated and produce free radicals and reactive oxygen species (ROS) which lead to DNA oxidation and lipid peroxidation. Lipid peroxidation and LDL oxidation is believed to be critical for arteriosclerosis, and DNA- oxidation may be a pathogenetic factor for development of cancer.

I am sending you a paper which I published last year, defining basic roles of Zinc on inflammatory cytokines and oxidative stress. I am trying to get a NIH grant to do more work in the elderly.

Also you should see a paper published in Archives of Ophthalmology, May 2004 which reports that subjects who received zinc for prevention of blindness in age related macular degeneration, showed decreased mortality. All theses observations are very exciting for the role of zinc. I think that zinc may have decreased incidence of infections, decreased oxidative stress, or decreased mortality due to cardiovascular events or even cancer. All these need to be studied and documented.

So I am at it! Life goes on and it is becoming more difficult to get funds. Many, many thanks for your previous support.

Your sincerely,

Ananda Prasad"


Going a step further, Dr. Prasad's abstract of his article Zinc modulates mRNA levels of cytokines. reads: "Zinc plays an important role in cell-mediated immune function. Altered cellular immune response resulting from zinc deficiency leads to frequent microbial infections, thymic atrophy, decreased natural killer activity, decreased thymic hormone activity, and altered cytokine production. In this study, we examined the effect of zinc deficiency on IL-2 and IFN-gamma in HUT-78 (Th0) and D1.1 (Th1) cell lines and TNF-alpha, IL-1 beta, and IL-8 in the HL-60 (monocyte-macrophage) cell line. The results demonstrate that zinc deficiency decreased the levels of IL-2 and IFN-gamma cytokines and mRNAs in HUT-78 after 6 h of PMA/p-phytohemagglutinin (PHA) stimulation and in D1.1 cells after 6 h of PHA/ionomycin stimulation compared with the zinc-sufficient cells. However, zinc deficiency increased the levels of TNF-alpha, IL-1 beta, and IL-8 cytokines and mRNAs in HL-60 cells after 6 h of PMA stimulation compared with zinc-sufficient cells. Actinomycin D study suggests that the changes in the levels of these cytokine mRNAs were not the result of the stability affected by zinc but might be the result of altered expression of these cytokine genes. These data demonstrate that zinc mediates positively the gene expression of IL-2 and IFN-gamma in the Th1 cell line and negatively TNF-alpha, IL-1 beta, and IL-8 in the monocyte-macrophage cell line. Our study shows that the effect of zinc on gene expression and production of cytokines is cell lineage specific."

In 1996, Bernhard Hennig, et. al. wrote an article titled "Antiatherogenic Properties of Zinc: Implications in Endothelial Cell Metabolism". They pointed out that: Zinc is an essential component of biomembranes and is necessary for maintenance of membrane structure and function. There is evidence that zinc can provide antiatherogenic properties by preventing metabolic physiologic derangements of the vascular endothelium. Because of its antioxidant and membrane-stabilizing properties, zinc appears to be crucial for the protection against cell-destabilizing agents such as polyunsaturated lipids and inflammatory cytokines. Zinc also may be antiatherogenic by interfering with signaling pathways involved in apoptosis. Most importantly, we have evidence that zinc can protect against inflammatory cytokine-mediated activation of oxidative stress-responsive transcription factors, such as nuclear factor KB and AP- 1. It is very likely that certain lipids and zinc deficiency may potentiate the cytokine-mediated inflammatory response and endothelial cell dysfunction in atherosclerosis. Thus, the antiatherogenic role of zinc appears to be in its ability to inhibit oxidative stress-responsive factors involved in disruption of endothelial integrity and atherosclerosis. We discuss antiatherogenic properties of zinc with a focus on endothelial cell metabolism. Nutrition 1996; 12:71 l-717.

Later in 2000, Hennig, et al. wrote: "Little is known about the requirements and function of zinc in maintaining endothelial cell integrity, especially during stressful conditions, such as the inflammatory response in cardiovascular disease. There is evidence that (my emphasis) zinc requirements of the vascular endothelium are increased during inflammatory conditions such as atherosclerosis, where apoptotic cell death is also prevalent. Apoptosis is a morphologically distinct mechanism of programmed cell death which involves the activation of a cell-intrinsic suicide program, and there is evidence that factors such as inflammatory cytokines (e.g., tumor necrosis factor [TNF]) and pure or oxidized lipids are necessary to induce the cell death pathway. Because of its constant exposure to blood components, including prooxidants, diet-derived fats, and their derivatives, the endothelium is very susceptible to oxidative stress and to apoptotic injury mediated by blood lipid components, prooxidants, and cytokines. Thus, it is likely that the cellular lipid environment, primarily polyunsaturated fatty acids, can potentiate the overall endothelial cell injury by increasing cellular oxidative stress and cytokine release in proximity to the endothelium, which then could further induce apoptosis and disrupt endothelial barrier function. Our data suggest that zinc deficiency exacerbates the detrimental effects of specific fatty acids (e.g., linoleic acid) and inflammatory cytokines, such as TNF, on vascular endothelial functions. We propose that a major mechanism of zinc protection against disruption of endothelial cell integrity during inflammatory conditions, is by the ability of zinc to inhibit the pathways of signal transduction leading to apoptosis and especially mechanisms that lead to upregulation of caspase genes."

Role of Taurine in Zinc for Angina Pectoris

One related aspect of zinc metabolism in aging involves taurine, a conditional amino acid made in the liver in non-infants. Taurine levels have been shown to decline in aging, resulting in cardiac and mental injury and reduced energy levels. Taurine appears to play a role in lipid metabolism, and it may inhibit atherosclerosis by regulating the bloods levels of zinc, copper and calcium. Perhaps, since atherosclerosis occurs primarily in older people, taurine must be supplemented to allow zinc, copper and calcium to have their natural, youthful cardioprotective effects. Recently scientists found that taurine treatment accelerates the regression of cholesterol-induced atherosclerotic lesions in rabbits without having any effect on the plasma and aorta lipid and lipid peroxide levels. Indeed, 2 grams of taurine 4 or 5 times a day is the only consistent treatment that prevents one hundred percent pre atrial contraction (PACs) cardiac arrhythmias in my 64-year old heart. Would you drive a 64 year old car in need of preventative maintenance? Doesn't that thought put things into perspective? Supplemental taurine is vital in aging for many different reasons and you may want to visit this link for much more information. Also, you may want to consider the multiple roles of taurine. In Timothy C. Birdsall, ND's article: "Therapeutic Applications of Taurine", he writes in his abstract: "Taurine is a conditionally-essential amino acid which is not utilized in protein synthesis, but rather is found free or in simple peptides. Taurine has been shown to be essential in certain aspects of mammalian development, and in vitro studies in various species have demonstrated that low levels of taurine are associated with various pathological lesions, including cardiomyopathy, retinal degeneration, and growth retardation, especially if deficiency occurs during development. Metabolic actions of taurine include: bile acid conjugation, detoxification, membrane stabilization, osmoregulation, and modulation of cellular calcium levels. Clinically, taurine has been used with varying degrees of success in the treatment of a wide variety of conditions, including: cardiovascular diseases, hypercholesterolemia, epilepsy and other seizure disorders, macular degeneration, Alzheimer's disease, hepatic disorders, alcoholism, and cystic fibrosis. See full article here: Alt Med Rev 1998;3(2):128-136. All of these disorders are "diseases of aging". One way in which the liver fails in aging is by loosing its ability to produce taurine, thus precipitating, and/or worsening these disorders. Interestingly, and profoundly important if this works in people, taurine augments (improves) the proliferative responses of T cell lymphocytes from both young and old mice. Taurine at 12 grams per day completely eliminates many cardiac arrhythmias and has a broad role in cardiology. In fact, there is no other nutrient that has such a beneficial effect on cardiology as taurine, perhaps because taurine production declines and can cease in aging, producing a large number of cardiovascular problems including death. See this article for much more information. Taurine is found in meat and especially in conch but is not found in the vegetarian diet, making supplementation vital to many in aging.

