Magnesium interrelationships in ischemic heart disease: a review
Mildred S. Seelig, M.D .• M.P.H. • and H. Alexander Heggtveit, M.D.
Magnesium ions are essential for the main followed by a rise . Dogs with myocardial tenance of the functional and structural integ· hypoxia secondary to hemorrhagic hypotension rity of the myocardium. Experimental mag had increased losses of myocardial Mg from 135 nesium deficiency induces cardiac necrosis and to 180 min after the bleeding (9). enhances susceptibility to cardiotoxic agents; Human material. Ventricular muscle of pa· magnesium administration is protective. Recent tients who died of myocardial infarcts. reported investigations indicate that cellular loss of by Iseri et al. (I 0), Meister and Schumann (II), magnesium may be a basic biochemical mecha Raab ( 12, 13) and Heggtveit et al. ( 14 ), had nism in the evolution of myocardial lesions of significantly lower magnesium content, particu diverse etiology. Other studies have shown that larly of the infarcted portion of the heart, as magnesium depletion influences coronary flow, compared with magnesium levels in nonin blood clotting, and atherogenesis. This paper farcted segments, and in hearts of patients who surveys the cardiovascular role of magnesium as died of other causes (Table 2). In the study of it relates to certain facets of ischemic heart Heggtveit et al. (14), hearts obtained at autopsy disease. within 2 hr of death were examined grossly and microscopically. Mg was assayed in samples of Loss ofmyocardial magnesium from ischemic left ventricular muscle by atomic absorption hearts; anoxic hearts spectrophotometry. The mean myocardial Mg Laboratory models. Magnesium loss from the content of normal hearts from sudden trau myocardium is one of the earliest changes matic deaths was 85.44 mEq/kg dry weight. found in several cardiomyopathic animal Acutely infarcted heart muscle showed a 42% models (1. 2), including production of cardiac average decrease in Mg content. whereas the hypoxia by coronary ligation, by asphyxia, or noninfarcted areas of .the same hearts showed a by hemorrhagic hypotension (Table 1). The 19% decrease. Thi~ latter diminution was time lag after induction of hypoxia influences comparable to that ' found in cases of sudden the degree of magnesium loss from the myo coronary death without detectable infarction. cardial muscle. Cummings (3) and Cummings Skeletal muscle Mg levels did not differ and Clark (4) first demonstrat~d loss of significantly between the control and coronary myocardial Mg (by II hr after a two-stage groups. Laurendeau and DuRuisseau (IS) re- coronary ligation). Rigo et al. (5) found less loss of myocardial Mg in hearts analyzed 6 days 1 Physician in Charge, Nutrition Metabolism, Gold· after coronary ligation . Jennings (6) and water Memorial Hospital, New York University Med ical Center, New York, N.Y. 10017; Adjunct Associate Jennings and Shen {7) found that 40 min after Professor of Pharmacology, New York Medical Col temporary ligation there was almost one-third lege; and Research Assoc4te, Pediatrics, Maimonides loss of myocardial Mg. which is not seen in Medical Center, Brooklyn, N.Y. 'Professor of Pa hearts of dogs 1 hr after permanent ligation. thology. University of OJJawa, and Pathologist, Ot· Hochrein and co-workers' {8) study of hearts tawa General Hospital. ~Ottawa, Ontario, Canada. Supported in part by g ~f'lts from the Ontario Heart from guinea pigs in anoxic chambers demon Foundation and by a grant from Mr. Julius Silver of strated an early drop in magnesium that was New York. N.Y.
S9 Tht Amtrican Journal of Clinical Nutrition 27: JANUARY 1974. pp. S9-79. Printed in U.S.A. 60 SEELIG AND HEGGTVEIT
TABLE LosJ of myocardial magne~ium in cardiac hypoxia (laboratory modeb)
Myocardial magnesium
Coronary ligation !dogs) Afler ligation Cummings and Clark 14) 8-11 hr Infarcted tissue: 30% I tv~ noninfarctedl Cummings (3) 8-11 hr Infarcted ventricle: 49':1> I } (vs ~ham~perated Noninfarcted ventricle: 7'J I heart)
Rigo et 011. (5) 6 days Necrotic area : 1 21 <;; } 1vs intact area) Perinecrotic area: 9~ I
Jennings (6); JeMings 40min, 29~ I (vs control heart) and Shen (7) then reflow 60 min I r: 1 (vs control heart)
Asphyxia (guinea pi&s) Duration. min Hochrein et al. (8) 0.5 I5 <;; 1 vs control 1.0-1.5 31 <;; ~ vs control 2.0 3 3':t 1 vs control 2.5-4.0 34'/r I VS COntrol 8.0 30% 1 vs control 10.0 25<:& 1 vs control 10.5 7':0 I vs control
Hemorrhagic hypotension After bleedina Right ventricle Left ventricle (dogs) Canepa et al. (9) 135 min 8% 1 vs control 14% 1 vs control 180 min 21% l vs control 29% I vs control
TABLE 2 ported that the hearts of 6 of 12 patients who Loss of myocardial magnesium in cardiac died with foci of myocardial necrosis, but not ischemia (human) necessarily with evidence of coronary thrombo· sis. had lowered levels of cardiac magnesium. Percentaae decrease in myo cardial maanesium !from control, This was most marked in diabetics with noninfarcted hearts: autopsy} cardiomyopathy. A patient who died of carbon monoxide poisoning also showed substantial Myocardial infarcts % reduction in myocardial Mg (IS, 16). How Jseri et al. (10) Infarcted segment 42 ~ quickly such a loss of myocardial magnesium Noninfarcted segment 33 ~ can occur is indicated by the findings of Singh Meister and Infarcted heart 19 ~ et al. (17). They biopsied human hearts Schumann (I I) subjected to anoxic arrest for varying periods of time during cardiac surgery and found losses of Raab and Kimura Noninf:ucted segment 32 l (12, 13) myocardial magnesium ranging from 2 to 19%.
