Vitamin E and coronary heart disease ROBERT E. HODGES, m. Projessor, Department of Internal Medicine; Chie), Nutrition Section, University of California School of Medicine, Davis The benefits of self-treatment of coronary heart disease with vitamin E are being promoted to the lay public, The bases for the claims, however, are quite tenuous and not based on con- trolled investigations carried out in @ scientific manner. ox Throughout the United States, one can see abundant evidence of the enthusiasm with which the public has greeted our latest “dosityourself” fad, vitamin E. Health food stores suggest vitamin E to prevent and treat heart disease and for sexual inadequacy, that “overaired feeling,” and a host of other ills. Phar- macy_shelvés are lined with bottles of vitamin E cor of alpha-tocopherol, and supermarket shelves filled with wheat germ and other foods “rich in vita- min E.” And if, by chance, we should browse through 1 bookstore, we may be astailed by a number of vol- ‘umes extolling the virtues of vitamin E. +. The leading proponent of vitamin E therapy is Dr. Wilfrid E, Shute of London, Ontario. He and his brother, Dr. Evan Shute, have long advocated large doses of vitamin E in the management of a wide va- riety of illnesses. The publicity which Dr. Wilfrid Shute has generated as a result of his hook, Vitamin E for Ailing and Healthy Hearts (1), has led to @ succession of other books (2, 3). Statements from three of them illustrate the major thrust of the claims for vitamin E. Vitamin F—an essential nutrient In 1922, Evans and Bishop discovered a fat-soluble substance which we now call vitamin E. This sub- stance has been shown to he necessary in maintaining reproductive function in female rats (4). It is now known that vitamin E represents a group of six or more related substances called “tocopherols,” fied as alpha, beta, gamma, ie the most potent ind so on} the alpha form biologically. Vitamin E has been ls and birds, as well as at Teast one A peculiar characteristic of + E deficiency is that different species may manifest dif. ferent symptoms (5-7) Although deficiency of vitamin E is rare in man, it has been chserved in children wit malnutrition (kwashiorkor) (8); in premature in- fants; and in such malabsorption syndromes. as steatorrhea, sprue, cystic fibrosis, pancreatitis, and chronic biliary obstruction. Tn 1960, nutritionists estimated that the typical American diet contained an average of about 16 mg. Jominct of The American Dietetic Associationvitamin E per day, but assays of food aliquots showed only half that amount to be present. The 1968 Recom- mended Dietary Allowance (9) for vitamin E was “up to 30 1.0." daily, but this figure will probably be reduced in the next revision. fi has been estimated that between 2 and 10 1. vitamin E are needed to prevent hemolysis of red blood cells in children and that the adult requirement may be slightly higher (10-13). A dietary intake of large amounts of poly- unsaturated fatty linoleic acid, may increase the requirement for vitamin E (14). Fortu nately, vegetable oils, which are commonly used in the American diet, contain an abundance of the to- copherols (15-18). Approximately 64 per eent of our dietary source of vitamin E is derived from fats and oils, whereas fruits and vegetables supply about 11 per cent, and cereals and grains, about 7 per cent. Egg yolks and meat contain small amounts. Customary methods for processing and storing oil products:do not result in serious losses of vitamin E activity in most instances. In fact, hydrogenation of fate may: actually protect the vitamin E content of certain products by reducing the number of unsaturated bonds. The impetus for the present wave of enthusiasm for the use of vitamin E apparently was the publication ‘of Wilfrid Shute’s theory. This theory was based on ‘a chance observation by his older brother, Evan, that 4 patient receiving a wheat germ oil product for an- other reason (1) enjoyed “complete relief of angina pectoris.” One thing led to another, and the Shute brothers eventually