Anti Heart Disease and Anti Cancer Nutrients

Heart disease and cancer are the two main causes of death in America and Europe. These diseases kill about 2/3 of all adults. The "fatty/cholesterol plaque" that can occlude arteries is called atheroma. The gradual development of atheroma in heart arteries is referred to as coronary atherogenesis; and a chief culprit in the process of atherogenesis is cholesterol/saturated fat. High levels of LDL cholesterol and/or low HDL cholesterol are generally believed to be the chief culprits in atherogenesis.

Thrombi vs. Atheroma
However, a mass of evidence dating back 40 years clearly points to another cause of heart attacks that may be just as important as atheroma/atherogenesis as the cause of our 20th century epidemic of heart attacks. In fact, Keeley and Higginson in 1957 suggested that thrombi [abnormal blood clots] rather than atheroma may be the major cause of myocardial infarctions (MIs). Thomas and his colleagues, like Keeley and Higginson, said that it was high time more concern be shown to the danger of thrombi. In 1980, Sinclair stated that thrombosis—not atheroma—is the major causal factor in MI.1

Platelet Aggregation
Kinsella, et al, also highlight the importance of platelet aggregation/thrombogenesis in MI deaths: "...the antioxidative agents in plant foods and wine may also be very effective in reducing thrombosis and blockage of narrowed arteries, which is a fatal event in more than 90% of deaths from CHD [coronary heart disease]... Thus, the partially occluded [by atheroma] artery is easily blocked by thrombi formed mostly from aggregated blood cells that rapidly aggregate and clump in response to specific stimuli."13

In a classic 1992 article about the "French paradox for heart disease," Renaud and de Lorgeril present evidence that dietary fat and blood cholesterol may not be primary MI villains, at least among the French. They note that the annual mortality rate per 100,000 population from coronary heart disease (CHD) is 78 in Toulouse, France, and 105 in Lille, France (for men), compared to 182 in Stanford, USA, 348 in Belfast, UK, and 380 in Glasgow, UK. Yet the saturated fat intake is about the same for all these groups—15% of total calories. The mean serum cholesterol is notably lower for men in Stanford (209 mg) than in France (230 in Toulouse, 252 in Lille), while Belfast (232) and Glasgow (244) levels are similar to France. Nevertheless, all three have higher MI mortality rates than France.

Renaud and de Lorgeril report that "...in the 17 countries that report wine consumption, wine is the only foodstuff in addition to dairy fat that correlates significantly with mortality...wine has a...protective effect."2 Renaud and de Lorgeril then present evidence that it is not through inhibitory effects on atherosclerotic lesions (atheroma) that wine provides MI protection, but rather through a decrease in the tendency of platelets to aggregate and ‘plug up' heart arteries. They note "...we have compared farmers from Var, Southern France (low in CHD mortality), with farmers from south-west Scotland for [platelet aggregation tendencies]. Platelet aggregation was strikingly lower in Var. Consumption of alcohol was greatest in Var (45g per day vs 20g per day in Scotland), mostly in the form of wine."2

Lest anyone derive from this the moral that alcohol, per se, is beneficial for heart health, several points should be noted. As Goldberg, et al, state, "...ethanol or a metabolite impairs the platelet function as a consequence of...platelet injury."3
 

The Red Wine Connection
Goldberg, et al, reported that the lowest risk of CHD mortality was among those who drank wine compared with those preferring [other alcoholic] beverages, especially at higher rates of consumption.3 These authors also reported that when "16 healthy subjects were given [pure] alcohol, white wine and red wine [for 15 days for each beverage], alcohol enhanced [i.e. increased]...platelet aggregation...Red wine led to a fall in ADP-induced [platelet] aggregation and increased HDL-cholesterol, clearly the most favorable response to the three beverages tested."3 Klurfield and Kritchevsky reported that "Rabbits were fed an atherogenic diet together with water (controls), or one of five different beverages containing equal amounts of ethanol. After 3 months, all the control rabbits had developed atherosclerotic lesions in the coronary arteries. The alcoholic beverages, except beer, reduced the incidence of such lesions, but the most dramatic reduction (to 40% of controls) occurred in the rabbits receiving red wine."3

The above is just a sampling of the evidence that it is primarily red wine, not spirits or beer, that is ‘heart-friendly.' Yet even red wine contains alcohol, and alcohol, especially through its chief metabolite, acetaldehyde, is a powerful and broad-acting metabolic toxin, with liver damage being just the ‘tip of the iceberg' of alcohol's destructive side.4

Thus, it became clear by the early 1990's that something relatively unique to red wine provided significant heart protection. Consequently, nutritional scientists began searching to find the ‘active ingredient(s).'