Role of Nuts in Preventing Cardiovascular Disease

The battle against cardiovascular disease has a ready ally in nuts high in zinc. Nuts are a rich source of many minerals such as zinc and other nutrients required to prevent cardiovascular disease in general. Nuts? You have been told to avoid them due to their fat content? That is some of the worst health advice ever given (advice by savion washington). Before I go on about nuts, read this wonderful article about nuts and their ability to reduce cardiovascular disease by over 50%. Initial evidence for the benefit of nut consumption came from population studies which looked at the diets of large numbers of people over long periods of time. In four US studies, the Adventist Health Study, the Iowa Women's Health Study, the Nurses' Health Study and the Physicians' Health Study, a total of over 160 000 men and women were followed for between 6 and 14 years. These studies showed very consistent indications for the health benefits of nuts. When compared with never eating nuts, the effect of eating small quantities of nuts (30 g) four to five times per week or more was a reduction in CVD risk of between 18 and 51%.

Variant Angina (Prinzmetal's angina)

In the case of "variant angina" (Prinzmetal's angina), I am personally convinced that the cause of the spasms occurring in variant angina or Prinzmetal's angina is magnesium deficiency, and at least 500 milligrams of magnesium should be taken every day in 125 mg doses at mealtimes and bedtime to maintain health generally and to prevent Prinzmetal's angina. I had a single episode of variant angina or Prinzmetal's angina (without any detectable arteriosclerotic plaque buildup) in 1998 (after ingesting much zinc since 1980), and the attending physician gave me an intravenous drip of magnesium sulfate (Epsom Salts). This, my only bout with variant angina or Prinzmetal's angina, was over in a few hours. I was instructed to increase my magnesium intake and variant angina has never returned. Magnesium deficiency is an extremely common nutrient deficiency in the West and some believe magnesium deficiency is the cause of much morbidity and mortality. Magnesium deficiency will cause much mental and cardiac problems. Note: Magnesium oxide is not biologically available.

My physician was right about magnesium, and this exact very rapid response was first reported by Czech doctors in 1973, later in 1986, and most recently by Israeli doctors in 1987. The Israeli doctors abstract showed that:

"The antithrombogenic effect of magnesium sulfate in vivo is shown at the site of endothelial damage induced by partial coronary and carotid artery constriction. The left anterior descending coronary artery of dogs and the right common carotid artery of rabbits were subjected to partial constriction with suture thread (40-60% reduction in transluminal diameter). Distal blood flow, as measured by electromagnetic flow probe, was not reduced. Scanning electron-microscopic examination of vessels fixed by glutaraledhyde perfusion and dried by the critical-point technique showed endothelial damage at the site of partial constriction ranging from crater- and balloon-like vesicular defects to cellular desquamation. Marked platelet deposition on exposed subendothelium and microthrombi could be seen with the maximum degree of luminal protrusion reaching 30% of the luminal diameter. Animals pretreated with magnesium sulfate (50 mg/kg, i.v.) showed platelet deposition restricted to a maximum of 1 or 2 discontinuous layers of platelets with most vessels showing only isolated platelets on exposed subendothelium. Microthrombi were not seen in any of the magnesium-treated animals. It is suggested that the therapeutic implications of magnesium in ischemic heart disease might be extended from its use in certain tachyarrhythmias and in arterial spasm associated with Prinzmetal's angina to the more classic episodes of ischemic heart disease where thrombus formation plays an unequivocally major role. Clearly magnesium sulfate is the treatment of choice for variant angina (Prinzmetal's angina). We will investigate further the effects of zinc in angina pectoris.


From Harvard Health Letters, November 2002Why do we have such an epidemic of angina pectoris and cardiovascular disease? I vote for depletion of nutrients from the wheat refining process. Take out the zinc, magnesium vitamin B-6 and other nutrients, and presto, an instant boon to pharmaceutical industry!

Patenting Zinc for Angina Pectoris

Thinking we had discovered something new, Dr. Halcomb and myself filed U.S. Patent Application Serial Number 935,951 (11/28/86) for a patent titled METHOD FOR ALLEVIATING ANGINA PECTORIS ATTACKS. The patent was rejected because the role of zinc in preventing and treating angina pectoris was "well known in the art" and therefore not patentable. There was an article written in Polish that preceded our work, and this article is so important that it is republished in English as follows.



L. Giec, A. Wnuk-Wojnar, M. Trusz-Gluza, A. Szulc, and W. Kargul*:

Epidemiological evaluation of the coronary risk in physical laborers in nonferrous metallurgy. Part II: Coronary disease. [Epidemiologiczna ocena zagrozenia choroba wiencowa u pracownikow fizycznych przemyslta hutniczego metali niezelaznych. Czesc II: Choroba wiencowa.** Przegl Lek 1980;37(6):507-10.

*First Cardiology Clinic of the Cardiology Institute of the Silesian Academy of Medicine in Katowice. Director Prof. Dr. Hab. Med. L. Giec. Authors' address: I Klinika Kardiologii SI. AM, ul. Ziolowa 4, 40-634 Katowice. [First Cardiology Clinic of the Cardiology Institute of the Silesian Academy of Medicine in Katowice, 4 Ziolowa St., 40-634 Katowice, Poland]

*Accepted December 19, 1979.

Translated from Polish by the Ralph McElroy Co., Custom Division P.O. Box 4828, Austin, Texas 78765 USA

Abstract

Analysis was performed in 1000 physical workers (900 males, 100 females) aged 21-60 years with the professional exposure to zinc, lead or cadmium. Angina of effort according to Rose was present in 14.1% of studied population. True and probable features of coronary heart disease were found respectively in 0.5 and 3.4% of resting electrocardiograms. The sub maximal exercise test revealed probable ischemia response in 10.1% of studied persons. It has been shown that coronary pain is more frequent in workers exposed to cadmium. However, either angina in history or positive exercise test were less frequent in the persons exposed to zinc.

ADDITIONAL KEY WORDS: angina of effort - electrocardiogram at rest - exercise test - zinc - lead - cadmium

Introduction

The results of clinical, epidemiological, and experimental animal studies indicate a correlation between an excess or deficiency of certain trace elements and the onset and development of coronary disease [2, 15, 19]. Most of these correlations have not been unambiguously explained or even proved.

We decided to evaluate the incidence of coronary disease in a population occupationally exposed to zinc, lead, and cadmium, looking for any correlation between the disease and exposure to these elements.