concluded that vitamin E or, pref- erably, “alphactocophero” was highly beneficial in the treatment of various forms of coronary heart dis ‘ease, including acute myocardial infarction and an- gina pectoris. They also reported that patients with atherosclerotic disease of peripheral arteries benefited from large doses of vitamin E, Wilfrid Shute states in his book that he has treated more than 30,000 cer- diovascular patients and suggests that the rest of the ‘medical profession has “wasted a frantic twenty years of search for a drug that already exists.” In fact, he suggests that the modern diet, with its milled grains and purifed foods, contains much less vitamin E than the amount supplied by diets in the early years of this 1olume 62, June 1973 He believes that this accounts for the epi- ic of coronary heart disease now plaguing the United States which is “a disease entity that did not occur prior to 1910.” He then refutes the more com ‘monly accepted theories sbout hypercholesteremia and “saturated versus unsaturated fats,” but fails to ‘mention the potential effects of cigarette smoking, physical inactivity, or associated diseases, such as hy- pertension and diabetes, in the etiology’ of coronary heart disease In a venerable text of medicine published in 1895 (Stedman's Twentieth Century Practice of Medicine), T found some answers to Dr. Shute's questions (19, 20). In it, a disease process was lucidly described Which, in my view, was unquestionably coronary heart disease in its many manifestations. Physicians of those days, however, used somewhat different terms, including “hypertrophy and dilatation of the heart” (page 117), “atrophy of the heart” (page 74), “myo- carditis” (pages 124 and 125), “endocarditis” (pages 143, 164, 188), “fatty degeneration of the heart” (pages 339, 341, 342, 343), “thrombosis of the heart” (page 375), “angina pectoris” (pages 436 and 439), “chronic arteritis” (pages 551 and 552), and “ar. teriosclerosis” (page 562). In fact, these authors even described “myocardial infarction as a result of ather- ‘omatous occlusion of coronary arteries,” and quoted ‘medical papers of the eighteenth century which de- scribed this disease. ‘The Doctors Shute, along with their associates, have reported that vitamin E has benefited patients with coronary artery disease, arteriosclerosis of peti- pheral arteries, oF thrombotic disease of veins. Act ording to them, the principal mechanisms which ‘might account for the apparent benefits include an antithrombin effect of alpha-tocopherol, a fibrinolytic effect, a peripheral vasodilator effect, and an oxygen sparing effect. They claim that a patient treated with appropriate amounts of alpha-tocopherol (ten to forty times the amount specified in the Recommended Die- tary Allowances) should be able to avoid thrombotic diseases of the veins, as well as pulmonary emboli. In the patient with coronary artery disease, alpha- tocopherol should help to relieve the pain of angina pectoris, and for the patient who kas suffered a coro- 639nary occlusion, the prognosis is Proved [Although Willd Shute has had vast expert cre gaa epee never conducted controlled studies, but has relial only on his clinical impressions and on several enee of case reports presumably. im- Another investigator also reported (21) beneficial effects from large amounts of ed in the treatment of coronary heart third group questioned dentists and theis attempt to correlate the amounts of vitem dict with the frequency of cardiovacculn 4s reported on a medical questionnaire, increased amounts of vitamin E for a prolonged pe riod, they repeated the survey and reported cree in amptons (a) Hochrein and Zaqqirstdied funti heats and reported (33) Pherols increased the eff reduced its sodium conte apparent tocopherols disease. A ion in guinea pig that large amounts of toca: icieney of the myocardium, nt, and lessened the toxicity of digitalis. Te must be noted, however. that they were Perfusing the guinea pig heart with tremendously High concentrations of alpha-tocopherol acetate, Although