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June 13, 2005 (as accepted for publication)

High Dose Zinc to Terminate Angina Pectoris: A Review and Hypothesis for

Action by ICAM Inhibition

by A. Eby MS and W. Halcomb DO

Abstract

We reviewed the literature related to the effects of high dose zinc in

arteriosclerosis-induced angina pectoris. Lipid peroxidation and LDL

oxidation are believed to be critical for arteriosclerosis, and

consequently angina pectoris. Administration of biologically available

zinc was a beneficial treatment in a significant percentage of patients

with severely symptomatic, inoperable atherosclerotic disease. In these

patients, there was no difference in zinc concentration between patients

with and without atherosclerosis in whole blood, erythocytes or hair,

but there was a major difference between normal aorta and diseased

aortas (40.6 ppm zinc in normal aorta vs. 23.2 ppm zinc in

atherosclerotic aorta, 40.6 ppm zinc in normal aorta vs. 19.4 ppm zinc

in atherosclerotic aneurysm aorta), and no difference between normal and

aneurysm aorta, although copper was low in aneurysm aorta. Medication

with high dose zinc sulfate to raise zinc serum concentrations from 95

micrograms per deciliter to 177 micrograms per deciliter resulted in

objective improvement in 12 of 16 of these patients, including a patient

that also had Raynard's disease. Long term environmental exposure to

zinc resulted in a 40% reduction in the incidence of angina of effort

compared to people not exposed to environmental zinc (P<0.01) and a 40%

reduction in the incidence of probable ischemia in exercise (P<0.001).

Lead had no effect while cadmium exposure resulted in more than tripling

the incidence of angina of effort (P<0.001). The antioxidative action of

zinc prevents oxidation of LDL cholesterol and consequently stops the

main mechanism of atherogenesis. Zinc blocks calcium and its several

actions on atherogenesis. Increased amounts of cytotoxic cytokines such

as TNF-alpha, IL-beta and IL-8, often produced in the elderly, are

blocked by high dose zinc. We hypothesize that higher serum

concentrations of LDL cholesterol resulting from administration of 300

mg of zinc per day is caused by a release of low density cholesterol

from cardiovascular tissues, beneficially flushing it into the serum

where it is readily observed, thus decreasing arteriosclerosis,

increasing circulation, terminating angina pectoris and restoring more

youthful cardiac function. Although prevention of cholesterol-induced

arteriosclerosis by zinc is predicted from findings related to oxidative

stress and lipid peroxidation, removal of LDL might be attributable to

action of ionic zinc on ICAM inhibition. In stark contrast to current

practice, high dose zinc should be considered as basic in the strategy

of prophylaxis and therapy of the atherosclerosis process to terminate

angina pectoris and restore youthful cardiac function.

Keywords: Zinc, taurine, arteriosclerosis, angina pectoris,

cardiovascular disease, cholesterol, congestive heart failure, cardiac

rhythm, extrasystoles, Raynaud's Disease.

Introduction

Angina Pectoris (coronary chest pain) occurs when the myocardium doesn't

get as much oxygen as it needs usually when one or more of the heart's

arteries is narrowed or blocked by low density lipoprotein (LDL)

cholesterol-induced arteriosclerosis (hardening of the arteries). Lipid

peroxidation and LDL oxidation are believed to be critical for

arteriosclerosis. Increased amounts of cytotoxic cytokines such as

TNF-alpha , IL-beta and IL-8 are often produced in the elderly. 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 producing angina pectoris. Furthermore the

monocytes-macrophages become activated and produce free radicals and

reactive oxygen species (ROS) which lead to DNA oxidation and lipid

peroxidation. Zinc has beneficial molecular effects in regulating these

events.

(<http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve & db=pubmed & dopt=Abst\

ract & list_uids=12812920 & query_hl=1>)

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.

(<http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve & db=pubmed & dopt=Abst\

ract & list_uids=15374021 & query_hl=3>)

Today, the elderly tend to avoid meat and other high zinc content foods

due to fears of cholesterol.(</html/angina-aging.pdf>) Rather, they

increase consumption of refined wheat products. Wheat was a main source

of zinc in the historical diet, but zinc, magnesium and other critical

nutrients have been mostly depleted by the refining process.

(<http://coldcure.com/html/grain-drain.pdf>) Therefore, zinc deficiency

may play a major, perhaps the dominant role, in causing adverse cardiac

events.

High dose zinc (50 to 300 mg / day) significantly decreases serum

high-density lipoprotein concentration and increases low-density

lipoprotein.

(<http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve & db=pubmed & dopt=Abst\

ract & list_uids=6471270 & query_hl=48>,

<http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve & db=pubmed & dopt=Abstr\

act & list_uids=15727190 & query_hl=26>,

<http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve & db=pubmed & dopt=Abstr\

act & list_uids=12105816 & query_hl=7>)

while lower doses or biologically poorly available zinc compounds (zinc

oxide) do not.