Materials and methods

A description of the observed population of 1000 physical laborers (900 men and 100 women), aged 21-60, in nonferrous metallurgy, and an outline of the plan of study were given in Part I [17]. The subjects were interviewed concerning the working environment and given a modified and expanded Rose questionnaire [13]. All the subjects were given a 12-lead resting electrocardiogram (EGG) with a three-channel Multicard apparatus. Subsequently, if there were no contraindications from the resting EGG recording or a medical examination, they were exercised on a cycloergometer with submaximal exercise (75-85%). Electrocardiograms were recorded during, immediately after, and 2.5 and 5 minutes after exercise. They were evaluated using a modified [13] Minnesota code.

An epidemiological diagnosis of definite, probable, or questionable coronary disease was made on the basis of criteria given by Askanas and Rywik [1].

In addition, all the workers were tested for serum concentrations of lead and zinc, and the lead, zinc, and cadmium concentrations in the air of their workplaces were measured [4, 11, 17]. The data were statistically processed using the chi square test on an Odra 1305 computer.

Results

A detailed analysis of the measurements of zinc, lead, and cadmium in the air of the workplace and in the serum was given in the previous article [17]. Concentrations above the maximum permitted [threshold limit] concentration for the air of the workplace were found in 74.3% of the workers for lead, 57.9% for zinc, and 7% for cadmium. It also turned out that the degree of exposure did not differ significantly in different age ranges.

There was a positive interview for first and second degree angina of effort in 14.1% of the patients, while in another 9.8% there was pain in the chest cavity which did not meet Rose's criteria [13]. Pain reminiscent of myocardial infarction was reported by 3.6% of the patients. The frequency of subjective symptoms of angina of effort rose with age in 19.3% of men in their fifties and 32.2% of women in their forties. Only 1.2% of the workers were found to have had a previous medical diagnosis of coronary heart disease, while 0.2% had been treated for myocardial infarction.

Table I shows the incidence of electrocardiographic signs of certain, probable, and questionable cardiac ischemia in resting and exercise electrocardiograms of the workers by age and sex. Definite or practical signs of previous myocardial infarction were found in the ECGs only in men over 40 years old. The incidence of other signs rose sharply with age. Signs of questionable ischemia in the resting EGG and of probable or questionable ischemia in the resolved postexercise EGG (sometimes twice) were more frequent in women, especially those in their forties and fifties, while probable electrocardiographic signs of coronary disease at rest were more frequent in men.

According to the criteria given by Askanas and Rywik [1], epidemiological suspicion of coronary disease was recorded when certain or probable signs were present (Table II) in the anamnesis and/or electrocardiogram. Coronary disease was suspected in up to 25% of the workers studied. A more definite basis for such a diagnosis was a positive EGG result together with a positive interview for angina of effort, with such confirmation in only 3% of the patients, while 4.9% of the subjects had both angina of effort and ECGs with questionable signs of ischemia.

Statistical analysis by the chi square method demonstrated a definite relation between the occurrence of signs of coronary disease and toxicological exposure in the work environment (Table III). In individuals exposed to zinc, signs of coronary disease were statistically significantly rarer in the anamnesis and electrocardiograms. Angina of effort was more often reported in workers exposed to cadmium, while electrocardiographic signs were less frequent in those exposed to lead.

Discussion of results

The incidence of suspected coronary disease in our population (25%) is much higher than that reported by other Polish authors [8, 10, 14, 16]. This is primarily because we used the additional diagnostic criterion of the exercise electrocardiogram. A positive interview for angina of effort was found in the studies of Sznajd et al. in 5-6% of those questioned [16]. In a similar age group (41-60), we obtained a positive interview in about 17% of the subjects. This confirmed the observation made for the populations of Sochaczew, Plocek, and Cracow [8, 10] that women more frequently reported subjective symptoms of angina of effort. In an epidemiological study [6], it was suggested that morbidity from coronary disease may actually be higher in women than in men. Our own experiments and those of the authors of [10], who carried out repeated studies of morbidity and susceptibility to coronary disease, lead us to seek the reason for the imperfections in the questionnaire recommended by the WHO [World Health Organization], which can give false positive results.

The incidence of certain and probable signs of coronary disease which we obtained in the resting EGG increases sharply with age and these signs are present mainly in men, as in the studies of Rywik et al. [14] and Wojcikiewicz et al. [18]. The use of submaximal exercise produced probable electrocardiographic signs of coronary disease in a large group of workers (10% of those studied). Only 5 persons in this group reported complaints qualified as coronary disease. Other authors [9, 12] describe a positive result for the exercise test in 3-13% of "symptomless" men. The diagnostic specificity of the exercise test in detecting cardiac insufficiency is variously evaluated in the literature [9, 12]. The frequency of false positive results ranges from 6-50%, depending on the choice of the group studied and the type of verification of the diagnosis (clinical or angiographic). This method is rather questionable in studying clinically healthy persons [12], in whom coronarography can demonstrate significant narrowing of the arteries in no more than 40-50% of cases with a positive exercise test. However, isolated observations of persons with significant stress-related ST depression indicate a much higher incidence of myocardial infarction, sudden coronary death, and other symptoms of coronary disease in these persons [5]. The fact that we very rarely had a positive result for the exercise test in young men and a much higher incidence in persons over 40 is definite evidence that ECG changes of types IV1, V1,2, and VII1 (according to the Minnesota code) may be ischemic in nature. Signs of questionable ischemia or less specific ST-T deviations occurred after exercise significantly more frequently, even in young persons.

In the population which we studied, the group of women was small. Many of them had more or less pronounced irregularities in the electrocardiogram, primarily after exercise. Gumming [3], in exercise studies of 357 healthy women, showed that there were ST-T changes in 25-60%, depending on age, and suggested that the obligatory criteria of exercise EGG evaluation for men could not be extended to women.

Epidemiological suspicion of coronary disease was more frequent, due primarily to the higher incidence of angina of effort and probable ischemia in the exercise EGG. In view of the specific occupational exposure of these persons to zinc, cadmium, and lead, we attempted to determine whether the appearance of signs of coronary disease is dependent on these factors. In those persons working with cadmium, we found a significantly higher incidence of signs of pain after exercise and more frequent (although not statistically significant) signs of ischemia in the exercise EGG. The relation between environmental contamination with cadmium and the occurrence of coronary disease has been recognized in the literature for years [19]. Studies of 28 American men showed a significantly higher mortality due to arteriosclerotic disease in cities with elevated levels of cadmium pollution in the air [2].

The effect of lead on the cardiovascular system has been described by numerous authors [15, 19]. There is no convincing proof, however, that this element has a definite effect on the onset or course of coronary disease. Among our workers, signs of ischemia in the exercise EGG were even rarer in persons exposed to high levels of lead. It is also possible that lead itself is responsible for the high incidence of less specific irregularities in the ST-T segment and other electrocardiographic signs not discussed in this report, via its effect on the sympathetic nervous system and the heart muscle [7].

A beneficial effect of zinc on the course of arteriosclerosis and its complications was suggested by other authors [19]. This was confirmed in the population which we studied. In workers exposed to zinc, in addition to more frequent elevated blood pressure levels [17], there was a lower incidence of subjective and electrocardiographic signs of coronary disease.