the Shute brothers were the first to de- scribe a supposedly beneficial effect of large doses of ‘itamin E in the treatment of peripheral arterial di ai they again did ot pertonn oe ne Harzer (S) in Sweden and Wisner a [london Canada, aid perfor wea) studies and reported apparent beneft to some of their pe, ; w United States, Ochs. tients. In the southern Part of the st DeBakey, and DeCamp enthusiastically advocated CNC are ee Iphastocopherol to prevent hromaboses in the ry patients. Kawa. in Jepan, Kay in New Orlean, and MaSare and coworkers 3989) in Deion ta reported that lenge doves of Spt tocthen ton creased the eaagulability of blood. Zierler et al. have Aesribed G3) an enttheonbie ac en roteolytic action of alpha-tocopherel pl hhosphate in vitro, The contrary evidence Although it may seem, up to this point, that there is much support for the Shute brothers’ theories, let us now examine the contrary reports. I found fifteen re |ports (34-48) representing thirteen separate clinical trials of tocopherols in patients with coronary heart isease. All of them failed to confirm the impressions [fof the Shute brothers. Eight of these studies involved ncontrolled treatment of coronary patients ‘with large doses of vitamin E or alphatocopherel, and |fhere was no apparent benefit. In the remaining fe | fudies, suitable controls seere provided by rleorhe | medications. Here, again, no benefits could be shown, n these thirteen studies, more than 450 patents were | ftvolved. The unanimous conclusion of the vartovs | futhors was that alpha-tocopherol has nothing to offer } the patient with coronary artery ducare “Foshan fnore, additional blood clotting ct | \ copherol simultaneously, Poul et al, (49), at th te University of Western O1 in London, Ontario, failed to demonstrate any on the blood clotting mechanisms after adminiat 1600.mg. doses of al Ipha-tocopherol daily for Jdays to each of eleven men. Vitamin E requirement This brings us to the question of what is the mini daily requirement for vitamin E and what ae should be recommended. As mentioned above, we sume that the average American ingests abort 8 Yitemin E daily in his dit; it has been reported & British citizens may get somewhat less (50). Sine of serum or plasms concentrations of tocopherel hx shown that apparently normal adults have shout mg. tocopherol per 100 mi. or slightly more in th blood, as do patients with heart disease (31), chemical evidence of deficiency, a8 manifested by i creased hemolysis of red cells exposed to a dilute cal tion of hydrogen peroxide, does not appear until t blood level of tocopherols falls helow 0.5 mg. per I i. (52.54). On the other hand, subjects given lar gmounts of vitamin E may have serum levels appro: imately double the presumed normal range (26). Shute has suggested that coronary heart dicen from the present American diet, whid it go of the unsaturated bonds in lilo unsaturated fatty acids. This is true, contain polyunsaturated fatty ach equate amounts of vitamin E to offee the additiogal requirements. Indeed, Denton ceo oe served GoD thar men fel cach ane Prolonged time had twice as much tocophersl in ther enero Aid control subjects eating & normal dice It is essential that we consider not only the poten fiat therapeutic effects of massive doses of ine ee Pherols, but also any posible advere effects. Apron ently vitamin E is a remarkably harmless substence, | and other poly but the oils tha also contain a for lange excesses can be given to lower animale wy ‘man almost with impunity. A few reports, howecen geet that toxicity might occur AlfnSlater et of take shown (8) that rats fed very large amounts of | E had abnormally large quantities of cholo terol in their livers. Mare et al. demonstrated that large amounts of vitaniin E eould induce chee terol deposition on the intimal lining of the aorta of rats, and Levander et al. showed GO) that rats fod large amounts of alcohol developed more severe hepat ie lesions if they were given large doses of alpha te than when vitamin E was re Yournal of The American Dietetic Asocitionmoved from their diet. Telford reported that ant of min Ee ad linen sscrel crt ad mplnt ejects sacasane iwing dongs a ge noun Need for controlled research It is not unusual in clinical medicine to find that a controversy can persist for several decades. Usually, the controversy arises from an honest difference in in- texpreting data; other controversies arise from inade- quate or inappropriate experimental design. I be- lieve the latter is true in the case of vitamin E.