Hegatveit et at. Infarcted segment 42 I Changes in plasma magnesium ajier (14) Noninfarcted segment 19 I myocardial infarction Carbon monoxide Patients wi th myocardial infarcts who were poisonins admitted to a hospital have been reported to Laurendeau and have lowered serum magnesium levels by three DuRuisseau (15) 23 I DuRuisseau (16) groups of investigators (18-20) and to have levels not significantly different from controls Induced cardiac arrest in surgery by two (21. 22). Hollmeier ( 18) and Hughes and Tonks (19) took blood from acute myocar· Cardiac surgery dial infarct patients shortly after admission to Singh et al. ( 17) Myocardial biopsy 2-19 I the hospital and reported significantly lower MAGNESIUM II'ITERRELATIONSHIPS IN HEART DISEASE 61
than control levels of plasma Mg. Nath and have been derived from tissue stores. This is co-workers (20) reported low Mg levels the I st suggested also by the lower myocardial Mg in week after infarction that fell further the 2nd dogs with hemorrhagic hypotension (9). week. Brown et al. (21) and Hyatt et at. (22) who reported no such decreases did not specify Protection against anoxia; ischemia when in the course of the hospitalization for by magnesium infarction the blood samples had been drawn. That these differences may be due to differ· Laboratory models. There is laboratory evi ences in time of testing after the ischemic dence that magnesium salts protect against event, as suggested by Lossnitzer (23 ), is hypoxic damage to the heart (Tables 3A- C). supported by experimental findings. Nath et al. Harris et al. (26) first demonstrated that either (20) reported that I hr after experimental the sulfate or chloride of magnesium, given myocardial infarction in dogs, serum Mg levels in !ravenously at a dosage of I mEq/liter dropped markedly. Blood drawn 24 and 48 hr suppressed the tachycardia and ectopic rhythm after the infarction had normal levels of serum that had been caused by coronary ligation in 46 Mg. Clark and associates (24) and Cummings and 70% of the test dogs, respectively (Table (3) drew blood 8 to II hr after coronary 3A). Clark and Cummings (27) found that each ligation, at the time the ectopic rhythm was of three successive infusions of MgS04 cor established (and when magnesium was leaving rected the multifocal ventricular tachycardia the heart) and found elevated plasma Mg. The caused by coronary ligation (B . B. Clark and elevations in serum Mg after repeated bleeding J. R. Cummings, personal communication). of rats, withdrawing up to 40% of total blood Carden and Steinhaus (28) then reported that as reported by Goldsmith et al. (25) may well Locke-Ringer solution lacking magnesium ex-
TABLE JA" Protection against structural and functional damage of cardiac hypoxia by magnesium salts (laboratory models)
Model and reference Magnesium salts
DO(IIS Harris et al. (26) 0 Duration of suppression of the ectopic M~~ • f I mEq/liter, iv rate to 'h control rate. M Cl diluted to 20 cc, iv : g 1 MgSo 4 successful in S of II dogs (46%); MgCI, : successful in 9 of 13 dogs (70%) Dogs
Cummings (personal MgS04 : 100 mg/kg in 20 ml Conversion of ventricular communication) H,O, iv tachyc:ardia to sinus rhythm
Dogs Carden and Steinhaus Locke-Ringer solutionb 1 (28) Mg (0.05 mEq) } Protection against ventriculaa Mg (2.00 mEq) librillation MJ (0.05 mEq) in 0.9% NaOJ No protectionb Mg 12.00 mEq) in 0.9% NaCI t Fibrillation" Locke-Ringer solutionb Mg 10.05 mEq) in S?h dextrose"
Rabbits Weber et :al. (30) MJ + K aspartate iv (:alone Protection against ECG changes and in combination)
Rats Bajusz and Selye (29) Mg or K chloride, oral Protection against cardiac necrosis prct reatment for 5 days (autopsy 14 days after ligation) pre ligation
"Coronary ligation. b Ringer's solution without Mg. c Two milliequivalents Mg in 5% dextrose. 62 SEELIG AND HEGGTVEIT
erted no effect on the ventricular fibrillation constant pressure) through the coronary ar ~:aused by coronary ligation. whereas the same teries of hearts being perfused with the bal solution, to which either 0.05 mEq or 2.0 mEq anced perfusion fluid (containing Mg and KCI). of Mg was added, exerted a protective effect. Rosen and associates (35) showed that when The same concentrations of Mg in 0 .9% NaCI Mg and K aspartates were substituted for the were similarly protective, as was 0.05% in 5% chlorides. there were much greater rates of flow dextrose. (The larger concentration of Mg in through the coronaries, whether the perfusion the dextrose solution. however. actually in fluid was anoxic or normally oxygenated . creased fibrillation .) Bajusz and Selye {29) Possibly this was a retlection of the greater reported that oral administration of MgCI 2 or systolic amplitude of the hearts perfused with KCI for 5 days before ..:oronary ligation fluids containing the aspartates (Fig. 1). protected rats against cardiac necrosis. Protec The foregoing studies reported protection by tion by Mg and K aspartates against hypoxia the magnesium salts (with and without potas induced electrocardiographic changes has been sium) that do not seem to be predominantly a demonstrated by Weber et al. (30) in rabbits function of a substantial effect on coronary with ligated coronary arteries. blood flow. This is not to negate the known Lamarche et al. (31-33) found that iv Mg coronary dilation produced by even relatively and K aspartates, but not the ..:hloride salts, low concentration of MgCI2 {37 . 