Conclusions

  1. The use of the exercise test to detect coronary risk made it possible to better identify an additional group of persons requiring preventive or therapeutic measures.
  2. An evaluation of the population exposed to cadmium, zinc, and lead indicates that cadmium may increase the incidence of signs of coronary disease, while zinc may decrease it.
REFERENCES
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  2. Carrol, R. E.: The relationship of cadmium in the air to cardiovascular disease death rates. J.A.M.A., 1966, 198, 177.
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  4. Dutkiewicz, T., Kesy-Dabrowska, I., and Piotrowski, J.: Determining toxic substances "in the air, PZWL [Polish Medical Publishers] . Warsaw, 1965.
  5. Ellestad, M. H., Wan, M. K. C.: Predictive implications of stress testing. Follow-up of 2700 subjects after maximum treadmill stress testing. Circulation:, 1975. 51, 3C3
  6. Kannel, W. B., Feinleib, M.: Natural history of angina pectoris in the Framinham study. Am. J. Cardiol., 1972. 29, 154.
  7. Kosmider, S. and Petelenz, T.: Electrocardiographic studies in cases of chronic occupational lead poisoning, Pol. Arch. Med. Wewn., 1961, No. 31, p. 1349
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  9. McHenry, P. L.: The actual prevalence of false positive ST-segment responses to exercise in clinically normal subjects remains undefined. Circulation, 1977. 55, 6S3.
  10. Mikolajcjyk, W., Liszewska-Pfejfer, D., Rywyk, S., Korewicki, J., Szcypiorowski, B., and Wagrowska, H.: Morbidity and susceptibility to coronary disease in longwave studies of the populations of Plocek and Sochaczew, Przegl. Lek., 1978, No. 35, p. 873.
  11. Pines, I.: Determination of lead in the air of workplaces, Med. Pr., 1968, No. 19, p. 299.
  12. Redwood, D. R., Borer, J. S., Epstein, S. E,: Whither the ST segment during exercise? Circulation, 1976, 54, 703.
  13. Rose, G, Blackburn H.: Cardiovascular Survey Methods,WIG Org., Geneva 1968.
  14. Rywik, S., Charzewska, J., Napierala, M, Szostak, W. B. , Wagrowska, H., Bieganowska, K. , and Michalski, E., Incidence of changes in the range of the circulatory system in a population of men aged 40-59 studied in the Polish Experiment on Multifactorial Prevention of Coronary Disease, Przeq. Lek., 1977, No. 34, p. 621.
  15. Stofen, D.: Environmental lead and the heart: J. Mol. Cell Cardiol. 1974, 6. 285.
  16. Sznajd, J., Szczeklik, A., Magdon, M., and Olszanecki, S.: Coronary risk in a population of men in South Poland, Przeg. Lek. 1978, No. 35, p. 48.
  17. Trusz-Glaza, M., Wiernek, I., Giec, L., Dosialy J., Kisielewicz, Z., and Szulc, A.: Epidemiological evaluation of the coronary risk in physical laborers in nonferrous metallurgy, Part I. Risk factors, Przeq. Lek., in press.
  18. Wojcikiewicz, O., Kawecka-Jaszcz, K., and Kocemba, J.: Incidence of deviations in the Q wave, S-T segment, and T wave in the population of the city of Cracow, Fol. Med. Cracov., 1976, No. 18, p. 539.
  19. Underwood, E. J.: Trace elements in human and animal nutrition. Acad. Press, New York, London 1971.


These cardiac cadmium, lead and zinc findings were replicated in 2004 by Japanese scientists. Also, wound healing in the skin depends upon the availability of appropriate trace metals as enzyme cofactors and structural components in tissue repair. Wounds receiving 1.0% cadmium chloride failed to heal or fully re-epithelialize within 7 days. Wounds showed a persistent mass of inflammatory cell infiltration, oedema, wound debris and aberrant epidermal cell growth. In the wound, 1.0% cadmium chloride induced statistically significant (P > 0.001) changes in local concentrations of zinc and calcium at key stages in the healing process, and as a consequence disturbed the trace metal balance necessary for normal wound repair. The cytotoxicity of cadmium is considered to be largely responsible, and such is likely to apply to cardiac tissue too. On the other hand, zinc enhances wound healing. Topical zinc, in the form of divalent zinc ions, has been reported to provide antioxidant photoprotection for skin. Two antioxidant mechanisms have been proposed for zinc: (1) zinc ions may replace redox active molecules, such as iron and copper, at critical sites in cell membranes and proteins; (2) alternatively, zinc ions may induce the synthesis of metallothionein, sulfhydryl-rich proteins that protect against free radicals. No matter how they work, topical zinc ions may provide an important and helpful antioxidant defense for skin.

George Responds to Patent Office

Ah Ha! George, not being a dummy could see that "preventing" atherosclerosis and angina pectoris was much different than what we were trying to patent, that being a "treatment" to "cure" angina pectoris, most likely by removing arteriosclerotic plaque from coronary artery walls with "therapeutic" amounts of zinc. So we responded and the United States Patent Office clerk sent us another rejection, this time citing a paper in a book that demonstrated that zinc could be an effective treatment for arteriosclerosis and angina pectoris. The article is presented in full here:



TRACE ELEMENTS IN ATHEROSCLEROSIS, EFFICACY OF ZINC MEDICATION AS A THERAPEUTIC MODALITY

by J. H. Henzel, M.D., B. Holtmann, M.D., F. W. Keitzer, M.D., M. S. DeWeese, M.D., and E. Lichti, Ph.D.Department of Surgery, University of Missouri - ColumbiaMedical Center University of Missouri - Columbia. In: Trace Substances in Environmental health, Conference 2nd proceedings 1967-68.

ABSTRACT

Certain trace elements are now being investigated as possibly having a role in atherosclerosis, and recently administration of zinc has been described as beneficial treatment in a significant percentage of patients with severely symptomatic atherosclerotic disease. A study was therefore initiated in which certain patients with severe atherosclerosis were evaluated, medicated with zinc sulfate, and then re-evaluated at bimonthly intervals in order to assess the efficacy of therapy. Objective patient evaluation included treadmill walking, electrocardiography, plethysmography, and positional photography of ischemic limbs. Objective improvement was observed in 12 of 16 patients;however, six improved patients were discounted since factors such as weight loss and cessation of smoking may have contributed to improvement. Assessment of objective findings', subsequent to subjective improvement, and comparison of pre- and post-treatment serum and urine zinc concentrations, suggests that zinc acts as a therapeutic pharmaceutical (rather, than as replenishment for subnormal biologic stores) in those patients with occlusive vascular disease who experience improvement when medicated with this micronutrient.

INTRODUCTION

The incidence, pathogenesis, and development of atherosclerotic occlusive vascular disease are known to be related to numerous factors and variables.(8) However, in spite of millions of research dollars, untold man-years of laboratory investigation, and exploitation of hundreds of initially promising leads, the number of answers which have been "interlocked" as far as the prevention of atherosclerosis is concerned are indeed few in number and tenuous in stability.

It is particularly fitting to present and discuss investigative results pertinent to this disease at an environmental health conference. The reasoning behind this statement is realistic and sound. Albeit the clinical specialties are able to recognize and "palliate" or "delay" the progressively incapacitating symptoms of atherosclerosis; however, it has been the public health or environmental medicine approaches which have defined certain geographic, hereditary, and dietary "constants" that hold the key to prevention rather than prophylaxis.