[Un carefully planned end controlled studies have been performed by a number of investigators, it seems ap- Propriate to adopt a “null hypothesis” regarding the Yalu of vitamin En the treatment of coronary hear ‘The facts are that coronary artery disease is not a| new condition which suddenly appeared after we be- gan to eat white bread, and the American diet eannot be shown to be deficient in vitamin E. In fact, an in crease in polyunssturates in the American diet ean be expected to increase rather than decrease the | amount of blood vitamin E, Contrary to the state- | ‘ments of Shute and others, there have been many ef { forts by members of the medical profession.to eval uate in an objective manner the potential benefits of | alpha-tocopherol for patients with coronary heart dis- | ease, These studies have yielded negative results. ‘This re-emphasizes the futility of reporting medical observations based on uncontrolled series of patients, ‘especially when testimonial evidence is relied upon. Furthermore, it seems to the author that medical re- search should he done by physicians and not by the lay public which seems to have a fatal fascination With self-medication, The mysteries of vitamin E have yet to be un- ayeled. A umber of positive observations, made dler controlled conditions, seem to warrant additional investigation, The positive results are limited largely to peripheral vascular disease of the arteries and veins. Judging from the currently available evidence, there seems to be little, if any, promise of benefit to the patient with coronary heart disease. Summary Vitamin £ is an essential, fat-soluble substance rep- resented by a group of clocly related tocopherols, the alpha fraction of which is most active. The require- iment for vitamin E is not known precisely, but an adequate allowance probably lies somewhere in the range of 8 to 16 mg. daily, Despite claims that large doses of alpha-tocopherol may benefit patients with coronary artery disease, the weight of evidence ap- pears to be strongly against this hypothesis. Although it seems wise to conduct additional, carefully con- trolled investigations of the theoretical potentials of [olume 62, June 1973) alpha-tocopherol, these investigations must be per formed by qualified medical personnel, if they are to he meaningful. The author does not recommend that the general public indulge in self-medication with vitamin E. References Q) Sucre, WE, axo Taun, HJ: Vitamin E for Ailing and Healthy Hears, N.¥.: Pyramid Books, 1972, (2) Di Cyax, EB Vitamin E and Aging. Nev: Pyramid Books, 1972, (8) Eros, Mur The Troth sbout Vitamin E, N.Y.: Bantam Books, Ine, 1972 (8) Evass, HEME, axo Bisson, KS: On the relation be tween fertility and watrtion, 2. The ovulation zhethm in the rat on inadequate nnteiional regimes, J- Metab. Fee, 1: 335, 1922, (5) Dass, Hy Grananos, H., ano Praxce, Li. Tnluence of to diffrent fate on reproduction eapacity of vitamin E deficient rats. Acta Physiol. Scand. 