NEGATIVE RESULTS OF TOCOPHEROL THERAPY IN CARDIOVASCULAR DISEASE* eo By Cartes K, Doxecax, M.D. CARDIOVASCULAR FELLOW IN MEDICINE Appisox L, Messer, M.D. Epwanp S. Oncatx, M. ASSOCIATE FROFESSOR OF MEDICINE AND eee D. DURMAM, NORTH CAROLINA (From the Department of Medicine, Duke University School of Medicine, and Duke. Hospitaly —___ carried on in experimental animals to determine the metabolic function of vitamin E in relationship to the repro- ductive, muscular, and vascular. sys- tems. In the rat! it has been shown that vitamin E is necessary for repro- duction. In the rat, guinea pig, rabbit and hamster, vitamin E deficient diets produce a profound alteration in the skeletal muscles microscopically similar to that found in the human muscular dystrophies?** It has been demon- strated that the oxygen consumption, creatine and ehlonge content of'mis. cles in vitamin E deficient animals may be’ influenced by feeding alpha toco- herol The Cinkeal applications of Fhowe stadies, however, Rive been ds: appointing, |At one time enthusiasm Mb expres Over the possible value OF vitenin Ein the provdetion of spom taneous and habitual abortion of un- known etiology in humans."? The more err tnely negative fests in the treatment of the muscular dystophies with vite min E5%1 There is ample evidence that the blood evel of vitamin Ev can be raised with tocopherol therapy." Although the germ of cereal grains and Sent Pe eer ele eee the richest natural sources of vitamin E, So universal is ie distsbution in the ers mre ae able to devise a diet of natural foods ‘hie stedy nas supported y eon fm Dillion Produts, In. andthe ob (26) suitable for the spcingess rode / tion of vitamin E deBcienc A considerable number of animals have been observed to die suddenly while on vitamin E deficient diets+-One bovine which died suddenly was fol- Towed. with serial electrocardiograms that showed gradual and progressive changes. Atrophy and scarring of eardi- ac muscle fibers were found to appear, along with an increase in the cellular elements. It was concluded that cardiac failure could be produced in cattle by deficient diet. means of a y The rep vitamin Ein varfous types of heart disease with much attendant publicity have stimulated an interest in the pos- sible therapeutic effects of this drug. Although there has been no critical study of the effects of large doses of vitimin E, an increasing number of patients have been seen by the authors 4n consultation who have been plaezd on vitamin E by their physicians. The present study was undertaken in an attempt to evaluate by laboratory tests and clinical examinations the ef fect of tocopherol therapy in selected types of cardiovascular disease, Procedure. In this study 7 pationts with Iypertensive vaseular disease without exrdine caorgement by: Roentgen-ray (Group 1), 7 patients with hypertensive vascular disease fand cardise enlargement. by. Rozntgen-ray (Group 2), patients with classical andfeuttnely stable angina pectoris (Group 3) sere selected. The patients Were sean ual mn taal over pst of 310 20 Each patient was given the benefit of a complete nisory and physical exarsnation for purposes of clusiiciton, Eletrocaraogans nal 3 meter tcleroeatgenograms of the cheat ‘were taken along ‘with Blood plasma, loco: Pherol levels to serve as contiols At cach Ecbeefient vst of the patent the pertizent interval history was recorded; a cardiovascular ‘satire was-perfonned; and the above Inhoratory data were repeated. Medication in each instance was begun with oral ‘placebos; cach patient reseed intily placebos inditinguhable: fom. the ciprules containing tocopherol for 1 months Alter T month of placebos, the patint was gen tocopherol orally for’ 1 meuthy ‘These 2 preparations were then alternated for periods af Limoath each throughout the poved af ‘hservaion. Parposaly every patient bas given the impression that he received the ideatcal ‘medication on each orcesion Daring’ the exter period. of study, toco hier therapy was begin with a dale dosage of 130 mg. of the mised tocopherols Later, tocopherol treatment was tnitated at levels ‘of 300 mg. daily of the alpha tocopherol At subsequent visit the dota of tocopherol was increased so that duing the period of obser. ‘ation 13 patients received ally dosage of (000 me; 3 patients received duly dosage of 300° mg. ‘of the. alpha toconherol for st least ot more months and for 6 patient the ‘masimum ‘dally dovage was 150 mg, of the mixed tocopherols (See Table 1). Results and Discussion. The results |are summarized in Table 1./In ev | patient, it was found that the blood [Heel could be sased sigitcandy ‘by the oral administration of tocopherol. Jn 21 instances of patients to whom 150 mg. per day of mixed tocopherols were administered for 1 month there was an average increase of 47% in the blood plasma tocopherol level (mean {increase from 