The history of science in general, and medical research in particular, is dotted with periodic spectacular developments in knowledge which have enhanced man's healthful existence on this planet. However, there have been few areas for new investigation which can compare with the trace substances as far as a real need for an interdisciplinary approach to research in concerned. Being cognizant of this fact, and recognizing that every field of scientific endeavor either directly or indirectly benefits man's health and longevity, I feel comfortable discussing a clinical disease before an audience which contains representatives from such varied fields of specialization as analytical chemistry, agriculture, horticulture, physics, and nutrition. I feel at ease not because of some macabre satisfaction that all of us within this auditorium have some degree of atherosclerosis, and certainly not because most of us suppress the fact that "if something else doesn't get us, " hardening of the arteries will. Nor is it because of the prevalence of this disease that I feel justified in discussing a clinical study; rather, it is primarily because of a conviction that with respect to the trace substances, meaningful investigation, as well as interpretation and application of study results, requires a cooperative interdisciplinary approach, based on an awareness of and respect for what each of us has to contribute. As clinicians we can never hope to treat or eliminate biologic accumulation of a "toxic" trace substance if we do not have some understanding of its biosphere distribution, route of entry into the organism, and sensitivity of analytical methodology applied to biologic specimens. Along this same line of thought, discovery and/or development of fertilizer-enrichment trace substance combinations developed to enhance crop yield demands some knowledge on the part of agriculture and horticulture specialists of-whether cumulative biologic uptake may eventually produce toxic results.Finally, it will serve little purpose for the analytical chemist to be able to detect tissue concentrations of a particular micronutrient at 15 ppm if he is unaware that his laboratory technicians are accumulating hazardous biologic levels through cutaneous absorption which occurs at 40 ppm.

In preparing a presentation for this conference I learned two valuable lessons. First, it behooves one to check the program for the title of one's own talk before attempting to compose his presentation; and second, it 4 is wise to be punctual when submitting a title to the Program Chairman so that he isn't forced to politely select a comprehensive heading which has one scurrying through a general literature review at the same time that he is compiling his own data. When we started to prepare a presentation for this conference, it was with the assumption that we would limit the material to our own particular area of interest and endeavor. However, we are indebted to our Program Chairman, Dr. Hemp hill, for designating a title which necessitated a literature review, for if this audience presently has any doubt that certain trace substances occupy a role in occlusive vascular disease, it should resolve while listening to the investigative threads which are slowly beginning to interweave. It would not be practical, nor is it necessary, for us to discuss all of the trace substances which have been investigated as potentially having a role in the pathogenesis or development of atherosclerosis. Therefore, we have only attempted to condense those investigative results which have enkindled our research protocols, and which have probably encouraged your own research endeavors. Of the five trace elements which have been strongly implicated in vascular disease, only two (zinc and copper) have been included in our own studies. In considering a possible interrelationship between trace substances and atherosclerosis, it is important to recognize that certain diseases which do not in themselves constitute occlusive vascular conditions nonetheless may provide a "fertile environment" in which development, progression, or sequelae of atherosclerosis is potentiated. Thus we believe it pertinent to allude to copper and arterial aneurysm formation, cadmium and hypertension, and chromium in relation to diabetes.

Copper:The provocative experimental studies which Dr. Boyd O'Dell (9 ,10) has carried out on this campus are well known and stimulated our group (in a very preliminary fashion) to test this investigation on one small group of clinical patients. After observing large artery aneurysm formation with rupture and high mortality in copper-deficient chicks and pigs, Dr. O'Dell found that the deficient levels of elastin (a substance whose presence and structural integrity characterize healthy aortic tissue) present in copper-deficient arteries were related to subnormal activity of a copper-dependent elastin-producing enzyme. The specific biochemical site at which copper deficiency results in retardation of elastin synthesis by inhibiting the formation of lysine-derived crosslinkage units of elastin has since been identified by Hill. (5) Since Dr. O'Dell had called attention to the microscopic structural similarity between the aneurysmal arterial wall lesions which occurred in copper-deficient laboratory animals, and the cystic medial necrosis which is occasionally associated with aneurysm formation in humans, we performed copper assays on specimens obtained from nine patients who required resection of diseased abdominal aorta for either occlusive or aneurysmal changes. Of these nine patients, four had atherosclerosis without aneurysm, three had atherosclerosis and abdominal aortic aneurysm, and two had aneurysm without visible evidence of atherosclerotic occlusive disease. Table 1 presents the copper concentrations found in the resected arterial wall specimens from the nine patients. The average copper concentration in the four patients who had atherosclerosis but no aneurysm was 26.3 ppm, while the average concentration for the three patients with atherosclerosis and aneurysm was 21.2 ppm. However, for the two patients who had aortic aneurysm without visible evidence of atherosclerosis, the average concentration of copper dropped to 14.2 ppm. Although only a small number of patients have been studied, this suggestive evidence that copper deficiency may have a role in development of some of the aneurysms which develop in humans will hopefully stimulate additional investigations along these lines.

Manganese-Cobalt:(14) Studies have revealed that manganese possesses choline-like lipotropic properties, contributes to prevention of experimental atherosclerosis in rabbits, and may have a favorable effect on lipid metabolism in certain patients. Georgel and Curran observed a depression in cholesterol synthesis when cobalt was added to rat liver homogenate. Tennet et al. observed reduction in serum cholesterol when cobalt was administered with the diet, but increased when the cobalt was injected parenterally.

Vanadium:(1,2) This trace metal has been shown to inhibit cholesterol biosynthesis both in vitro and in vivo. Curran and Costello demonstrated that in rabbits "rendered" atherosclerotic with high cholesterol diets, supplementation of vanadium was associated with mobilization of cholesterol from aortic walls. Although the precise role of vanadium in cholesterol synthesis has met with experimental roadblocks and contradictions, it appears that this element can assume a "regulatory" role in experimental cholesterol synthesis, and that for some reason this regulatory role is apparently age-dependent as demonstrated by the observation that vanadium decreases cholesterol synthesis in young rats but actually has the opposite effect in older, heavier animals.

Two diseases which are well recognized "accelerators" of the development and/or progression of atherosclerosis are essential hypertension and diabetes mellitus. For both of these clinical diseases, specific trace substance investigation has transcended from the laboratory animal to the clinical patient. One cannot help but delight in the enthusiasm with which Dr. Walter Mertz describes his work with chromium. (3,4,5,6,7) In similar fashion, a sense of excitement is aroused when one listens to Dr. Henry Schroeder unfold the newly discovered relationship between hypertension and cadmium. (11, 12, 13) Realizing that environmental uptake of cadmium "promotes human hypertension de novo and enhances that arising from organic renal ischemia, (13) and that the impaired glucose tolerance of certain patients with diabetes "showed statistically significant improvement during the oral supplementation with chromium," (6) one cannot help but believe that at least an indirect relationship exists between the development and progression of atherosclerosis in certain patients and these two trace substances.

It would be foolhardy for any individual whose presentation follows one on diabetes and precedes another's on hypertension to say much more then very little about the relationship between certain trace substances and these two diseases. By this same token, it is with some humility that we introduce a description of our own efforts, which thus far have been primarily concerned with studies of biologic and pharmacologic zinc in patients with severely symptomatic inoperable vascular disease.