Flavonoids
In a 1995 article, researcher David Goldberg rhetorically asked "What on earth has the color of the wine got to do with it all? A great deal, it seems. The only consistent difference between the red and white wines is that the red contains more phenolic compounds. Among these phenols, the major difference is in the flavonoids...[including] compounds such as quercetin (QRC), rutin, catechin and epicatechin..."5 Goldberg points out that ‘flavonoids' have been demonstrated to have powerful biological effects, including the ability to inhibit eicosanoid synthesis and pathological platelet aggregation, as well as the ability to inhibit cancer growth and development. Goldberg also notes these red wine-phenolics are individually and collectively 10 to 20 times more potent than vitamin E in protecting low-density lipoproteins (LDL) against oxidation (oxidized LDL is now considered to be a powerful initiating mechanism of atherogenesis). Yet Goldberg also points out that people who eat a decent amount of fruits and vegetables will already ingest a fairly healthy dose of flavonoids, so ‘why the fuss about red wine?' (Indeed, the Zutphen Elderly study showed that even the modest amount of flavonoids found in tea, onions and apples, seemed to provide significant protection against death from MI among elderly men consuming these 3 foods, compared to those not consuming them.6

Resveratrol
Goldberg then asked the rhetorical question "Does [red] wine contain a biological component that is present only in limited amounts in a typical diet? Indeed, it does: resveratrol (RSV). This trihydroxystilbene is synthesized by grapes, being present in the canes, leaves and the skins of the berries. Because these are present during the fermentation of red wines, but not white wines, only the former contain significant amounts of resveratrol in the finished product."5

The resveratrol story does not begin with its (recent) discovery in wine. It actually started in the early 1980's among Japanese scientific researchers. Report-ing in 1982, Arichi, et al, noted that the dried roots of Polygonum cuspidatum have been used in traditional Japanese and Chinese medicine in a product called ‘Kojo-kon.' Kojo-kon was used to treat a wide range of afflictions, including fungal diseases, various skin inflammations, and diseases of the heart, liver and blood vessels. Resveratrol and its glycoside ‘polydatin' have been shown to be the primary active ingredients of Kojo-kon.7

In 1985, Kimura, et al, discovered the key to resveratrol's metabolic activity. Working with rat leukocytes (white blood cells), they showed that resveratrol possesses a powerful ability to inhibit eicosanoid production.

Clinical Studies
In 1995, Pace-Asciak, et al, reported a dose-dependent inhibition by trans-resveratrol of the aggregation of platelets prepared from healthy human subjects. The IC50 concentrations for resveratrol were approximately 100 micromoles, while ethanol required 1,000 times higher concentrations to achieve the same effect. The standard antioxidants BHT and vitamin E were ineffective at inhibiting platelet aggregation, as were the major wine phenolics catechin and epicatechin.10

Pace-Asciak, et al, also found that trans-resveratrol strongly inhibited the COX-catalyzed thromboxane synthesis by platelets, with approximately 60% inhibition at 10 micromoles resveratrol. None of the other wine phenolics or antioxidants tested had any major effect at that concentration. Only resveratrol—of the other phenolics and antioxidants tested exerted modest LOX inhibition at higher levels.

Platelet LOX activity generates hepoxillins from arachidonic acid (AA), which induce vascular permeability and neutrophil activity, two partial causes of atherogenesis.8,10 As Soleas, et al, note, "...resveratrol at micromolar concentrations is able to inhibit thromboxane A2 production."9 In 1997, Soleas, et al, reported that "...by applying information obtained from dose-response curves, the [platelet] antiaggregatory effect of de-alcoholized red wines could be computed as approximately that expected from its concentrations of resveratrol...."11

Blood Vessel Biology
To more fully grasp the importance of eicosanoids in platelet aggregation, it is necessary to understand a simple fact about blood vessel biology. Healthy, smooth, intact blood vessel linings (the endothelium, a layer only one cell thick) "...synthesize and secrete prostacyclin [PGI2], a strong vasodilator and the most potent inhibitor of platelet aggregation known."13 "...the platelet thromboxane pathway is activated markedly in acute coronary syndromes...PGI2...contri-butes to the non-thrombogenic properties of the endothelium...PGI2 and TXA2 [thromboxane A2] represent biologically opposite poles of a mechanism for regulating platelet-vessel wall interaction and the formation of hemostatic plugs and intra-arterial thrombi."8

In other words, PGI2 prevents clots from plugging up heart arteries, keeps the arteries dilated (wide open), and promotes healthy endothelial lining. TXA2, however, promotes pathological clotting, constricts arteries, and can damage the blood vessel endothelial lining-i.e. promote atheroma.8 PGI2 is routinely made by healthy endothelial cells from AA, and then secreted into the bloodstream. Prostacyclin synthase (PS) is the enzyme that transforms AA into PGI2.