1.20 mg. per 100 cc. to 176 mg. per 100 éc., Table 2), There was an increase in the blood plasma to- copherol level in every instance, and the increment was thought to be signif- cant in 20 of these. In 11 instances of patients who re- ceived 800 mg. per day of alpha toco- TOCOPHEROL THERAPY IN ‘CARDIOVASCULAR DISEASE 295 pherol for 1 month there was an average increase of 54% in the blood plasma tocopherol level (mean increase trom 1.28 mg. per 100 ce. to 197 mg. per 100 ce., able 2). There was a signi- ficant increase ia 10 instances. There was some question whether the medi- cation was taken in the 1th, In 23 instances of patients who were jiven 600 mg. per day of alpha toco- Pheral for one’ month there was an average increase of 85% in the blood tocopherol lvel (mean inrease rom 1.59 mg, per 100 ce. to 2.95 mg. per 100 ce,, Table 2). An inerease in blood level was noted in every instance; in 22 the increase was thought to be signifi- cant. In the hypertensive group without { cardiac enlargement (Group 1), 2 pa- tients felt generally better during the period of placebo therapy. This im- ovement Was maintained throughout" the period ‘of study ‘with alternating / tocopherol and placebo therapy with- out significant change in blood pres- sure, In 2 patients the T-waves of the electrocardiogram became lower while on tocopherol therapy. One patient felt less well during tocopherol therapy. The remainder of the patients mani- fested no significant changes. In the hypertensive group with | ‘cardiac enlargement (Group 2) 2 pa- tients improved subjectively’ on placebo therapy but exhibited no objective changes. This improvement was main- tained. ‘Two patients with bundle branch block developed increasing en- largement of the heart; 1 of them pro- gressed to congestive failure. ‘No improvement was noted in the other patients of this group. OF the 7 patients having angina, (Group 3) only 1 reported an increase talerance to excreige which began while receiving tocopherol. This im- provement was sustained throughout the period of study. An additional pa- | tient improved while on placebos and | maintained improvement” throughout } | \DONEGAN, MESSER, ORGAIN: ream morta suena “1 dor ‘anivang stiasay 40 siskwey—F wavs,y a san2eg ey ‘eeminaversee DONEGAX, the follow-up period. One further pa- tient became worse on_ tocopherol therapy. No change subjectively or objectively was noted in the remainder. Thus it seems well demonstrated that tocopherol therapy produced no appreciable benefits in this group of patients. There was no significant im- provement in symptomatology nor in objective findings. Specifically there was no lowering of the blood pressure, no decrease in heart size by Roentgen- ray, nor improvement in the electro- cardiogram. The changes which were recorded indicating improvement in some and progression in others were no more than one might expect in the Tantx 2.—PLassu SSSER, ORGAIN: natural evolution of their cardiovas- | cular disease. No toxicity from the drug | was noted in any patient. There was no correlation between the level of blood plasma tocopherol and the clinical course of the patient. In patients with congestive heart failure we found that the tocopherol blood levels'* were nor mal and not reduced. Conclusion. In a series of 21 patients with cardiovascular disease followed from’ to 20 months, tocopherol therapy was found to produce no appreciable benefit either subjectively or objec- tively. ‘The blood level of tocopherol can be significantly raised by the oral admin- istration of the drug, Tocoraxnor Levess ar Vanious Stacks oF niu: Srv0%, ae. im. 2 aie sans 7 es ame yoo GE ER, nee aes cage ee wie BE. UN TA ai tgs a Ail paren cepreec Bond paso tcoperal lees nm. pe 109 ee : REFERENCES Evans, H. M, and Bishop, K. Goettsch, Mand Pappenheimer, A. Mz Gallickson, #. W., and Calverley, C.F Minot, A. S., and Feank, TEE Am. J Science, Evans, HM, and Burr, G, O.: J. Biol Chen Hares, MMs ARE J. MED. SCL, 203, Houchin, O. B. ond Mattill, H. A. I. Biol. Chem,, 146, 501, 1942, Mason, K. E+ Yale J. Biol.'and Med, 14, 605, 1942, 156, 650, 1929. 8, 273, 1928, J. Exp. Med. $4, 145, 1931, Seience, 104, 312, 186, 58, 1941, Dis. Child, 67, 871, 1944‘TOCOPHEROL THERAPY IN CARDIOVASCULAR DISEAS 299 ©. MeBryde, A., and Baker, L. Du J. Pediat, 18, 727, 1041, 10. Quaife, Mand Harris, B. Le: J. Bil. Chem, 156, 499, 1944 AL, Shelden, C. Ii, Butt, H.R, and Woltman, H. W.r Proc. Sta’ Meet, Mayo Clin., 15, i, 1s. “E7AS. Shute, W. Ey Shute, E. Vs and Vogesang, A. By Med. Rec, 160, 13 Shute; W. E> shut, E. V3 and Vogelang, A: Bs Med. Rec’ 160, 1 Unpublehed “bseritons, AIS. Vogsnang, By Ste EV, and Shae, W. Es Med, Nec, 160, BAe: Wogctong, Ac By Shute LV and Shute W, Sled Ree 100, 163, Tor If, Watson, EM Cana Sed, Asaf Ba, 194 3958 15, Wester, Sy Mayer, ©: Gy and Sabah Poe. Soc, Exp. Biohand Med 58 170) 1048,