EXPERIMENTAL MATERIALS AND METHODS

Approximately two years ago we initiated a triple-phase study designed to answer three questions. First, is biologic zinc deficiency a factor in the pathogenesis of atherosclerosis? Second, can the clinical improvement which certain atherosclerotic patients experience when medicated with zinc be attributed solely to supplementation with this micronutrient, rather than to other factors such as a subjectively-positive, objectively-negative placebo effect? Third, if documentable, statistically significant, objective improvement accrues exclusively because of zinc administration, is the improvement in clinical status related to replenishment of subnormal biologic stores of this element or, instead, to a heretofore undescribed therapeutic action of zinc?

As a preliminary step to instituting a rigidly controlled Clinical Research Unit program of zinc supplementation to a group of patients with severely symptomatic, inoperable atherosclerosis, we assayed whole blood, serum, erythrocytes, hair, and arterial wall from more than 100 patients who had clinically demonstrable atherosclerosis, and from an equivalent number of patients in whom no evidence of this disease could be demonstrated. The results of this survey-type effort are summarized in Table 2. We failed to be impressed by any significant difference in hair zinc concentration between the two groups and stopped assaying hair after data were available on about 20 patients in each group since results were variable, as they had also been in two other studies which we were conducting on burns and wound healing. While it is conceivable that study of additional patients may have yielded a "positive" difference, we have eliminated hair assays serum in preference of serum determinations which are not "exposed" to the same potential sources of contamination, and which in actuality constitute a more uniform reflection of dynamic in-vivo availability. It is evident in Table 2 that there was a difference in zinc concentration between healthy aortas and diseased aortas. However, there are two reasons why we are presently uncertain of the significance of this observation. In the first place, our specimens of normal aortic tissue were obtained following traumatic death, and it turned out that the average age of these specimens was 23 years younger than the average age for the atherosclerotic group of patients. Secondly, most of the atherosclerotic arterial specimens which were assayed contained varying degrees of calcific plaque formation, and it became evident that zinc levels in the less diseased portions of some arteries approached the low-normal zinc concentrations which we encountered in aortic tissue from non-atherosclerotic patients. Nonetheless the impetus to proceed with a definitive, controlled Clinical Research Unit study arose out of observations made on arterial wall and serum zinc concentrations in this early phase of our work. There was little doubt that as a group, atherosclerotic patients exhibited lower serum zinc concentrations than did their non-atherosclerotic counterparts.

The remainder of the material which we will discuss today comprises one portion of a broad-scale, long-term investigation which is currently being conducted at the University of Missouri Medical Center. The eventual overall aim of the investigation is to correlate alterations in biologic micronutrient stores with aberrations of blood viscosity, serum lipid fractions, and coagulation processes in patients who have early onset atherosclerotic occlusive disease. A certain number of these patients who have rapidly progressive, symptomatic, inoperable occlusive arterial disease are being medicated with zinc sulfate, and we are attempting to explain why a significant percentage of these patients experience lessening of their symptoms when they are medicated. Table 3 outlines the various parameters which are being ascertained and followed on all patients who are studied. All data are being accumulated and stored for eventual correlation-type computer analysis as disease develops, progresses, and initiates morbidity and mortality during coming years.

Physicians who treat patients with atherosclerosis, and patients who have this disease, realize that in many instances symptoms resulting from atherosclerotic blockage of blood flow to organs and limbs can frequently be controlled and even lessened by such factors as weight loss, selectivity of diet, graded exercise programs, and cessation of smoking. It therefore becomes of particular importance when evaluating the supposed role of any biologic factor in atherosclerosis, or the efficacy of any therapeutic agent administered in the treatment of this disease, to control rigidly (insofar as this is possible) any factors which may simultaneously be influential in altering symptoms and clinical findings. Of equal importance is that the investigator supplement subjective evaluation with sensitive, objective "recorders" which can quantitatively confirm or refute a patient's subjective impression of clinical improvement.

Table 4 outlines the objective studies that are performed on all patients during follow-up visits. In order to minimize bias, all evaluations, including the physical examination, are performed by personnel who are not directly involved with the study.

RESULTS

We are interested in the results obtained when zinc sulfate was administered to 14 patients with extensive, inoperable, symptomatic atherosclerosis, and two patients who had disabling vasospastic disease. All patients gave written consent. to receive an investigational drug and volunteered to return to the Clinical Research Unit at bimonthly intervals in order to assess the efficacy of their treatment. [The investigations described have been approved by the committee of associates of the investigators in accordance with this institution's (University of Missouri - Columbia Medical Center) assurance on clinical research. Patients are studied initially and re-evaluated during follow-up in the General Clinical Research Unit.] Length of treatment has ranged from three to eleven months. In order to be as rigidly objective as possible in evaluating the zinc therapy, we have eliminated from our evaluation all patients who altered their smoking habits, lost more than five per cent of pre-study body weight during the period of medication, and who for one reason or another started progressive exercise tolerance programs on their own. While a particular effort was made to avoid informing patients about the relationship between these factors and alteration of the symptoms associated with their disease, it became evident that some patients who volunteered to participate in this study were individuals who were sufficiently motivated that they undertook dietary restriction and cessation of smoking on their own. Six out of the 16 patients who we have studied are therefore discounted for this reason. Four of the remaining ten patients experienced no improvement, and two of these had rapid progression of their disease to the point of amputation.

We are therefore left with six patients who experienced improvement with zinc sulfate, and who did not undergo any significant change in body weight, alteration of smoking habits, or increased exercise program while receiving medication. Table 5 summarizes serum and erythrocyte zinc concentrations and 24-hour urine zinc excretion for these six patients. It is evident that serum concentrations were subnormal (less than 95 micro-gm/ 100 ml in our laboratory) in five of these six patients. Erythrocyte concentrations were not subnormal in any of the patients. Subnormal 24-hour urinary excretion (less than 350 mg/24 hr) was encountered in only one patient. While being medicated with zinc sulfate, serum zinc levels increased in all patients to an average of 177 micro-gm/100 ml. Urinary zinc excretion increased to levels which usually ranged between 1.5 and 2.75 mg/day; however, levels as high as 4 mg/day were encountered in two 24-hour urine collections. We did not observe any significant alteration in erythrocyte zinc concentration subsequent to medication of these six patients with zinc sulfate.

Table 6 reveals the objective findings, as documented by EKG, plethysmography, and treadmill, in the six patients who experienced demonstrable improvement which we were unable to ascribe to anything besides the zinc sulfate medication. The first three patients were males with severe claudication of their lower extremities. All three of these gentlemen demonstrated marked improvement on treadmill exercise. The first gentleman actually improved to the point where he was able to walk three-quarters of a mile without onset of pain in the calves of his legs. Prior to starting zinc sulfate medication he had experienced severe pain from walking distances as short as 100 yards. The fourth patient is a lady who had almost complete blockage of the artery to her left arm. She presented to us complaining that she was unable to knit or crochet. After five months of medication, she was able to do needlework to the point that "eyestrain" or "headache" are now the limiting factors.

The last two patients represent what we believe are the most exciting observations made to date. Both patients were males who had severely symptomatic vasospastic conditions of the extremities which had resisted all modes of therapy. They had been suggested as candidates for surgical treatment, but were first referred to us for a trial with zinc sulfate. Rather than attempt to describe their response to medication with zinc sulfate, we obtained photos of their extremities which are included below.