3R). The protected against ECG changes of anoxia in demonstration by Scott et al. (39) of the effect guinea pigs (Table 38). Hochrein and Lossnitzer on ..:oronary arterial resistance exerted by slight (34) tested only the aspartates in guinea pigs ionic changes of the blood (within normal exposed to asphyxia and found that Mg and K limits) shows that such increases in plasma ~ 2 aspartates, in combination, doubled the cardiac or Mg • actively dilate the coronary vascular tolerance of anoxia. They found that the bed. A comparable study with hearts subjected magnesium salt alone exerted a lesser degree of to coronary ligation should provide valuable protection; the potassium salt alone was inef clarification of some of the dynamics by which fective. the magnesium salts protected against ischemic Studies with isolated he:lrls of rats. rabbits. damage in the experimental models just dis and guinea pigs exposed to anoxic conditions cussed. Studies designed to demonstrate the have compared mixtures of Mg and K aspartate pharmacologic cardiac effects of hypermag with Mg and K chloride (Table 3C). The nesemia are not relevant. either to the cardiac aspartates exerted a greater protective effect protection laboratory studies or more particu- than the chlorides against the ECG changes and larly to the accumulating clinical data. · reduction in systolic amplitude caused by Clinical evidence. Epidemiologic findings. anoxia (31-33. 35 . 36). In these studies. the Kobayashi {40) t1rst demonstrated a relation immediate effect of anoxia was to increase the ship between vascular disease and the hardness rate of perfusion of the fluid (maintained under of drinking water. showing that the death rate
TABLE 3Ba
Model and reference Magnesium salts Parameter
Guinea p~s Lamarche et al. (31) ~lg + K aspartate, iv Protection at~ainst ECG Iaione and in combination) changes and again~t tachycardia Lamarche et al. (33) ~lg or KCI Not elfective
Guinea pigs Hochrein and Lossnitzer 134) ~lg + K aspartate Doubles cardiac tolerance of asphyxia (cardiac respiration) K aspartate No protection ~~~ aspartate Some protection (less than with combination) ~lg + K aspartate Decreases loss of myocardial K
0 In vivo hypoxia; asphyxi;!. ~-
Model and rcfcrencl.! Magnesium salts Parameter
Rats } Tnebslci and Mg + K aspartate ln~:rea sed ~:oronary flow (of perfusion Rabbits Lcwartowski (36) Mg + K chloride fluid)
Mg + K aspartate Increased resistance to anoxia: (but not chloride) I. 3-7 times less reduction of systolic amplitude 2. Protection agllinst ECG changes 3. Increased worktime
Guinea pigs L:amarche and Royer (31) Mg + K aspartate Negligible effect on coronary Lamarche and Tapin (32, 33) (0-aspartate not now L·aspartate) Protection against anoxia: I. Protection against ECG chang~!! 2. 35% prolongation of time to produce 75% reduction of systolic amplitude
Guinea pigs Rosen et al. (35) Ml! + K aspartate Increased resistance to anoxia { 1.0 mg/ml of Chenoweth {increased time for amplitude of heart solution) more effective than beat to decrease to SO% control) Mg + KCI at equivalent concentration
Mg + KCI Coronary llow increased over perfused nonanoxic heart
Mg + K aspartate Coron01ry flow increased in both nonanoxic and anoxic hearts
0 In vitro hypoxia; anoxia (isolated heart).
from apoplexy in Japan was higher in soft Alabama and South Carolina where the white water areas than where the water was hard. male versus total male coronary death rates are Schroeder (41 - 45) then correlated the death 433: 176 and 619:217/100,000, respectively, rates from hypertensive and arteriosclerotic and where the nonwhite population contribut heart disease in the states with the average ing to the total figures is predominantly black. hardness of drinking water3 and found an Phillips and Burch (46) analyzed the literature inverse correlation. This was particularly no in which the racial incidence of ischemic heart table for white men of 45 lo 64 years of age as disease was given and evaluated their own data; regards coronary heart disease death rates. The they also found a significantly greater incidence scatter graph (Fig. 2) shows that. with few of ischemic heart disease among white than exceptions, the states with the hardest drinking black men. Bersohn (47) and Bersohn and water had lower, and the states with the softest Oelofse (48) also commented on the much water had higher than average, death rates from greater susceptibility to ischemic heart disease ischemic heart disease. Further analysis of the of the African whites than the blacks and states with the hardest and softest water reveals considered the higher serum Mg of the blacks a the markedly greater susceptibility to fatal possibly significant factor. heart attacks of white men aged 45 to 64, as Figure 3 also demonstrates that the more compared with the total (age adjusted) male highly industrialized and more densely popu· population (Fig. 3). lated states tend to have higher coronary death It is possible that this substantial difference may be caused by a racial difference in ~Average hardness figures hide m01jor differences in susceptibility to this disease. This is suggested hardness of water in different areas, particularly in by the figures from such southern states as la~J!e states. SEELIG AND HEGGTVEJT
