Varbanov, G.

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L I P O P R O T E I N - L I P A S E A C T I V I T Y A N D H E P A R I N E F F E C T ON B L O O D S U G A R L E V E L A N D S E R U M L I P I D S IN P O S T -M Y O C A R D 1 A L - 1 N F A R C T I O N P A T I E N T S G. Varbanov In atherosclerosis and, more part icularly, in myocardial infarction se-rious disorders are established not merely in the l ip id , but also in the car-bohydrate metabolism. Along with that, the mutual dependence existing between the two processes is noteworthy. In myocardial infarction many authors (3, 7, 10, 12, 14, 16, 17, 20, 24, 25, 28) find elevated values of cho-lesterol, beta-lipoproteins and total l ipids. The cholesterol/ phospholipids ratio reflects more adequately the sus-cept ibi l i ty or resistance of cholesterol to arterial wa l l infi l trat ion. Many authors emphasize the importance of this indicator which exhibi ts increas-ed values in atherosclerosis, especially in its active stage (11). Gertler and co-authors (cited by 11) established a high cholesterol /phospholipids coefficient both in atherosclerosis and diabetes mellitus. Upon single administration, and in the course of prolonged treatment as we l l , heparin brings about a decrease of cholesterol and increase of pho-spholipids (1), i . e. it exerts a beneficial effect on the cholesterol/phospho-lipids indicator. I t is a well known fact that phospholipids cause s tabi l i -zation of the cholesterol molecule and interfere wi th its infil tration into the vascular w a l l . I n a study on atherosclerosis, Leopold and Wieland, Schrade and co-authors (cited by 11) found a higher triglyceride content in the serum compar-ed wi th that of cholesterol. In coronary disease a great number of authors (16, 17, 19, 2 1 , 25) observed disorders equally in the cholesterol, and par-t icu la r ly in the triglycerides' exchange. Thus, according to Hayes and Nei l l (22), in myocardial infarction even triglyceride metabolism distur-bances are more frequent than those of cholesterol. G l ive ra and Boyd, Kr i t zman and co-authors (cited by 11) and many others (3, 12, 14, 16, 24, 25) report an increase of beta-lipoproteins and a substantial increase of bound cholesterol in cases wi th myocardial in-farction. Meyer and Davj idovsk i i (cited by 11) and Olivera (26) admit that lipoproteins rather than cholesterol underlie the atherosclerotic process, and might play a definite role in atherogenesis. The level of beta-lipoproteins is more sighificantly and regularly de-creased by therapeutically applied heparin than the cholesterol level (2), and not only in myocardial' infarction (3), but also in diabetes (£), myxedema (4) and in healthy subjects (4) , In myocardial infarction the lipoprotein-lipase ac t iv i ty is lowered (12, 27)", while its inhibitors are enhanced (15 and Hood, cited by 9) . The con-1 84 G. Varbanov tent of endogenic heparin is l ikewise reduced ( N i k k i l a , Antonini , Chazov — cited by 9, and 6, 13, 15). The lowered lipoprotein lipase ac t iv i ty and en-dogenic heparin content favour the prethrombotic and thrombotic condi-tions in the organism. Hyperglycemia and glucosuria in acute infarction of the myocardium are probably due to a forme fruste of diabetes mellitus (28) . 4 Along wi th the well krtdwn l ipolyt ic effect of heparin, in the past few years reports have been published on its hypoglycemic action in healthy subjects, as well as in certain diseases. Proceeding from literature data and from the results of previous studies, we undertook the task to study the ac t iv i ty of lipoprotein lipase using an improved method, as wel l as the effect of heparin on the level of blood su-gar and serum l ipids in patients w i th past history of myocardial infarction. Mater ia l and Method The heparin test was applied to 15 patients wi th past myocardial infarc-tion, sustained s ix months previously, and 17 healthy individuals — controls. The age of the patients ranged from 33—69 years or 54 years