Free Radicals and Antioxidants
What impairs the activity of PS? Various free radicals and oxidants, especially lipid peroxides and hydroperoxides—these are, essentially, ‘rancid' fats.12,16 Kinsella, et al, state that the prevailing hydroperoxide ‘tone' or concentration is a result of the balance of pro-oxidants (e.g. free copper or iron ions, cigarette smoke), antioxidants and oxidative substrates (i.e. the fatty acids in the blood), and that this balance influences the propensity toward oxidation/ free radical production.13

Thus, in order to maximize production of heart-friendly PGI2, it is necessary to minimize the ‘prevailing hydroperoxide tone' in the blood, since high hydroperoxide tone = low PGI2 synthase activity = low PGI2. (It also helps PGI2 production if one minimizes or eliminates fried fats from the diet, too—these provide rich sources of hydroperoxides/peroxides.) "Antioxidants inhibit lipid peroxidation by reducing general [hydroperoxide] tone...The polyphenolics [including RSV and QRC], commonly found in wine, are potent antioxidants...De Whalley, et al (1990), reported that flavonoids act by protecting (and perhaps regenerating) the primary antioxidant, tocopherol [vitamin E], by direct antioxidant effects, and by scavenging free radicals and peroxy radicals."13 Frankel, et al, reported both RSV and QRC to be more powerful antioxidants than vitamin E in protecting human LDL against copper-catalyzed oxidation.14

In 1994, B. Stavric wrote that "It appears that a number of the biological effects of...flavonoids may be explained by their antioxidative activity and ability to scavenge free radicals."15 It also turns out to be very important to minimize free radical/lipid peroxide production in order to minimize pathological platelet aggregation due to TXA2 excess.

Thus, "the synthesis of these compounds [TXA2 and PGH2] by cyclo-oxygenase is enhanced by lipid hydroperoxides."13 "Free radical production is intrinsically linked with the enzymatic generation of prostaglandins, thromboxanes and leukotrienes from [AA]...Lipid-derived hydroperoxides (HPETE's) are obligatory intermediates in the generation of prostaglandin/thromboxanes... from AA.... Bryant, et al, reported that GP [glutathione peroxidase] reduces the hydroperoxide compound 12-HPETE derived from AA, to its [relatively harmless] derivative 12-HETE.... Any impairment of GP (by lack of availability of [selenium]...) may lead to abnormal accumulation of the HPETE peroxides, which are potent inhibitors of the prostacyclin synthetase."16

Conclusion For Blood
Thus, a combination of resveratrol and other bioflavonoids, vitamin E, vitamin C, and the trace mineral selenium may be expected to have a highly synergistic effect in reducing pathological platelet aggregation (thrombogenesis), maximizing PGI2/minimizing TXA2 (thus dilating arteries for healthy blood flow as well as opposing platelet aggregation) and minimizing free radical damage/disruption to blood vessel linings (i.e. preventing/minimizing atherogenesis).

Anti-Carcinogenic Properties
Resveratrol may also have a similarly beneficial effect in preventing cancer, or even aiding in its cure. Jang, et al (1997) reported the results of a series of biochemical, cell culture, and animal studies with RSV in the prestigious journal Science. They reported that "Resveratrol inhibits cellular events associated with tumor initiation, promotion and progression."17 In other words, resveratrol is able to block all three mechanisms of cancer formation!

These authors also wrote that "...we studied tumorigenesis in the two-stage mouse skin cancer model in which DMBA was used as initiator and TPA as promoter. During an 18-week study mice treated with DMBA-plus TPA developed an average of two tumors per mouse with 40% tumor incidence. Application of 1, 5, 10 or 25 [micromoles] of resveratrol together with TPA twice a week for 18 weeks reduced the number of skin tumors per mouse by 68, 81, 76 or 98% respectively, and the percentage of mice with tumors was lowered by 50, 63, 63 or 88%, respectively. No overt signs of resveratrol-induced toxicity were observed...."17 These authors also noted the importance and potency of RSV's anti-COX activity and antioxidant/anti mutagenic activity in preventing tumor promotion and initiation.

The Cancer, Blood and Antioxidant Connection
In his textbook Cancer & Natural Medicine, J. Boik reports the importance of platelet aggregation and eicosanoid issues in cancer. Thus he writes: "The importance of platelet aggregation in cancer metastasis is more widely accepted... Activated platelets are sticky and may enhance the adhesion of tumor cells to the endothelial lining. Platelet-secreted factors...may stimulate the growth of tumor cells and contribute to their survival within the blood circulation. Experimental studies have shown that migrating cells from some cancers induce platelet aggregation by modifying the eicosanoid balance...Tumors promote platelet aggregation by stimulating the production of PGI2...Tumors synthesize eicosanoids through ...the COX pathway...."19 Given the prior discussion in this article of resveratrol as premier COX-inhibitor, and as an excellent anti-platelet aggregator, its potential anti-cancer benefit should be evident.