~~Les than do the rural states. Comparison uf magnesium . there has been more attention paid d.e-.lth rates in three cities with hard. average. to the possibility that it is calcium that is the QDd soft water. illustrates strikingly the intlu protective "water factor" (50. 51, 53, 55 . 5R, ~-oce of the "water protective factor'' in the 59). Those who have had favorable experience high risk group (Fig. 4 ). in the treatment of ischem ic heart disease with There has since been corroboration that the magnesium salts consider the hard water protec \,' Bolo- SaN. (c-lot ... •ICC! I ness and by the calcium and magnesium • .• ,; ... ••a•-+ K .-_roote SuMt.- components. His mathematical c.:omputatior• . • • ...... I( ...,.,.. ••• ~ suggest that the protective effect of hard water ··· • • . Mtottc AcWI....., ~ is due to the magnesium component. In terms of percentage variation in death rates. he found that magnesium was more effective than total hardness, which in turn was more effective th:Jn calcium in favorably inlluencing the rate of sudden deaths from ischemi..: heart disease (Fig. "< 6 ). Allen's ( 49) decision to separate coroner , ~ • c . r certitled c.:oronary deaths from total cardio . ..~ vascular deaths. which revealed magnesium to 0 be the most significant factor. was based on the PERIOD 01' ANOXIA observations of Crawford and Crawford (54) FIG. I. Protection against anoxia by magnesium and of Anderson et al. (50). These investigators citd potassium aspartate solution (isolated guinea pig (50, 54) had observed that the incidence of ~~ in Chenoweth (modified Locke-Ringer solution; J.. Lab. Cl.in . Med. 31 : 600, 1946)). Adapted irom sudden death from ischemic heart disease is ()5). notably higher in soft than in hard water areas. 300 AYDIAIG(I • t.Ow OfNSITY I'OI'IA.AT!Otll<751-l • A HIGH OOOSIT'r I'CPUI.AT!Otl 1>1501$0.MII I : ~~~~:T!Otl 175•1501"1 .. 1 I • • •I I • • I • I • •• I • J • I • 120 • •• • I • • 100 ------+----e e • ~ ------MolfRAG( 80 • I • • tt• •• • •I • • • • • • 20 • I • • ' • I • • 0 lOO 360 leo 420 410 500 S40 ~ 620 MD 700 AVDUIG£ c;(R)NARY ~€ART OIS[AS( O£Ant RAT[/100,000 WHIT[ liE" AGED 45·64 . FIG. 2. Correlation of coronary heart disease death rates (1950) of white: mc:n 45 10 64 years ol age with JtVdness of water by states in the United Stales. Adapted from (41). MAGNESIUM INTERRELATIONSIIIJ>S IN HEART DISEASE 65 extensive siUtl y dearly con firmed Ihe condu· Ml sions of Am.lerson e1 :.11. (50). 1------rr Ill(~ Anderson and his as ..;od:~les (50) suggesled IUS I thai there is something in hanl water thut specifically protects ag:tinsl fatal c:adiac ar· rhythmia arising shortly after a myocardial infarction . Bajus:l (67) had earlier called atten· I tion to the possi bilily lhal it might be the I AYG - - --L- • - . -- --ror.o&. magnesium in hare.! water thai protel.'ls the 111(10 fUSI myocardial cell against the insull ..:auscd by ischemia. as WL'II as improving its ability to re sisl polentially ..::m..li•ll•>xk agenls. When he first nutcd rhc relarronship between w:~ter i ~ v v hardness and cardiova s~:ubr mortality. S~:hroe I o so 010. ..,. ,_, - ...... co-.-c .., ~- dcr (43. 44) puinll:d l)Ut that in ..:ities with OAA MO: WI& C.AIIIO - 1W 14? Uf Uf tr U II II II U higher and lower coronary heart disease death =~':, .,la..o- 1..o- U. ..,.,.. HOt MIOM LOW LOW L.o. 1 rates for 45- to 64-ye:~r-old white men . the FIG. 3. Deaths from ischemic heart dis.:asc of white men aJed 4S to 64 yean versus total popul:llion of tO 100 1110 100 uo men (;age~orrected) by states and with hard versus soft water. Adapted from (41 ). 1 I I I I JU JIIO Jft 400 418 CMIIOIIICI' M IICAntl I'CII 100,000~'1"1011 FIG. 5. Correlation of cardiovasc ular dealhs wirh total hardm:ss of wafer and daily intake of magnesium. Data on tolal hardness of drinking water from (64a and 64bl. Adapted from t65). q II -TOTM.-IS IZ c:::::l C.tLCll.* ~~ 10 rz21-IIUM 4. Deaths from ischemic heart disease of while FIG ;: '!! t men ~ ~ed 45 to 64 years in cities with hardest. a average, and softest water. Adapted from (41 ). '! • &e: .....1' The rates of sudden coronarv J~aths were Si~~ ri derived from death reports in coroner~ertified r~ -' toOT Ont:aio by Anderson et aL (50) as likely to .. , CMT have been caused by rapidly fatal arrhythmias. --·· ol • ;yJ • ..: vJ •VA • ·u • .. ..,, Peterson et al. (57) wnllnned these lintlings in MAL[ 'f-.l -u """'-' _, fDIA&.l 4S-14 _, _,... 61•14 the state of Washington. Neri et al. (66), however. evaluated the data from Ontario FIG. 6 . Percentage of the total variations in death differently. Allen (49) has resuh·ed the contlil.:l rates (.:orom:r-certified d~ath s from <'Oronary heart in interpretations by pointing out that Neri et d'iseas.:) from ischemic heart di,casc as inllm:nced by at. (66) had examined only the percentage of water hardnc~s . lhL' l~tkium L'o mpnnl'nl. and the magnesium .:omponl'nr: highlr signifil.:ant variations. cardiovascular deaths that were curoner~erti Adapted from H. A . J. Alh:n d octoral dissertation, fied . r:llher than the a~:tual death rates. His own 1'17:!t4'1). 66 SEELIG AND HEGGTVEIT magnesium content of the water was 4 : 16 , TABLE 4 respectively . He and his t.:o-workers (6R) later Magnesium deliciency sensitizes to conduded, on the basis of their own extensive cardiopathic diet~ . drugs , stre~ analyses as well as from indirect evidence (69 ), Diets that a good argument could be made for the Vitamin D, existence of magnesium defkiency in the Atherogenic { Saturated fat; Thiouracil diet United States. They accepted as likely that lCalcium load diets high in calories and low in magnesium Saturated fat. cholesterol are atherogenic. They questioned. however. Jnfarctoid High protein whether the amount of magnesium provided by Vitamins D , D, diet 1 hard water is sufficient to serve as the only { High in Ca. Na, 1'04 protective factor against deaths from cardio Low in Mg . K, Cl vascular dise ase . Goldsmith (70) and Hankin Stress: isolation and Goldsmith and Margen (71) have calculated Go:nctic susceptibility : cardiomyopathy that 12% of the daily Mg intake is derived