ave-rage, and 6f the healthy persons — from 20 to 56, or 36 years in the ave-rage. The test was conducted in the following fashion: in the morning before meal, 150 mg heparin were introduced v i a intravenous drip infusion of 500 ml physiologic saline over a 4-hour period. .Determination of blood sugar, serum lipids, endogenic heparin and lipoprotein lipase ac t iv i ty was per-formed just prior to and immediately after the infusion. Blood sugar was determined according to Haggedorn-Jensen, cholesterol — according to I lko , total l ip ids — Bragdon Bloor, phospholipids — according to Svan-berg—Svannerholm, beta-lipoproteins — after Burstein, non-esterified fatty acids — after Dancomb, endogenic heparin — after P ip ta and lipopro-tein-lipase ac t iv i ty — after Lukas ik . Unquestionable E C G evidence of myocardial infarction sustained in the past was established in al l patients. Results The results of the study show that in post-myocardial-infarction patients the content of cholesterol, total l ipids, phospholipids, triglycerides and beta-lipoproteins is s ta t is t ical ly significantly increased as compared to healthy subjects, whereas the content of endogenic heparin and lipopro-tein-lipase ac t iv i ty are lowered. No stat is t ical ly reliable difference is established between bldod sugar and non-esterified fatty acids' content. I n patients w i th a past history of myocardial infarction, the chole-sterol-phospholipids coefficient is s l ight ly higher (Table 1). Under the effect of heparin, a s tat is t ical ly reliable reduction of total l ipids, phospholipids end teta-lipcproteins, as well as an increase of non-Lipoprotein-Lipase Activity and Heparin Effect. 86 esterffied fatty acids and endogenic heparin take place in the post-infarction patients. The cholesterol-phospholipids coefficient remains practically unchanged. Changes in the blood sugar level are not observed in a l l the patients ; in four of them wi th obvious carbohydrate metabolism disorders, the blood T a b l e I Correlation between Blood Sugar, Serum Lipids, Lipoprotein-Lipase Activity and Endogenic Heparin in Patients with Past Myocardial Infarction and in Healthy Individuals With myocardial infarction n = 15 M ± T Healthy in­dividuals n = 17 M ± т . . t P Blood sugar in rag % Cholesterol in mg % Total lipids in mg % Phospholipids in rag % Triglycerides in rag % Beta-lipoproteins in F . E . Non-esterified fatty ac'ds in |iM/ml Lipoprotein-lipase activity in |iM/ml Heparin in U/ral Cholesterol/phospholipids coefficient 114±40 270±109 685 ±143 218±31 196 ±108 6 8 ± 1 8 0.62±0.17 1.73 ±0.54 7.50 ±2 .4 1.23±0 105±14 223 ± 3 7 568 ± 7 3 196 + 26 153±44 40±11 0.52 ±0.1 2,40 ±0.42 9 ±0.61 1.14±0 13 o.i 6.4 0.001 7.7 0.001 3 0.01 2.87 0.02 1.2 0.001 1.66 0.1 3.35 0.01 7.5 0.001 0.1 0.1 sugar shows an increase under the effect of heparin, but the difference proved to be stat is t ical ly unreliable (Table 2 ) . T a b l e 2 Effect of Heparin on the Level of Blood Sugar and Serum Lipids in Patients with a Past History of Myocardial Infarction n Pre-heparin value Post-heparin value * p Blood sugar in mg % Blood sugar in patients with disturbance in carbohydrate metabolism Cholesterol in mg % Total lipids in mg % Phospholipids in rag % Triglycerides in rag % Beta-lipoproteins in F . E. Non-esterified fatty acids in jxM/ml Lipoprotein-lipase activity in u-M/ml Heparin in U/ml Cholesterol/phospholipids coefficient 15 4 15 15 15 15 15 15 15 15 ' 15 114±40 161 ± 4 7 270 ±109 683 ±143 218±34 196 ±108 68 ± 1 8 0.62 ±0.17 7.5 ±2.4 1.23±0 114 + 34 148±52 262 ± 5 5 628 ±122 205 ± 3 4 168 ±106 47 ± 2 5 0.82 + 02 1.73±0.54 8.6 ±2 .2 1.27±0 0.15 1.46 0 55 4.5 3 2 7 6.6 5 0.1 0.1 O.i 0.1 0.001 0.01 0.05 0.001 0.001 0.001 0.1 1 4 86 G. Varbanov In the patients wi th and without hypertension under review, heparin exerts a moderate, regular reduction of the blood pressure. Discuss ion The lipoproteinMipase ac t iv i ty in atherosclerosis, respectively in patients w i t h myocardial infacrtion in the past history, is