18: 161, 1949. (6) Bussten, KL: Vitamin E in health and diseases of cattle and sheep. Jn Hartis, RS, et al, eds: Vitamins fnd Hormones, Vol. 20. N¥.: Academic Press, 1962. (1) Masox, KE2 Effect of nutritional deficiencies upon rmvccle. In Bourne, GL, ed: Structure and Function fof Muscle. N:¥.1 Academic Press 1966, (8) Wurraken, J, Foss, EC, Visoxtsaxt, Sy axp Die sis, JS. Hematalogic texponse to vitamin E in the fnemia. sociated with proten-calorie. malnutrition. ‘Am, J. Clin. Nute. 20; 783, 1967. (9) Fooo & Neve Bo: Recommended Dietary Allowances, Seventh Revised Edition, 1968, Natl Acad, Sci. Pub, No. 1694, 1968, (10) Viternin E requirements, Dairy Council Digest 33: 1 (MarchApe.), 1902, (QD) Hoxwirs, MAK, Cexruny, B, asp Zeman, AWA: Exp thiocste eurvival time and reticulocyte levels after to ceopherol depletion in man, “Am. J. Clin. Nutr. 12: 99, 1963, (12) Bien, 1G, Teers, Ly Beravaog, By Axo Axons, ELL:' Serum vitamin E levels in normal adult popu: Iotion in the Washington, D.C. area. Proc. Soe. Exp. Biol, Med, 117: 131, 1964. (13) Hanns, PL, Hanoixar0ox, F.C, Drax, Fl ER, asp feasts, JL Blood’ tocopherol normal huinan adilis and incidence of sitamin Ede: Feieney. Proc Soc. Exp. Biol, Med, 107: 381, 1961. Q) Hosas, PLL) aso Esumer, ND: Quantitative con. siderations of the effect of ‘polrunsaturated fatty seid content of the diet upon the requirements for vitamin E. Am. J. Clin. Nut. 1: $85, 1963, (18) Goviso Rao, MK, ano Penxss, E.G.: Ientfcatio land estimation of tocopherols and tocotrenols in vege {able ails-using gas chromatographymare spectometry. J. Agee. Food Chem, 20: 240, 1972. (16) Dicks, MWe: Vitamin E content of foods and feeds for human and animal consumption, Unie. of Wye. ming Agvie, Exper, Sta. Bull, 485, 1965 7) Bossent, RH, Kearse, J, Quanesivo, A., aso Pane sas. GK: Alphatocopherol content of foods, Am. J, Clin, Nate, 17:1, 1968. (18) Fienttse, D.C, ax0'Dnony, ELE: Vitamin E content of vegetable ils and fats. J. Nut. Bl: 335, 1968 (19) Sassou, AE! 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Weekenshe Bee ie GB Bie ie, 9 Seay, Wes, Nin E hry a ean heace"Wis Nek. Ji 38 8 Rav {Se iso Rare tain in th wet mnt af ange pece N. En Tae. 2S 3 ‘Vitamin E in angina pectoris. Lancet 3: Her Vitamin E: 2 therapeutic perpetration, ‘What's ina name? South Me 10819. dition” Aon NY. Sead Sc Pf BW @ Bata, S. Heise, Wal, ano Grurono, DB: The use of vitamin Fin heart disease, Am. J. Med, Sei. 215: 542, 1948, (ph) Levy, 1, ax0 Boas, EP-: Vitamin E in heart disease. ‘Aan Tet. Med, 28: 1117, 1938 Doricas, CK, Messen AL, Oncats, ES, ano Rer- His, JM.: “Negative resus of tocopherol therapy eatdiovascular disease, Am, J. Med, Sei, 217: 20), 190. (48) Gras, NJ, ano Scuseror, Viz Ambulant E-vitamin- erapi vod HHjertesygdomme, Nord. Med, 37: 82, 191 Pavi, RM. Less, JA. ano DeLves, HLA: The lack of effec of vitamin E on the blood eluting mechanism, Can, J. Biochem. Biophys, 32: $47, 1954, (50) Sun, CL, Ketusnes, J, Losowsky, MS, axo Mor nasit, Ne “The content of vitamin E in British diet Br. j. Nave. 26: 88, 1971. (SD Leiey, JM, Gate, RE, Fomuax, RH, Curamse: ox, ME, Dane, WJ, aso Mentecr, GR: Plasma tocopherol levels in cardiac patients.” Am. Heart J. 39: 1029, 1019. (52) Marat, AS, Disgane, IS, Azza, $.4,, ano Dano, We]-:" Vitainin E responsive megnlobastic anemia in infants with proteinalorie malauttion, Am, J. Cli Nate. 12: 374, 1963. (53) Ratoras, MAL, Hosstas, S, Tanoxoan, S.A, Arta, K, axp Brees, LG: Serum sitamin E levels nthe rural populations of East Pakistan, Proc. Soc. Exp. > Biol. Med, 117: 133, 1968, Braoxsrers, H.: Tocopherol deficiency in adults with chronic pancreatitis, Gastroenterology 40: 224, 1961, Hiiasax, RW: Tocopherol excess in man: Creatinu- ia vith prolonged ingestion, Am. J. Clin, Notr, 57, 1957, (56) Hanis, K.S.2 Influences of storage and processing on the retention of vitamin Ein foods. In Harris, RS. et al, eds: Vitomins and Hormones, Vol. 20. NY. ‘Neademie Press, 1962, (Sn)Davrox, S, Hiasunioro, S, Roseya.um, Diy aso Pearce, Mic: Vitamin E status of humans during prolonged feeding of unsaturated fats. J. Lab, Clin. Med, 65: 738, 1965. (sa)) AurtxStater, RB, Artencooo, Ln, ano Kiswintrr, S.: Invetzaions on byperitaminoss En ras, In Arve, ReCee Subtene Sn foam dn RIN clot oy tee ei Secure a peo met 1949, “Vanilla ice cream” is a standardized product and, if ¢0 labeled, must he flavored completely with real vanilla (beans or extract). If the label reads “vanilla flavored,” artificial flavoring has been used. And, if as much as half of the flavor label must say “artificially flavored vanilla ice eream.” 62 artificial, the Journal of The American Dietetic Association