from Drugs Mineraloco rticoid + P0 water. Among those using hard water only. as 4 Vitamin D1 ; dihydrotachysterol much as 18% of the Mg intake was from water Digitalis !arrhythmia) (70). an amount that may well be critical. Epinephrine; isoproterenol The findings of Crawford and Crawford (54) that men under 40, who were living in a soft water area and who had died in accidents, had Magnesium, /lOt calcium, as protective factor lower coronary magnesium levels and greater The question as to what it is in hard water evidence of prior myocardial disease than did that affords protection against both the devel comparable men from a hard water area (Fig. 7) opment of coronary arteriosclerosis and lhe support the contention that lower magnesium sudden death following an infarction is still levels are related to dinical ischemic heart controversial. The only definitive experimental disease. The higher coronary magnesi um levels study of the effect of calcium and magnesium in the older age groups were postulated by the in drinking water (on development of athero authors to have been caused by deposition of sclerosis) is that reported by Neal and Neal mineral deposits (Mg as well as Ca) in estab (7:!). They found that rabbits on atherogenic lished coronary lesions. That life-long exposure diets that were given hard water to drink had to soft water is not necessary for higher death less arterial damage than did those given rates to be manifest is indil.:ated by the evidence distilled water. Addition to the distilled water that softening previously hard water resulted in of magnesium but not calcium completely significantly elevated death rates from cardio protected against arteriosclerosis.4 vascular diseases from those in the community The preponderance of direct and indirect before the hard drinking water had been evidence also favors magnesium as the myocar softened (52. 58. 59). dial protective factor. Firstly, magnesium dell cit is known to cause funt.:tional and structural cardiovascular damage. including early mito u chondrial and san:osomal dumage (73 - 78) and -~s'!s.;: frank myocardial nenosis and calcitlcul ion (75, 76, 79-9H). Secondly. Mg deficiency sensitizes rzzJ=-· animals to myocardial necrosis produced in a number of laboratory models (Table 4), includ ing those of dietary imbalances, stress, and drugs (85, R7 - 89 ). and accelerates the develop ment o r cardiac necrosis in hamsters genetically predisposed to cardiomyopathy (98). Further < l l · l . t 4· S ' •·t.t <2 2· J .t 4·i.t •·t.t 10. more . magnesiu m delkiency increases suscepti- -SlUM ... I'll 100, on MIGIITI FIG. 7. Coronary magnc~ium in accident ~:ases of men under 60 years of ag.: in Glasgow and London. 4 lnfra vide . for further discussion of magnesium, Repr inted with permission of the publisher (54). atherogenic diets and serum lipids. MAGNESIUM INTERRELATIONSBIPS IN HEART DISEASE 67 bility to digitalis toxicity (23. 99-104), as uptake and greatly diminish the st ructural hypomagnesemia has been reported in patients damage (13X. 140). with digitalis toxicity (99, 100. 105). and The thesis of Covino and Hegnauer (I 41) magnesium is useful in counteracting digitalis further negates cakium as a protective factor. induced arrhythmias (100, 102, 106-1 10) and They suggested that small increases in intra has protected against the cardiac necroses of cellular Ca 2• :~re :~ssociated with :~ugmentation the above experimental models (85. 86. 90. 96, of cellular excitability. thereby contributing to 9!L I I 1-121 ). the development of ventricular :~rrh ythmia . Calcium administr TABLE 5 C"aldum/magnesium myocardial shift by cardiac necrosis-inducing do~es of adrenergic catecholamine~4 Hearl electrolytes, mg/kg Calcium Ma!!nesium Hours after injection Injection Control 3 6-7 24 Control 3 6-7 24 Isoproterenol 2.8 3.8 4.8 4.3 19.2 17.0 16.3 15 .6 Phenylephrine 1.7 2.5 3.3 10.4 19 .9 18 .7 17.8 17 .3 Epinephrine 1.7 2.1 4.5 9.1 19.9 18.7 18.5 16 .5 0 Adapted from lchr et al. tl 34 . 136. 13 7 ). 68 SEELIG AND lfEGGTVEIT a L:oro n<~ry vasodil<~tor dfeL:t. Elek and Katz co-workers ( 155. 156) have reported remark· ( 147) reL:ommended its use in I ~41 in ably good result s with MgS04 in the treatmeti'C: paroxysmal tachyc<~rdias associated with myo of patients during an acute allack of corona~·. L:ardial ischemia. They ~ommented that this use thrombosis. They reported a low death rare oT would be particularly appropri<~te beL:ause Mg I in 64 in their patients with myoca rdial infa r~i;:!> diminishes L:ardiac ischemia. whid1 it self tends so treated. Fur a~ute myocardial infarction. ir. to establish and maintain ectopk rhythms. addition to the usual supportive therapy. rhe7 Referring to the use of iv MgCI 2 by Seekles et generally inje~:t ~1gS0 4 iv or im (0 .5 ml of SO"'?: al. in 1930 ( 148) to prevent cardiat.: ar solution) immediately. 12 to 24 hr later. anci rhythmias evoked by CaCI1 (treatment of cows then I ml im the next day and every 2 to f' with milk fever or grass staggers. which was days thereafter until discharge. They maintatl\ shown soon after to be a Mg-deficiency patients convalescing from an infarct and thos~ syndrome (83. 