reduced (12, 27). Th i s is confirmed by our study too. Some authors relate the fa l l of lipoprotein-lipase ac t iv i ty to the enhanced ac t iv i ty of its inhibitors (15). Nevertheless, emphasis is being laid on the close correlation between disturbed synthesis, or reduced secretion of endogenic heparin in post-myocardial-irifarction patients, and the lowered lipoprotein-lipase ac t iv i ty . The lower lipoprotein-lipase ac t iv i ty and endogenic heparin content observed corroborates, although indirect ly, the close relationship exist ing between them (Table 1). The intense l ipolysis caused by heparin, introduced from outside (see Table 2) , is no doubt due to the enhanced lipoprotein-lipase ac t iv i ty un-der the influence of heparin. Th i s gives us sufficient reason to accept the lowering of lipoprotein-lipase ac t iv i ty as more probable than the enhance-ment of its inhibitors ' ac t iv i ty . I n compliance wi th the data submitted by Lobova and co-authors (10) and False t t i (cited by 10), it was established that in patients wi th past myocardial infarction, the content of cholesterol is augmented most fre-quently and to the highest degree (see Table 1). Despite conflicting lite-rature reports on the issue, we support \he views of the authors accept-ing that hypercholesterolemia has an essential bearing on atherogenesis. Para l le l to hypercholesterolemia, the content of total l ipids, beta-li-poproteins in particular, is also increased. Their elevated level in post-myocardial-irifarction patients is recognized practically by a l l the authors, and some of them attribute to lipoproteins a primary role in the pathoge-nesis of atherosclerosis. Phospholipids, although to a lesser degree, s imi la r ly display an increase of their content inpatients wi th past myocardial infarction, as compared wi th heal thy individuals . Moreover, the cholesterol/phospholipids coefficient i s also elevated in patients wi th a past history of myocardial infarction (3) , diabetes mellitus (3) and myxedema (4) , whereas in thyrotoxicosis th is indicator shows a slight decrease. The elevated values of the choleste-rol/phospholipids coefficient corroborate the idea already postulated above about the unquestionable role played by hypercholesterolemia in athero-genesis. The data concerning the significance of triglycerides in the pathogenesis of atherosclerosis are contradictory. According to the opinion of some au-thors (22), in myocardial infarction the disorders in triglyceride metabo-l i sm are more frequent, while according to Leopold and Wieland, Schrade and co-authors (cited by 11), the serum triglyceride content is higher than that of cholesterol. We found a rather insignificant rise of triglycerides as compared to cholesterol, and are therefore inclined to accept a constella-Lipoprotein-Lipase Activity and Heparin Effect. 8 7 tion between hypercholesterolemia and hyperlipemia in the pathogenesis of atherosclerosis. Many authors (25, 29) point out the important role* played by idiopathic hyperlipemia in the pathogenesis of myocardial i n -farction, s imilar to that played by idiopathic hypercholesterolemia. Recently a number of reports have been published in the literature deal-ing wi th the hypoglycemic effect of heparin in healthy persons (Wenke-et a l , cited by 8) , in diabetic patients (5), and in patients w i t h myo-cardial infarction in the past history and unsuspected even by them carbo-hydrate metabolism disorders (3) . We too observed a reduction of blood sugar, although stat ist ically unreliable, under the effect of heparin i n patients wi th myocardial infarction history, wi th manifest disorders i n carbohydrate metabolism. The mechanism through which heparin exerts its hypoglycemic effect remains unknown for the t ime being. T h e possibility of a direct hypoglycemic action is by no means ruled ou£, but anyway, the insulin route seems more probable. R E F E R E N C E S 1. A p T и M е H к o, Е. M. Сборник научн. работ, Рига, I I , 1961, 181 —185. — 2. Б