Figure 1 illustrates the endstages of the disease which we have been attempting to treat with zinc sulfate. The fact that these photos were obtained immediately prior to amputation represents reason enough to explore completely any new lead which may prevent the ravages of atherosclerosis. Figure 2 includes pre- and post-treatment photos of one of the vasospastic conditions which we mentioned above. The name Raynaud's had been attached to this man's disease at the Mayo Clinic some eight years ago. Every medication known to be even partially effective in this condition had been tried prior to initiation of medication with zinc sulfate. The follow-up photo in Figure 2 speaks for itself. Figure 3 is our second case of Raynaud's disease, and in this instance the condition involved the patient's fingertips. It seemed improbable that any reversal of the changes evident in the first photo could occur. Nonetheless, the dramatic improvement which occurred during short-term treatment with zinc sulfate is evident in Figure 4. This gentleman has now returned to active farming, something that he had been unable to do for two years prior to being referred to this institution for surgical treatment of his disease.

CONCLUSION

The material which we have discussed this afternoon, and the results of the studies which we have presented, were not described to startle or excite any audience. The findings have been presented, rather, as an example of what a cooperative effort by clinicians, analytical chemists, environmental health specialists, and others can accomplish when an interdisciplinary approach to trace substances research is utilized. Our results to date utilizing zinc sulfate in atherosclerotic patients seem to indicate that in vascular disease this micronutrient may act as a pharmacologic agent allowing; increased blood volume (in some as yet undescribed manner) to reach areas of the body in which diseased blood vessels have restricted arterial perfusion.

The entire field of the trace elements or micronutrients is new, exciting, and enticing. If medication of human patients with a metal that is used to galvanize washbuckets can also produce results in wound healing like the ones evident in Figure 5, one can anticipate with excitement the number and magnitude of beneficial discoveries which continued investigation of the trace substances will yield. We are optimistic and confident that cooperative, coordinated interdisciplinary research in this relatively new field of "investigative fertility" will yield findings far more exciting than what we have presented today.

FIGURES

The figures have been omitted due to the inability to reproduce their color and clarity by the journal.

LITERATURE CITED

  1. Curran, G.L., and Burch, R.G. 1967. Biological and Health Effects of Vanadium. Proc. First Annual Conference on Trace Substances in Environmental Health, p. 96.
  2. Curran, G.L., and Costello, R. L. 1956. Reduction of Excess Cholesterol in the Rabbit Aorta By inhibition Of Endogenous Cholester Synthesis. J. Exptl. Med. 103:49.
  3. Glinsmann, W. H. , Feldman, F.J., and Mertz, W. 1966. Plasma Chromium During Glucose Loading. Science 152:1243.
  4. Glinsmann, W.H. , and Mertz, W, 1966. Effect of Trivalent Chromium on Glucose Tolerance. Metabolism 15:510.
  5. Hill, C.H., Kim, C.S. 1966. Studies on the Role of Copper in Elastin Formation. Internatl. Congress Nutrition, Hamburg.
  6. Mertz, W. 1967. The Role of Chromium in Glucose Metabolism. Proc First Annual Conference on Trace Substances in Environmental Health, p. 86.
  7. Mertz. W. 1967. Biological Role of Chromium. Federation Proc. 26: 186.
  8. Moses, C. 1963. Atherosclerosis, Mechanisms As A Guide To Prevention. Lea and Febiger, Philadelphia.
  9. O'Dell, B.L., Bird, D. L. , Ruggles, D.L., and Savage, J.G. 1966. Composition of Aortic Tissue From Copper-Deficient Chicks, J. Nutr. 88:9.
  10. O'Dell, B.L., Elsden, D.F., Thomas, J. , Partridge, S.M., Smith. R.H. , and Palmer, R. 1966. Inhibition of the Biosynthesis of the Crosslinks in Elastin by a Lathyrogen. Nature 209:401.
  11. Schroeder, H.A. 1964. Cadmium Hypertension in Rats. Am. J. Physiol. 207:62.
  12. Schroeder, H.A. 1965. Cadmium as a Factor in Hypertension. J. Chronic Dis. 18:647.
  13. Schroeder, H.A. 1967. Some Prospects for Research on Biologically Active Trace Elements. Proc. First Annual Conference on TraceSubstances in Environmental Health, p. 20.
  14. Volkov, N.F. 1963. Cobalt, Manganese and Zinc Content in the Blood of Atherosclerotic Patients. Federation Proc. Transac.Supplement 22:897.


George's Response to the Second Office Action

Sir:

This paper is filed in response to the Advisory Action dated 02/01/89. It is respectfully requested that this application be abandoned as relevant prior art precludes patentability.





Does Zinc Prevent and Cure Angina Pectoris?

From Dr. Prasad's comments, research (finding decreased mortality with extra zinc), Bernhard's work, the Polish report, Henzel's book article and our direct observations of the effects of more than 200 milligrams of zinc per day zinc in terminating angina pectoris, zinc seems to me to be important in preventing and perhaps curing arteriosclerosis and angina pectoris. Zinc in the treatment and prevention of arteriosclerosis and angina pectoris merits much more research. We do know that in aging, people either reduce their consumption of zinc, or loose their ability to absorb zinc from their food (or both), perhaps contributing to, or causing, arteriosclerosis and, therefore, angina pectoris and premature death. However, direct evidence of zinc treatment to benefit angina pectoris and arteriosclerosis is anecdotal, and much more evidence is needed. Clearly, zinc deficiency is found in elderly hospitalized patients, and higher proportions of respiratory infections, cardiac failure, and depression were observed among zinc deficient patients as compared with the group of patients with normal zinc status. One thing that I have noticed from the literature. There are a number of articles reporting that up to 100 milligrams of zinc had no effect on cholesterol. Remember that each of the reports that used zinc beneficially to terminate angina pectoris or prevent angina pectoris used much larger doses. For example our doses were over 200 milligrams a day and dosages of 300 mg per day were clearly associate with INCREASED serum concentrations of low density cholesterol.

I now interpret the observation of higher serum concentrations of low density cholesterol from 300 mg of zinc per day to mean that zinc removed low density cholesterol from cardiovascular surfaces such as arteries and veins, thus decreasing arteriosclerosis and increasing circulation thus terminating angina pectoris and restoring youthful cardiac function.

zinc sourcesThese are the some of the best food sources of zinc, and you will probably realize that you rarely eat them. Another excellent source of zinc is East coast oysters. If you, the reader with concerns about angina pectoris (and arteriosclerosis), decide to take large amounts of zinc, there are some side effects that must be prevented. First, over 300 mg of zinc per day was strongly immunosuppressive after 30 day in healthy adults in at least one study. The immunosuppression reversed upon cessation of zinc treatment. Consequently, large amounts of zinc should never be taken for long without medical supervision to test for immune system problems. Second, if blood levels of copper are already low, 300 mg of zinc per day could easily lower copper serum levels with perhaps lethal results. You do not want "artery aneurysm formation with rupture and high mortality" as found in copper-deficient chicks and pigs by O'Dell and other scientists!

Copper deficiency has clearly been linked to aneurysms and even the very common rectal hemorrhoids. If you have had aneurysms or rectal hemorrhoids in the past or now, you are very likely to be copper deficient, and supplementation of large amounts of zinc without also supplementing copper first for several weeks might be very harmful or kill you. Study some of these Scholar.Google search articles for "copper" and "aneurysms", and this google search for "copper" and "hemorrhoids" as described by my friend Charles Weber.