149)). Boyd and Sdlerf(l50) with chronic angina pectoris by injecting eithet' contlrmed the effiL:acy of MgS0 4 therapy of 0.5 ml of the MgS0 4 im solution at 7-day paroxysmal tachycardia. Szekely ( 151) pointed intervals over an indetlnite period or larg€ r out that patients whose arrhythmias responded doses, given mure frequently in intermitter.! best to magnesium usually had advanced heart courses ( 154 ). Parsons et al. ( 159) reponed disease with congestive heart failure. Nonethe only I death in 33 cases of in farc.:tion. Perli <{ less. the use of magnesium in ischemic heart (162). in 1956. and more recently Savenkd disease has been slow to gain ac..:eptance. and associates ( 163) also reported strikin5 particularly in North America. Favorable results subjective imprO\·ement in over 9W and 79~ have been reported from the Southern Hemi of their coronary patients in response to r~ sphere (64. 152 - 161 ). from both Eastern (121. MgS04 ( 16~) or to parenteral and oral use C"j 162. 163) and Western Europe (23 . 31 . 106. magnesium adipinate and nicotinate (163). 164-177). and in Great Britain ( 1~. 63. The use of magnesium and potassium a$ 178 - 1XJ) . The reports have been predomi part ate. other organil: salt. or chloride alone, o( nantly based on noncontrolled dini~.:al trials of as part of a "pularizing solution" (containi~ the use of several magnesium preparations. glu..:ose and insulin) has been reported by man)'_ sometimes in association with other agents such German and French investigators to hav<-" as heparin ( 154. 159) and hyaluronidase ( 177) improved signilkantly the chances of surviyc~.J that complicate interpretation of results. of vic.:tims of acure myocardial infarction (lOt The llrst su..:h report (in 1952) was that of 165, 168 - 17~)- Prompt iv administration# HotTman and Siegel from Gennany ( 184 ). who Mg and K aspartate solution repeated daily ( ;1 reported exceUent results in tenns of reduced doses as high as 4 to 5 g/day during the r•1' incidence of anginal attacks during treatment of week of hospitalization. with substitutio'rl their coronary angina patients with an oral thereafter of oral treatment) has been reportti preparation of magnesium nicotinate <~nd thio by Nieper and Blumberger (I T2) to ha~ sulfate. Malkiei-Shapiro ( 154) and he and his relieved post infarction pain and to h~e markedly improved the rate of survival. .-\1.!)0 reported is the long-tenn efficac.:y of oral ~ : •«»r .., and K aspartates in patients with duon~ . I ,.-.---..____ - 22!!. ischemic.: heart disease . either after an acui: 1 ...- x·.- • ...... c.a. ·~ infarction or in patien ts with histories(/;' I ~· ~ · ·~·-----·-·--·-.. Noel II ~oronary insufficiency (164. 170 - 173) . lont~ ~ I •...... _ phoretic use of ~1g2 • and K + has also bds-'"1\ ~ described as helpful in the treatment of cardie.te ., "' ischemia (lho. 167). Thurnherr and Koch (lh\ reported that ~0~£. of 156 patients wi~ ltCI 10 coronary insutliciency responded both sutl §~-r~- TO .._·--·-····,····-··•I I - ~-I o o.a 1.0 1. 1 a.o a.s .. l•"'a.o. ••,,. ,.,,.. jectively (pain) and objectively (exerdse tot~ COl' ttcm:lffC IOUITfOIIII t anc.:e) to injection with a combination 6f 2 magnesium levulinate and hyaluronidase. The FIG. 8. lnlluencc of ~11! \ K', Na• and Ca>+ or; ..:oronary rcsiswm:e of in , jt-u dol! hearts at blood flow study was .:ontrulled and injections of phys-,·b_. rates of 96 to 100 mt/min. Adapt-ed from (39). lugi..:a l saline served <~S the placebo. MAGNESIUM INTERRELATIONSHIPS IN HEART DISEASE 69 .llecltanisms vf magnesium elf<'cts i11 terol. There has not been agreement. however. isdremic heart disease. that magnesium delkien~:y (as expressed by low plasma Mg levels) is ne~:cssari l y ~:o rrel:lled with Blvud lipids. A commonly c.:ited expl:lnation lipemia in ~::~ rdi o vas~:uhJr disease patients (~I . for the clinical efficacy of magnesium rel:~tes to ~2. 185-187). Some in sight into discrep:~ n cies its effect on the blood. Clinici:~ns from the in clinical results c.:an he obtained from :~nimal British Commonwealth (64, 154- 158. 161) studies (T;~bl es 6. 7). Depending on the nature and Russia ( 163) have reported th:~t magnesium of the fat given and the degree of the Mg therapy of patients wi lh is~:hemic heart disease defidency. the serum cholesterol rose. was is associated with decreased tl·lipoproteins. un~:hanged. or showed an in~:rease in esterifica increased a-lipoproteins. :~nd increased lecithin/ tion ( 103. 122. 132. lXX) . Correction of the ..:holesterol ratio, or a drop in serum c.: holes- magnesium deficit has protec.:ted ag:~inst cardio· TABLE 6 Effect of high :md low satur~ted ~nd uns~tur:~ted fat int:Jkcs :~nd of magnl!sium on serum lipids in rats0 Serum Serum Serum lipoproteins m~gnesium, cholesterol. mg/100 ml mg/ 100 ml Alpha Beta Un· Un· Un· Un· Satu- sa ru- Satu· satu· Satu· satu· Satll· satu· D iet~ry f~t 11 rated rated rated rated rated rated rated rated ·------Low fat in take. S% Low maa~nesiu m 1.011 I.:!S lOS I 27 9 .7 6.9 11.7 8 .8 Moderate magnesium 2.21 2.03 99 1311 8.S 10.0 IO .J 10.6 High magnesium 2.56 1.91 83 )]6 4. 1 7 .3 4 .8 7 .7 High fat intake, 20% Low magnesium 1.51 0 .96 I IS liS IS .9 8 . 1 I 1.8 8.S Moderate maa~n e~ium 1.89 1.99 113 123 16.J 6 .9 12.6 S.4 High maa~nesiu m 2.09 1.9S 97 102 7.7 4.0 6 .J 4.11 0 Adapted from (189). Low m~gnesium = 24 mg/ 100 ml: moderate magnesium= 96 mg/100 m l; hi!,!h ma~nesiu m • 192 mg/100 mt. Dietary fa t : saturated: hydrogenated ~:o11on seed oil: unsaturated : corn oil. TA BLE 7 Lipids in experimental magnesium deficiency in dogs Mg intake Fat intake Refl!rence •J.08% of diet Butter fat t Percent esterified cholestero l Kruse et al. 1 I !l!H (8% of diet) • Fa lly acids No change in total serum lipids Corn oil No change in b lood cholesterol Vitale et al. (103) (9% of diet) '!Oppm j Aortic lesions Bunce et al. 1 I 22) Animal fat 1 I Serum o.: holcstcrol 1110 ppm (:!0'·; of diet) j No aortic lesions 1 t Serum cholesterol ·1 Animal fat Card iopa thogenic Sos et al. (I J I - 131) 1 Also free of K. high in t Serum cholesterol vitamin D: Ca. PO •• protem) 70 SEELIG AND HEGGTVEIT v:~scular lesions of several species of :~nim:~ls on 4.5 g/d:~y) further dcmonslrates the inlerrela :11herogeni~.: Mg-deficient c.liets without :1 con tion between depression of Mg :Jnd increased sistent c:ffect on serum lipids (7~ . 