MYCOTOXIN-INDUCED ATHEROSCLEROSIS

A number of studies have indicated that there are unknown factors present in hyperlipidemia, attached to the low density lipoproteins, that are responsible for the smooth muscle cell proliferation/production of new connective tissue which is characteristic of atherosclerosis (Wissler 1979).

Mycotoxins, which characteristically bind to lipoproteins, are documented not only to cause these changes but to cause atherosclerosis in humans and animals.

Cyclosporin-Induced Atherosclerosis In Humans

 

Betina (1989) points out what is well known to mycologists, cyclosporin is actually a mycotoxin, a fungal-derived secondary metabolite, which is toxic to the immune system. Its extensive use in preventing organ rejection in transplantation has given us an unexpected somber side benefit of discovering that it causes accelerated atherosclerosis in almost all long-term survival organ transplantation patients.

Fyfe (1992) has compiled the published findings to date of transplant atherosclerosis. Based upon analysis of clinical risk factors, pathological features of endothelium, macrophages, lipoproteins and vascular smooth muscle cells, and the known pathophysiological mechanisms, Fyfe concluded that transplant atherosclerosis appears to result from a "response to injury" of the endothelium, similar to naturally occurring atherosclerosis.

Ergot-Induced Atherosclerosis-Type Clinical Manifestations

 

In humans, ergots induce spasm, stenosis and/or thrombosis of the coronary, carotid, aortic, renal, and peripheral arteries. Ergotinduced entities include angina, myocardial infarction, arrhythmia, carotid artery occlusion, stroke, intermittent claudication & gangrene.

Fumonisin-Induced Hyperlipidemia and Atherosclerosis in Primates

 

Fincham et al (1992) fed primates a low fat diet containing the mycotoxin fumonisin and induced hyperlipidemia and related blood lipid findings characteristic of those found in human atherosclerosis.

In a personal communication with Fincham, he has indicated that autopsy of one of the fumonisin-dosed primates which died during the experiment demonstrated severe generalized atherosclerosis identical in appearance to human atherosclerosis.

 

Haschek et al (1992) in their characterization of fumonisin toxicity in orally and intravenously dosed swine, found that blood levels of cholesterol were increased.

 

Fumonisin is a recently discovered Fusarium mycotoxin which is present in high concentrations in all corn kernels thus far examined. Corn is the principle grain used in the Western diet and is also a major part of feed for animals fed for the marketplace. Corn is generally not found in native diets except for that of Indians of the Americas. Data relative to the incidence of atherosclerosis in Indians is limited and confusing in that most now eat a Western-type diet rather than traditional Indian food.

 

Sporidesmin-Induced Hyperlipidemia/Vascular Disease.

Lipid deposition-type vascular lesions associated with very high levels of LDL occurs in New Zealand sheep exposed naturally or experimentally to the mycotoxin sporidesmin produced by a fungus common in the pasture lands of that country (Taylor 1971). As in human atherosclerosis, cholestyramine provides therapeutic benefit. Zinc is also of benefit.

 

T-2 Toxin-Induced Cardiovascular Lesions and Hypertension

 

Wilson et al (1982) found that rats given T2 toxin developed hypertension associated with microscopically severe cardiovascular abnormalities. The pattern of the findings were such that it appeared that T-2 Toxin, which often does significantly contaminate foodstuffs, may represent an important etiology of hypertension and its cardiovascular lesions in both animals and man. The relationship of hypertension to atherosclerosis is well known; the fact that both share an etiologic group of agents explains the relationship.

 

T-2 Toxin-Induced Coronary Artery Disease

Yarom et al (1982) studied the nature of the T2 toxininduced pathology in the hearts of rats and reported that the lesions consisted of interstitial edema, focal cellularity and damage to single or groups of myocytes. The small intramural coronaries were constricted, swollen and sometimes disrupted. After 7 days, most of the changes subsided. In rats killed 1 or 2 months after the last of 10 daily injections of T2 toxin, cardiomyopathylike changes were seen with hypertrophy, focal fibrosis and abundant cellularity especially in the subendocardial regions of the left ventricle. These findings, although nonspecific, indicate that T2 toxin is cardiotoxic and are quite provocative since subendocardial fibrotic changes are commonly encountered in human atherosclerotic hearts.

T-2 Induces Coronary Artery Damage and Increased Mast Cells.

Yarom and Yagen (1986) reported the effect of T2 toxin on the ultrastructure of coronary microvasculature. The capillaries were most severely damaged and were often disrupted. The plasma membrane of endothelial cells seemed to be the first structure affected. A direct cytotoxicity of T2 toxin to the myocardial capillary lining cells seems to be the pathogenic mechanism of injury. The abundance of mast cells in several of the hearts examined suggests a role for their vasoactive products in the genesis of the capillary lesions.

The presence of mast cells in atherosclerotic lesions in humans has been had no previous explanation; here then is proof of a mycotoxic etiology for this unique finding. Lipids and cholesterol do not induce the recruitment of mast cells.

 

T-2 Toxin-Induced Microvasculitis and Mast Cells

 

Yarom et al (1987) in their study of cutaneous injury by topical T2 toxin found that a microvasculitis was produced with involvement of microvessels and mast cells. Damage to the microvasculature was characterized by mononuclear cell infiltration, with many degranulating mast cells.

Ultrastructurally, as is the case in atherosclerosis, the endothelial cells were the earliest sites of change. Another early effect of topical T2 toxin was an increase in number and degranulation of mast cells.

 

The fact that a micovasculitis occurs in the pathogeneisis of atherosclerosis is not generally appreciated since once the pathologists sees atherosclerotic lesions, little attention is paid to the condition of the microcirculation.