(<http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve & db=pubmed & dopt=Abst\

ract & list_uids=12835492 & query_hl=9>,

<http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve & db=pubmed & dopt=Abstr\

act & list_uids=11925463 & query_hl=11>)

We hypothesize that transient increases in low density serum cholesterol

result from release of tissue bound low density lipoprotein by action of

ionic zinc. We found that zinc could benefit angina pectoris during a

zinc gluconate lozenge for common cold clinical trial.

Methods and Procedures

In 1981 while conducting a clinical trial using 23 mg of zinc from zinc

gluconate each two hours to treat common colds,(10

<http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve & db=pubmed & dopt=Abstr\

act & list_uids=6367635 & query_hl=13>)

a 65 year old man with severe, disabling angina pectoris evaded our

selection criteria and received zinc. His cold did not respond to zinc

and he consumed 300 mg of zinc on the first day and 276 mg of zinc on

the following days of the 7 day trial. No copper supplements were given

to alter the effects of high dose zinc.

Results

The patient returned a few days after the trial was over and wanted to

know whether he had received zinc or placebo. After 5 days on zinc, his

angina pectoris pain, very poorly controlled with any medication

including nitroglycerin, vanished for the first time in 15 years.

Indeed, his blood pressure was normal and he showed no outward evidence

of coronary damage. After his zinc therapy, he went snow skiing in the

mountains of Colorado for the first time in over 15 years and had no

cardiac discomfort. He obtained a new job and felt fine working hard all

day.

This effect was reproduced in a heavy 150 kg man with severe angina

pectoris. 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 him to discontinue

zinc because 300 mg of zinc per day would significantly decrease serum

high-density lipoprotein concentration and would increase low-density

lipoprotein. The patient died of congestive heart failure within a month

of cessation of zinc treatment.

The observation of zinc benefit to angina pectoris was incorporated into

clinical practice by one of us (WWH) but records of these results are no

longer available. Most persons that made dietary modifications (reduced

refined carbohydrate and fat intake), stopped smoking and supplemented

with 180 mg of zinc per day in split doses responded to treatment.

Discussion

There are several previous reports that show zinc was used to both

prevent angina pectoris and effectively treat it in humans, some animal

research and much biochemical and molecular biology research showing

means to prevent atherosclerosis. However, we found no insight as to how

zinc might treat it.

According to a report by Henzel et al. (11 </html/angina-henzel.html>)

in 1968, administration of zinc sulfate was a beneficial treatment in a

significant percentage of patients with severely symptomatic, inoperable

atherosclerotic disease. They found that there was no difference in zinc

concentration between patients with and without atherosclerosis in whole

blood, erythocytes or hair, but there was a major difference between

normal aorta and diseased aortas (40.6 ppm zinc in normal aorta vs. 23.2

ppm zinc in atherosclerotic aorta, 40.6 ppm zinc in normal aorta vs.

19.4 ppm zinc in atherosclerotic aneurysm aorta and no difference

between normal and aneurysm aorta), although copper was low in aneurysm

aorta. They medicated with zinc sulfate to raise zinc serum

concentrations from 95 micrograms per deciliter to 177 micrograms per

deciliter. Objective patient evaluation included treadmill walking,

electrocardiography, plethysmography, and positional photography of

ischemic limbs. Objective improvement was observed in 12 of their 16

patients, however 6 of the 12 improved patients were discounted since

factors such as weight loss and cessation of smoking may have

contributed to improvement. One of these patients also had Raynard's

disease, which promptly vanished. They suggested that zinc acts as a

therapeutic pharmaceutical (rather than as a nutrient) in those patients

with occlusive vascular disease who experience improvement when

medicated with zinc. Underwood (12 </html/angina1.html>) in 1971 also

reported beneficial effects of high dose zinc in angina pectoris.

Giec et al. (13

<http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve & db=pubmed & dopt=Abstr\

act & list_uids=7422925 & query_hl=18>)

(full text) </html/angina-giec.html> in 1980 reported on 1,000 physical

workers (900 males, 100 females) aged 21-60 years with the professional

exposure to zinc, lead or cadmium. They showed that environmental

exposure to zinc in mines in Poland resulted in a 40% reduction in the

incidence of angina of effort compared to people not exposed to

environmental zinc (P<0.01) and a 40% reduction in the incidence of

probable ischemia in exercise (P<0.001). Lead had no effect while

cadmium exposure resulted in more than tripling the incidence of angina

of effort (P<0.001). Ripa and Ripa (14

<http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve & db=pubmed & dopt=Abstr\

act & list_uids=7854558 & query_hl=20>)

in 1994 argued that the antioxidative action of zinc prevents oxidation

of LDL and consequently stops the main mechanism of atherogenesis. Zinc

blocks calcium and its several favorable actions on atherogenesis. In

stark contrast to current practice, they pointed out that zinc in

suitable doses, should be considered as basic in the strategy of

prophylaxis and therapy of the atherosclerosis process.