104. ln. tendency tmv:~rd thrombosis. Th:~l the eslro 121:!, 11:!9-193). Except for :1 series of studies gen-induced hypercoagul:.~bility of the blood tlwt showed Mg suppl!!ment:Jtion to lower m:~y also be mediated in pari by llecre:~sed serum cholesterol of milk-fed rats ( 194- llJ6l. serum Mg h:~s been suggested by Goldsmith et and :~nother that showed no effect on either al. (25. 20o-209). They have shown that cardiovas~.:ui:Jr or serum lipids uf r:Jbhits on estrogen or:JI ~ontracept ives lower serum mag :Jtherogenic diets (197). :Jdministratiun of mag nesium levels both in women {206, 207. 209) nesium ..:hanged the distribution of lipid com and in rats ( 25 . 206. ~OH ). ponents somewhat or even raisec.l the levds (1::!. The antagonism of magnesium for calcium 104. 12R, 189. 193). Nakamur:J et al. (100) for dotting f:~~· rors (210). even al concentra found that for a notable dfect on :~ortk tions produced :~fter om I :Jdministration ( 182). deposition of lipic.ls :Jnc.l serum lipic.l s. sub st:lll has bc:en cunstc.lc:red :~nother explanalion of irs ti:~l and long-term Mg supplement:~t i on is :Jntico:~gubnt :~ctivity (171L 182. 210.21 1). A nece s s:~ry. single oral dose has produced a delay iu Fibrino~l·sis/cuagu/arion. The! effic:~cy of thrombin generarion. lasting for up to 6 hr. in magnesium in ischemic he:1r1 dise:1se has been patients with ischemil..' hear! disease (178. 182). :Jllributed to irs anlithrombotic :.~~.:tivity . both Stevenson and Yoc.ler (212) have recently enhancement of fibrinolysis and inhibition of shown that \1g deficiency in calves and rals coagul:11ion being consiJereJ :.ts meJi:tling !..'a used sJwrtenc:J partial lhromboplastin time mechanisms. Sub s t:Jnti:~lly in..:re:lsec.l libnno and thrombm dotting tun!! but tH> signillcant lytk :~ctivtty of the blood of c:.~rdi:.tc isd1emia l..'hanges in platekt aggregarion or prolhrombin p:Jtients on Mg lherapy has been reported by time. Szelenyi el al. (213 . 214) demonstraled Parsons et al. ( 159. I bO ). This observation that the hypercoagul:~bilily of blood . elicired in rec:~Us the explanation of the effic:~cy of lhe rats by atherogenic diets rich in animal fats and e:~rlier use of Mg in prevention of po s toper:~tive vitamin o~ . could be repressed by oral or thrombosis ( llJ~. (~)')) :Jnu in tre:Jtment of intr:~venous :.~dm i nistration uf MgCil in acute peripheral th rom bot ic d ise:Jse CWO. 20 I). The and long-term experiments. Five times the :~ntithrornbotk effect nf magnesium ha s al so norm:JI m:.~gne sium requirements. added to this been :Jttributed to st:Jbilization uf platelet diet. prevented the acceler:J ted clotting of membr:mes (~00. 202) and to inhibition of blood seen in :.~nimals that were given the fatty pi:Jtelet :~ggregr:~tion ( 19 . liD, 203 . ~04) . diet bur with less m:.~~nesiurn . The m:~gnesium Supportive of the platelet membrane theory is supplementation normalizeJ the coagulalion recent work th:Jt h:.~s shown th:Jt Mg is time and prothrombiu consumption times in necess:.~ry to rn:~int:Jin 'the Jisc s h:.~pe of pl:.~telet s both rats (Fig. •>) and Jogs (Fig. I 0) on the high (205). Addition of MgCI~ to fresh human fat diets. These investigators suggesl rhat blood, under conditions that maintained elec magnesium intluences thrombosis: I) by inter trolytes and enzyme systems :.~s ne:~rly norm:~! fering with in trav:Jscular coagui:Jiion through ib as possible . resulted in reJu~o: tion in the size and wmpetition with ~· aktum :~nd by stabilizin ~· number of platelet dumps anu :m in~.:re:.~ se in fibrinog.:n and the pi:Jtdets. :n by promotin~ the number o f discrete pi:Jtelets (I HJ ). Hughes fibrinolysis . :.~nJ J) hy c:wsing vasodilatation. and Tllnk\ (I')) observ:~Jions that r:.~hhits with A nwdific:Jtion of this Jiet (poor :~lso in Mg . intr:.~vascul:Jr co:~gui:Jti o n (induced by miner:Jio K. ;~nd Cl) ha s been used by Sos :.~nd Rigo et :JI corticoid :~nd monob:Jsic sodium phosph:~te) {I 18, 1~0 . 130-13~) 1<1 proJuce myocardi:.~ l have a 40% redw.:tion of plasma Mg suggested infarction in sever:JI :~nim:.~l species. High M ~ to them tii:Jt the subnoml:JI Mg pi:J sma levels of int:Jke prevented the C :Jr •c;age of magnesi um required for fav orable terns . The evidence as to its importance in t'ects in the above study (2 I 3 ). That this maintaining mitochondrial integrity and in >se rvation has dinil::.d relevance is suggested reta ining m yo~.::.~rdi a l po t:J ssium has been con the tendency of people in the Occident to sidered elsewhere ( I). Magnesium is involved in nsume too much fat and by the evidence that normal mitochondrial contraction with forma amin 0 2 intake , too. may be excessive in tion of the ~.:ompad Mg-ATP complex and is :ne of those wh o drink fo rtified milk (2~4 - involved in the electron transport system (Fig. 6 ). whereas the Occidental diet tends to be I 1). With depletion of cardiac magnesium . v in magnesium (68 . b9). Thi s combination whether from i s~.:hemia or cardiotoxk drugs. dietary imbalances may produce sufficient mitochondri:JI swelling progresses to disorgani 1gnesium deficiency to con tribute to the zation and disruption (Fig. I 2). rdiovasc.:ular disease problems of the Wes tern The impo rtan ~.: e of magnesium and potassium >rid (I. 2, 69.227. 