Garrison and Somer state that "Several studies report that vitamin E reduces tumor growth and exerts an anti-cancer effect in both the initiation and promotion stages because of its antioxidant and immuno-enhancing actions... vitamin E appears more effective in conjunction with other nutrients, such as selenium and ascorbic acid, than by itself in the prevention of tumor growth."18

Some question has been raised over the oral absorbability of resveratrol, but recent results clearly demonstrate its excellent absorption. Soleas, et al, comment that "...the difference in thrombin-induced platelet aggregation between the commercial and resveratrol-enriched grape juices argues in favor of the absorption of this compound in biologically active concentrations by human subjects..."9

 

 

 

Uses and Doses

A simple yet elegant and potent anti-heart attack/anti-cancer program may thus be constructed from synergistic nutrients: Resveratrol, vitamin E, vitamin C and selenium. Recommended dosages: 1-10 mg trans-Resveratrol, 3 times daily. 100-400 IU d-alpha tocopherol or d-alpha tocopheryl succinate (vitamin E), once daily with a fat-containing meal. 250-1000 mg ascorbate (vitamin C), 4 times daily. 100 mcg once daily, or 50-100 mcg twice daily, selenium as l-selenomethionine and/or sodium selenate.

 

Technical Note
Caution: Anyone who suffers from platelet deficiency or blood-clotting difficulties should use this program only under medical supervision, if at all. Similarly, anyone taking medical blood-thinning drugs (e.g. aspirin, coumadin) should use this program only under medical supervision, if at all.

Highly recommended source of nutrients and supplements.

How did we qualify VRP?

REFERENCES

1. W. Martin (1984) ‘The combined role of atheroma, cholesterol, platelets, the endothelium and fibrin in heart attacks and strokes' Med Hypoth 15, 305-22.

2. S. Renaud, M. de Lorgeril (1992) ‘Wine, alcohol, platelets, and the French paradox for coronary heart disease' Lancet 339, 1523-26.

3. D.M. Goldberg et al (1995) ‘Beyond alcohol: Beverage consumption and cardiovascular mortality' Clin Chim Acta 237, 155-87.

4. J. South (1997) ‘Acetaldehyde: A common and potent neurotoxin' VRP Nutr News 11, 1-2, 9-11.

5. D.M. Goldberg (1995) ‘Does wine work?' Clin Chem 41, 14-16.

6. M.G. Hertog et al (1993) ‘Dietary antioxidant flavonoids and risk of coronary heart disease: the Zutphen Elderly study' Lancet 342, 1007-11.

7. H. Arichi et al (1982) ‘Effects of stilbene components of the roots of Polygonum cuspidatum... on lipid metabolism' Chem Pharm Bull 30, 1766-70.

8. J.G. Hardman et al, eds. (1996) Goodman & Gilman's The Pharmalogical Basis of Therapeutics NY: McGraw-Hill, 601-10.

9. G.J. Soleas et al (1997) ‘Resveratrol: A molecule whose time has come? and gone?' Clin Biochem 30, 91-113.

10. C.R. Pace-Asciak et al (1995) ‘The red wine phenolics trans-resveratrol and quercetin block human platelet aggregation and eicosanoid synthesis: Implications for protection against coronary heart disease' Clin Chim Acta 235, 207-19.

11. G.J. Soleas et al (1997) ‘Wine as a biological fluid: History, production and role in disease prevention' J Clin Lab Anal 11, 287-313.

12. D.Lonsdale (1986) ‘Free oxygen radicals and disease' in 1986: A Year in Nutritional Medicine, J. Bland, ed. New Canaan:Keats, 105.

13. J. Kinsella et al (1993) ‘Possible mechanisms for the protective role of antioxidants in wine and plant foods' Food Tech, April 85-89.

14. E.N. Frankel et al (1993) ‘Inhibition of human LDL oxidation by resveratrol' Lancet 341, 1103-4.

15. B. Stavric (1994) ‘Quercetin in our diet: From potent mutagen to probable anticarcinogen' Clin Biochem 27, 245-48.

16. S.A. Levine, P.M. Kidd (1986) Antioxidant Adaptation: Its Role in Free Radical Pathology S.F.: Biocurrents Pub., 36-37, 164-167.

17. M. Jang et al (1997) ‘Cancer chemopreventive activity of resveratrol, a natural product derived from grapes' Science 275, 218-220

18. R.H. Garrison, E. Somer (1995) The Nutrition Desk Reference New Canaan: Keats, 88-89.

19. J. Boik (1996). Cancer & Natural Medicine Princeton, MN: Oregon Medical Press, 40-41, 48-49.