Hennig et al. (15

<http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve & db=pubmed & dopt=Abstr\

act & list_uids=8936496 & query_hl=23>)

in 1996 pointed out that 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. 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. In 2000, Hennig

et al. (16

<http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve & db=pubmed & dopt=Abstr\

act & list_uids=10501286 & query_hl=3>)

suggested that zinc requirements of the vascular endothelium are

increased during inflammatory conditions such as atherosclerosis.

Clemons et al. (17

<http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve & db=pubmed & dopt=Abstr\

act & list_uids=15136320 & query_hl=25>)

showed that age-related macular degeneration patients randomly assigned

to receive zinc (80 mg zinc from zinc oxide) had lower mortality than

those not taking zinc over a 6.5 year period (RR, 0.73; 95% CI,

0.61-0.89). Dietary supplements of copper or zinc both inhibited aortic

atherogenesis in the cholesterol-fed rabbits. (18

<http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve & db=pubmed & dopt=Abstr\

act & list_uids=15379959 & query_hl=27>,

19

<http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve & db=pubmed & dopt=Abstr\

act & list_uids=11906114 & query_hl=29>)

Variant angina (Princemetal's angina) (20

<http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve & db=pubmed & dopt=Abstr\

act & list_uids=4726977 & query_hl=31>,

21

<http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve & db=pubmed & dopt=Abstr\

act & list_uids=3724238 & query_hl=33>,

22

<http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve & db=pubmed & dopt=Abstr\

act & list_uids=3441141 & query_hl=35>)

has been shown to benefit from prompt magnesium sulfate administration ,

and IV magnesium sulfate terminated variant angina in one of us (GAE),

who after 8 years of previous high dose zinc treatment showed no

coronary artery blockage.

Although the mechanisms by which zinc can prevent arteriosclerosis are

defined, we are only left with the hypothesis that higher serum

concentrations of LDL cholesterol resulting from administration of 300

mg of zinc per day results from release of LDL cholesterol from

cardiovascular tissues. Zinc appears to flush LDL cholesterol, perhaps

by action of ionic zinc on ICAM-1, into the serum where it is readily

observed, thus decreasing arteriosclerosis, increasing circulation,

terminating angina pectoris and restoring more youthful cardiac

function. We suggest that the increase in low density lipoprotein shown

by Chandra and others with administration of 300 mg of zinc per day is

extremely beneficial rather than harmful as suggested by Chandra.

Caution with high dose zinc treatment is advised because 300 mg of zinc

per day for 30 days suppresses primary immunity in young healthy

adults,(<http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve & db=pubmed & do\

pt=Abstract & list_uids=6471270 & query_hl=48>)

while 200 mg per day enhances primary immunity in old people. (23

<http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve & db=pubmed & dopt=Abstr\

act & list_uids=6972165 & query_hl=47>).

Second, high dose zinc will lower copper serum concentrations,(24)

<http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve & db=pubmed & dopt=Abstr\

act & list_uids=15762288 & query_hl=29>

which might increase incidence of aneurysms. Copper (4 to 6 mg/day)

should be given to help prevent aneurysms. Copper (from copper chloride)

treatment, starting 14 days before zinc treatment, should be given to

help prevent aneurysms. To further minimize these potential side

effects, treatment with high dose zinc to terminate angina pectoris

should not be given for longer than 14 days.

High dose zinc treatment of atherosclerosis-induced angina pectoris

should be studied immediately and extensively in nationally supported

clinical trials of daily 300 mg zinc (from a biologically available

source such as zinc gluconate, chloride, acetate, glycinate, histadinate

or sulfate). Taurine (8 to 16 grams/day in split doses) to help treat

angina pectoris, (25)

<http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve & db=pubmed & dopt=Abstr\

act & list_uids=4416046 & query_hl=3>

(full text) </html/taurine.html> regulate cardiac rhythm, (25)

<http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve & db=pubmed & dopt=Abstr\

act & list_uids=4416046 & query_hl=3>

eliminate extrasystoles (25)

<http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve & db=pubmed & dopt=Abstr\

act & list_uids=4416046 & query_hl=3>

and prevent congestive heart failure (26)

<http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve & db=pubmed & dopt=Abstr\

act & list_uids=3888464 & query_hl=1>.

We suggest that widespread consumption of refined grains depleted of

their minerals is a principal underlying cause of cardiovascular

disease. We suggest that the practice of refining grain should be

abolished world-wide. To eliminate angina pectoris, patients should eat

whole grains, seeds and nuts, stop eating refined carbohydrates, reduce

animal fat intake, stop smoking and receive high dose zinc treatment for

fourteen days. Ironically, in the United States, marketing nutrients to

treat, cure, diagnose and prevent diseases is essentially illegal under

the overly broad Dietary Supplement Health Education Act of 1994.

The English translation of the Polish Giec article and the difficult to

find Henzel article, and links to the other articles are on the Internet

at <http://coldcure.com/html/angina.html>.

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