о г о я в л е н с к и й , Б . Ф. Бюлл. морф, и физиол. Сборн., Благовещенск, I I I , 1962, 122. — 3. Б о з а д ж и е в а, Е., Г. В ъ р б а н о в , Л . Б е л ч е в . Вътр. бол., 6, 1965, 779—782. — 4. Б о з а д ж и е в а , Е., Г. В ъ р б а н о в . Год. труд, на ВМИ — Варна, V I , 1967, 3, 97—ЮЗ. — 5. Б о з а д ж и е в а , Е., Г. В ъ р б а н о в . Пробл. эндокр. и гормон., 4, 1966, 4S—48. — 6. Г а н е л и н а, И. Е., И. Н. К о м а р о в а , И. В. К р и в о р у ч е н к о , Б . М. Л и ц о -в е ц к и й. Обмен липидов и атеросклероз. М., 1965, 245. — 7. И л ь и н с к и й , Б . В. Клин, мед., 8, 1970, 29—33. — 8. К а з н а ч е е в , Б . П. Вопросы физиолог, и патолог, гепарина, Сборн. матер, от симпоз., Новосибирск, 1965, 113—145. — 9. Л е й т е с, Ф. Л . Успехи совр. биол., 59, 1965, 2, 226—245. — 1 . Л о б о в а H . М., М. В. Б а в и н а, Г. Г. А р а б и д з е. Тер. арх., 9, 1970, 72—75. — 11. М я с н и к о в , А. Л . Гипертон. бол. и атеросклер., М., 1965, 343—357. — 12. П а н ч е н к о, В. М., Г. Г. Б а з а з ь я н. Сов. мед., 11, 1965, 60—65. — 13. Р я з е н е в, В. В. Фармак. и токсикол., 4, 1963, 501—506. — 14. С т а р к, В. М. Кардиология, V I I , 1967, 6: 81—87. — 15. С т е п а н о в а, М. П. Кардио­логия, I I , 1962, 6, 82—86. - 16. B r a u n s t e i n e r , Н. , S. S a i l e r , F . S a n d -h o f e r , R . D i P a o l i , F . G a b l e , A . J u n g . Wien Klin. Wschr., 77, 1965, 44/45, 859—862. — 17. В r a u n s t е i n е r, H . , S. S a i l e r , F . S a n d h о f е r. Med. Welt, 14, 1966, 685—689. — 18. В г о w n, D. F . Heart Dis., 54, 1961, 646. — 19. C a r l s o n , L . A. Acta med. scand., 167, 1960, 399—413. — 20. D a y t o n , S. , I . M. C h a p m a n , M. L . P е a г с e, G . I . P о p j a k. Ann. intern. Med., 72, 1970, 97—109. — 21. D o l e , V . P. , E . G о r d i s, E . L . R i е r m a n. New Engl. J. med., 1963, 269—686. — 22. H а у е s, D. , D. W. N e i l 1. Clin. Sci., 26, 1964, 185—192. — 23. M a r t t, J . M., W. E . C o n n o r . Arch, intern, med., 1961, 492. — 24. M i l l s , G . L . , T . A. W i l k i n s o n . Brit. Heart J., 28, 1966, 5, 638—645. — 25. Ney, Е. R . J. Atheroscler. Res., 6, 1966, 1, 18—25. — 26. О l i -v e r a , J . M. Amer. Heart J., 67, 1964, 177. — 27. R o b i n s o n , D. S. Advances in L ip id Research, vol . I , Academic Press, New York—London, 1963, 133. — 28. T r a n-i w e i n , H . , R . J u 1 i t z. Med. Klin., 62, 1967, 10, 364—369. 1 88 G- Varbanov ЛИПОПРОТЕИНЛИПАЗНАЯ АКТИВНОСТЬ И ЭФФЕКТ ГЕПАРИНА НА УРОВЕНЬ САХАРА В КРОВИ И СЫВОРОТОЧНЫЕ ЛИПИДЫ У БОЛЬНЫХ, ПЕРЕНЕСШИХ ИНФАРКТ МИОКАРДА Г. Вырбанов Р Е З Ю М Е Л и п о п р о т е и н л и п а з н а я активность и эффект гепарина на уровень са­хара в крови и липиды сыворотки крови исследованы у 15 больных , перенесших инфаркт миокарда, и у 17 клинически здоровых лиц. У б о л ь н ы х , перенесших инфаркт миокарда, в сравнении со здоровыми л и ц а м и статистически достоверно повышены содержание холестерина, количества общих липидсв, фосфолипидов, триглицеридов и бета-ли-попротеинов и понижено содержание эндогенного гепарина и липопро- ' т еинлипазной активности. Повышен т а к ж е коэффициент холестерин/фо-сфолипидов. П о д в л и я н и е м гепарина у больных, перенесших инфаркт миокарда наступает статистически достоверное снижение количества общих ли-пидов, фосфолипидов и бета-липопротеинов и повышение количества эндогенного гепарина и незстерифицированных жировых кислот $ крови . Уровень с а х а р а в крови практически не изменяется в общем у всех больных, перенесших инфаркт миокарда , а лишь у 4 из них, у которых существовало явное нарушение обмена углеводов, под влиянием гепа­рина уровень сахара в крови снизился . 

LIPOPROTEIN-LIPASE ACTIVITY AND HEPARIN EFFECT ON BLOOD SUGAR LEVEL AND SERUM LIPIDS IN POSTMYOCARDIAL-INFARCTION PATIENTS

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LIPOPROTEIN-LIPASE ACTIVITY AND HEPARIN EFFECT ON BLOOD SUGAR LEVEL AND SERUM LIPIDS IN POSTMYOCARDIAL-INFARCTION PATIENTS

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