On the other hand copper is being depleted to treat lymphomas and other cancers. The concept of treating cancer by restricting the blood supply to malignant tumors has recently gathered intense interest in the medical community and the press. In January 2000, University of Michigan researchers published a preliminary report of a human trial showing that reducing body copper levels can be a minimally toxic means to inhibit the growth of small blood vessels feeding solid tumors, thus being a means of slowing or stopping the development of some cancers. See this article. Consequently, one can see that there is much to be learned about manipulating metals to treat diseases, and no one knows all of the answers yet.

People with white hair have lower copper content than those with colored hair, consequently caution is strongly advised for white haired people. If you decide to supplement with copper, I suggest that the best plan would be to supplement with 4 to 6 milligrams of copper for 14 days prior to starting high dose zinc, and to limit high dose zinc to no more than 14 days of treatment.

copper sourcesCopper solution chemistry is a bit different than other metals in that ligands (the thing that the copper is attached to) that are common in dietary supplements often bind copper so tightly that copper is not biologically available and will not be helpful.

These copper compounds are biologically available from solution chemistry data: copper malate, copper sulfate, copper lactate, copper chloride, copper succinate, and copper tartrate. These copper compounds will be dissociated by stomach acid into ionic copper and the ligand.

Common dietary supplement forms that are not biologically available from solution chemistry data include: copper oxide, copper gluconate, copper aspartate, copper citrate, copper cysteinate, copper EDTA, copper glutamate, copper glycinate and copper histidinate. These copper compounds will NOT be dissociated by stomach acid into ionic copper and the ligand.

Perhaps the best idea would be to eat large amounts of foods very high in biologically available copper for two weeks prior to starting high dose zinc. Would you like oysters and liver, twice or three times a day?

According to Ripa and Ripa, the relationship between zinc and atherosclerosis is shown. Administration of strong doses of the mineral can turn out atherogenic through three mechanisms: (1). Through the alterations of the lipidic arrangement: decrease of HDL, increase of total cholesterol and LDL cholesterol (action promoted by the induced hypocupremia). (2). Through the alterations of the vasal wall, in consequence of the biochemical modifications of the basic substance (again, through secondary hypocupremia) [this is strong reason to give copper]. (3). Through the increased platelet aggregation which seems to be produced by strong doses of zinc. In addition to these harmful actions, the antioxidative action, typical of zinc, must be stressed, which prevents oxidation of LDL and consequently stops the main mechanism of atherogenesis. Besides, the mineral restricts and nullifies the loss of metallothionein in zinc, produced by free radicals and subsequent functional alterations. Moreover, the calcium antagonist action of zinc (like that of magnesium) must be considered: it blocks calcium and its several favorable actions on atherogenesis.

In consideration of these last aspects, the rule of zinc, in suitable doses, could be considered as basic in the context of a strategy of prophylaxis and therapy of the atherosclerosis process. BASIC? BASIC? BASIC? Yet, no physician that I know, except Dr. William W. Halcomb, DO, of Mesa Arizona, uses zinc to treat angina pectoris.

Lacking the funding for clinical trials, I know of no other way to document these effects than to post them on this page and to submit for publication this recently accepted medical journal article. Upon request, I will post your results on this page, either good, bad or indifferent and we will see what impact publication of my article has. My guess? Probably none, because there is too much money invested in major medical programs to "treat" this disease and there is no financial incentive to find a cure, in fact there is a negative incentive to find a cure for angina pectoris and arteriosclerosis.

Regardless, do not use "zinc oxide", rather use highly biologically available "zinc gluconate" or "zinc sulfate", because zinc oxide is not very biologically available. In other words, zinc oxide will not work. Be aware that zinc, magnesium, taurine and copper deficiencies are relatively common in the West, particularly in the elderly who have reduced their caloric intake and their meat intake due to fears of "cholesterol". Unfortunately, this reduction also reduces intake of zinc, magnesium, taurine and other vital nutrients since meat is the main source of these nutrients in the Western diet. Clearly, junk food, so popular in the West, is low in zinc, taurine, magnesium and other critical nutrients, a certain receipt for cardiac disaster. The extremely important movie "Super Size Me" is vital to your understanding of what is actually happening to humans eating refined "junk food" diets. Yet, our government allows the sale of nutritionally depleted foods called "refined grains". I believe that this single 1900s era invention is the cause of most chronic health issues of our time. Good sources of many trace minerals necessary for cardiac and muscle function are cashew nuts as shown here, and all whole grains, nuts and seeds.

Understand that zinc for angina pectoris (and arteriosclerosis) remains experimental and the results if obtained by others (such as yourself) are of immense importance. Upon request, I will post your results on this page, either good bad or indifferent. I suspect that 1.25 milligram of zinc per pound of body weight would be equivalent to the dosages used in Dr. Halcomb's patients and should provide equivalent beneficial results. I also think that dosages should be limited to 60 mg per meal with some more - if needed - at bedtime, and that 4 mg of copper (as suggested in this link) should be supplemented daily also to prevent potentially lethal aneurysms. However, please remember that copper was not added in the studies that were effective in raising low density cholesterol or in eliminating angina pectoris symptoms. Additive copper may defeat the beneficial function of large doses of zinc in treating angina pectoris, but I do not know. A very cautious approach seems advised to me. One final comment. Doses of zinc gluconate in excess of 30 to 40 mg zinc often produce nausea. On the other hand, some people do not become nauseated at these doses or even much higher doses. I do not know what these symptoms means other than the obvious.

I very strongly suspect your physician will advise you against experimentation with zinc for arteriosclerosis and angina pectoris, due to their general concern about patients "experimenting" with "unproven" treatments. They are absolutely correct, and I do not "recommend" that you take large amounts of zinc, because zinc for treatment of cardiac issues needs to be studied in controlled, clinical trials under the most careful of circumstances. Unfortunately, Big Pharma has control of research funds for nearly all drugs, and since zinc is very cheap and is not patentable, zinc will likely never find a commercial use in the treatment of angina pectoris. What is a person to do? Beats me, it's your life and your wallet!


Further study and research is vitally needed by physicians and cardiovascular research scientists, of which I am neither.




Our first report is here! A man with horrible Raynaud's disease on the tops of his hands, across his face and nose used 60 mg of zinc (from zinc gluconate) 3 times a day to eliminate this ugly looking, gray skin, poor circulation problem. It disappeared in 4 days. His type of Raynaud's phenomenon was associated with various diseases that affect arteries, such as atherosclerosis - the gradual buildup of plaques in blood vessels that feed the heart (coronary arteries). There are many treatments for Raynaud's disease, but none worked over the years nearly as well as zinc. And, zinc was much cheaper and probably safer since it seems to have corrected the problem rather than mask it.


High Dose Zinc To Terminate Angina Pectoris, A Review and Hypothesis for Action by ICAM Inhibition

A Google search for "angina pectoris" and "zinc"

A Scholar.Google search for "angina pectoris" and "zinc".

A PubMed search for "angina pectoris" and "zinc".

A PubMed search for "arteriosclerosis" and "zinc".

A United States Patent Office search for "angina pectoris" and "zinc".