T-2 Toxin-Induced Endothelial Damage and Smooth Muscle Cell Proliferation

 

Yarom et al (1987) studied the effect of T2 toxin on rat aorta and found that T2 toxin showed endothelial cell damage, accumulation of basement membranelike material in the intima, and activation with proliferation of smooth muscle cells.

Interestingly, three or more weeks after the last injection of 0.3 mg/kg T2 toxin the endothelial cells were normal but an excess of fragmented intimal basement membranelike

material persisted and smooth muscle cells were still activated. Note the presence of the "membrane-like material in the intima for it is what Virchow also saw in human lesions.

 

These changes are characteristic of the early changes of atherosclerosis.

 

Aflatoxin-Induced Small Vessel Disease

 

Jaskiewicz et al (1988) in their preliminary studies on the toxic effects of Aspergillus-produced cyclopiazonic acid alone and in combination with aflatoxin B1 in nonhuman primates found that the mycotoxin caused significant damage to the small blood vessels.

Cyclopiazonic Acid-Induced Small Vessel Disease

 

The Aspergillus flavus mycotoxin cyclopiazonic acid (CPA), induces in nonhuman primates significant damage to the small blood vessels (Jaskiewicz et al 1988).

Citreoviridin-Induced Myocardial Ischemia.

 

Nishie et al (1988) reported that citreoviridin, a mycotoxin isolated from Penicillium citreoviride administered to animals, had dramatic cardiac ischemic effects with initial lowering followed by flattening and finally inversion of the T wave of ECG. These are the type of changes seen in humans with coronary atherosclerotic disease.

 

The interesting human application of the Nishie report is that there are clinical entities in humans of silent myocardial ischemia, myocardial infarction without coronary artery obstruction, long term angina pectoris without myocardial infarction, etc., which are etiologically entirely unexplained. The burden of proof would appear to have to shift towards proving that mycotoxins are not the cause of these functional cardiovascular problems. The nature of the ergot-induced vascular occlusive phenomena appears to backup this new understanding of the role of mycotoxins in cardiovascular disease.

THE DIETARY MUSHROOM CONNECTION TO ATHEROSCLEROSIS

 

Mushrooms (Edible) Induce Vascular Smooth Muscle Cell Proliferation, a Characterisitic Finding in Atherosclerosis

 

Toth and her co-workers (1985) reported that phydrazinobenzoic acid, a metabolite produced by the edible and commonly consumed mushroom, Agaricus bisporus, causes severe atherosclerosis-like smooth muscle cell proliferation in mice. The mice were fed the mushroom metabolite for a period of 20 weeks which is consistent with the concept that it is the long term dietary pattern in the Western diet which correlates with the incidence of atherosclerosis. In the case of humans with atherosclerosis, there is no published data relative to the effects of chronic mushroom consumption on human health. It is also important for the mushroom-consuming public to understand that the mushroom is not a vegetable but rather the fruiting body of a fungus whose major form of existance is hidden in the soil layer upon which it erupts to cast out its spores.

THE YEAST CONNECTION TO ATHEROSCLEROSIS

 

Baker's/Brewer's Yeast (Bread, Beer, Wine, Yeast Tablets)

The recent Harvard study of the dietary habits of 90.000 American nurses followed for 5 years revealed increased atherosclerosis occurred in those nurses who were heavy consumers of two items characteristic of the Western diet, cookies and bread (Lancet 1993). The bread is of course a Baker's yeast fermentation product and many cookies have yeast added either for raising the dough or flavor or both. The sugar and fruit (fructose) in cookies are well known to elevate human blood cholesterol levels and to contribute to obesity problems, a well known risk factor for atherosclerosis.

The grains used in cookies and bread not unusually contain toxicogenic fungi and mycotoxins and the moisture content of these finished food products tend to promote further growth of these fungi (stored bread and cookies get moldy).

 

Baker's Yeast Inhibits Liver Detoxicating Function

Double stranded RNAs are present in Baker's yeast, S. cerevisiae. When Masycheva et al (1988) administered these yeast-derived RNAs to mice, they observed that they had an inhibitory effect on the liver detoxicating function.

This ability of Baker's yeast to decrease the efficiency of the liver to detoxify toxins points to an enhancing effect of Saccharomyces on the toxicity of mycotoxins in general, a situation which hardly can be considered desirable in the dietary intake.

Baker's Yeast is Itself Atherogenic.

 

Zhikhar et al (1990) investigated the metabolic efficiency of baker's yeast fed to rats. Atherosclerotic-type morphologic changes were observed in the aorta and did not depend on the amount of the yeasts fed to the animals. The kidney became infiltraed with lipids and cholesterol.

 

FUNGAL/MYCOTOXIN-INDUCED CORONARY ARTERITIS

 

Candida-Induced Coronary Arteritis

 

Murata and Naoe (1984) found that they could induce coronary arteritis and thrombotic occlusive aneurysms in mice by injecting an extract of Candida albicans isolated from a typical patient with Kawasaki disease. It was interesting that five daily injections of the Candida extract produced no lesions but a second round of five injections 5 weeks later induced severe vascular lesions of the coronary arteries as well as to a lesser extent, the renal and mesenteric arteries. The pattern was similar to the distribution found in humans with Kawasaki's disease.

One can only speculate what might be the appearance of such Candida extract-induced vascular lesions in humans exposed to long term interrmittant Candida colonizations over a period of many decades. There is another possibility suggested by the experiment. Could the fungal overgrowth which occurs as a result of penicillin therapy be related to the well known fact that penicllin is the most common known cause of vasculitis.

When one pursues this lead further, one finds that there are a number of reports correlating fungi as the etiology of microvascultitis. This correlates quite well with the fact that all of the diseases postulated by the author to be of fungal/mycotoxin etiology have the finding of microvascultis as an important part of the pathology.
 
 

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