228). in myocardial aerobic metabolism has been stressed by Laborit (1 68). who studied the :gnesium and myocardial metabolism effe cts of the aspartates of these cations in \1agnesium has a pivotal posit ion in normal experimental cardiac an oxia (supra vide). and vsiology . participating in many enzyme sys· by Nieper and Blum berger ( 172) who intro duced the use of the substances in the clinic. The latter investigators consider the int r :~cellu lar metabolic effects of magnesium far more ...!... 1... ..l. ~ .1.. CONTIIOL 8UTTOI 8UTTEII IUTT[~ 8UTT[~ VITAMIN 0! VrT..... N ()t VITA.. N 01 THIOUUCIL VIT-0) Y1TA-0) SUGAR THIOUUQ. TH101..11W:1L ~c . +lloiQ :soo 100' 20 .. I 100 10 20 0 MOUIS ,... l ,, 0 l l 0 ,.... , 0 COMULATION l'ltOTMIOMtiN nOoK COOI-TION ' IG . 9. Effect of magnesium on coagulation times FIG. 10. Effect on canine d o lling functions of ·ats on thrombogenic, cardio pathic diets. Adapted acute butter load w ith and witho ut intravenous '1 (213, 214). magnesium. Adapted from (213). MITOCHONORIAL CONTRACTION Mt- DPN ..... Mt·l- OPN c.•• AT Poat Unoc:t iva led I -~·Deer. Active ton Tran• porl-~- MITOCHONDRIAL SWELLING r-JG . I I . Ph ysio to!_!ic mitocho ndrial processes. From ( 1) . 72 SEELIG AND HEGGTVEIT INCREASED MITOCHONDRIAL SWELLING ..... c••• REVERSIBLE •• LOSS 1:1 C.U'II CITY lO .tCC ...... LAT( 111• ACIIOSS CONC[NTRATION G~AOI(HT MITOCHONDRIAL IRREVERSIBLE DISORGANIZATION I I CELL DEATH DISRUPTION FIG. 12. Mitochondrial changes with magnesium deficiency. From (I). important in the treatment of c.: ardiat: is ~: hemia potassium. and 3) is important in maintainin than its antithrombotic.: effects. They have the integrity of the sub cellular structures. It pointed out that Parsons et al. (I nO), who role in maintaining normal rhythmicity of th stressed the importance of the at:tivation of heart in the face of an ischemic insult may wei fibrinolysis by magnesium, c.:ommen ted on the explain the difference in sudden cardiac deatl striking improvement in mortality rates of rates in hard and soft water areas. Therapeut i. patients with infarctions on MgS04 as ~:om use of magnesium in acute ischemic hea r pared with the one·third fatality rate when disease may well be justit1ed. The long-tern routine anticoagulant therapy was used (the prophylac.:tic use of magnesium for the inhibt year before institution of the magnesium tion of atherogenesis or the prevention of acut< therapeutic regimen). Nieper and Blumberger ischemic attac.:k, or both, requires further study (172) recommend use of the magnesium and potassium aspartates on the grounds that better penetration by Mg and K of the cell membrane may thereby be provided . They have reported References that such treatment has t:orrected the abnormal 1. SEELIG. M. S. Myocardial loss of function~ oxidative metabolism of the ischemic.: or digi magnesium. Part I. Effect on mitochondri,, intel! rity and potassium retention. In : Myoc:~rd i talis-treated heart , as measured by an increase olog-y. edited by E. Bajusz and G. Rona to a more normal pyruvic acid/lactic acid ratio Baltimore: University Park. 1972, vol. I, p. 61 5 . and by elevation of a-ketoglutamic add (an 2. SEELIG. M. S. M y o~-.Hdial loss of functional indicator of activation of the tricarboxylit: acid mal!ntsium. Part II. Cardiomyopathies of divers.: .:tio logy. \lyocardio logy . .:dited by E. Baju' l cycle). Simon ( 175) considers all of the dted and G. Rona. Baltimor.:: University Park, 197 : mechanisms to be operative in the favorable vo l. I . p. 626. effects of Mg in the treatment of myocardial 3. CU\1\IINGS, J. R. Electrolyte changes in heart infarction, a judgment in which the present tissue and coronary arterial and venous pla sm ~ foU owing coronary occlusion. Circulation Res. authors concur. 8 : 865 , 1960. 4. CUMMINGS. J. R .. AND B. B. CLARK. Electro · Concluding comments lyte studies o n coronary dog pr.:parations. Pharmacol. Exptl. Therap. 389, 1957 (abstr. The usefulness of magnesium in ischemic 1239). heart disease is probably best explained by its 5. RICO. J.. T . GATT, E. POSCH AND I. metabolic effects at the cellular level, but its SZELE~YI. Die infolg.: 1.h:r ligatur dn.:s Aste> interrelations with lipid metabolism and coagu der A . coro naria zustandekommend Electrolyt lation-11brinolytic mechanisms are probably v.:rand~rung.: n in llt yokard. VitalstotTe Zivilisa tionskran kh. II : 18 t , 1966. also significant. It I) c.: ounteracts the adverse 6. JENNINGS. R. IJ . Symposium on tht pre:· effet:ls of exc.: essive intracellular caldum. 2) ho >-pita l phase o f acute m yocardial infarction. plays an important role in retaining intracellular Part 11 - Early Phase of Myocardial lschemk MAGNESIUM INTERRELATIONSHIPS IN HEART DISEASE 73 Injury and Infarction. Am. J. Cardiol. 24: 753, AND J. F. DOYLE. Ma)!nesium-lipid relations in 1969. health and in patients with myocardial infarc 7. JENNINGS. R. B .. AND A. C. SHEN. Calcium in tion. L10cet 2: 933, 195H. experimental myocardial i!~<:hemia. In : Myocardi 22. HYATT. K. H .. L. LEVY.~ . NICHAMAN AND ology. edited by E. IJajusz and G. Rona. M. OSCHEWITZ. Relationship of serum mag Baltimore: Univ. Park Press. 1972. vol. I. p. 639. nesium levels to serum ~:holcsterol and tri· 8. HOCHREIN. H., H. J . KUSCHKE. Q. ZAQQA gly..:eride levels and to myocardial infarction. AND E. FAHL. Das Verhalten dcr lntracellu Appl. Spectros.:opy 20: 142. 1966. l:&ren magnesium-konzentration in myoc:&rd bei 23. LOSSNITZER. K. Cardiolo)!ical aspects of hypo lnsuffizienz, Hypoxic und Kammerllimmern. and hypermagnescmia. Klin. Wochs~:hr. 49: Klin. Woch~hr . 45 : 1093. 1967. 1153. 1971. 9. CANEPA . J. R .. AND 0. A. GOMEZ-POVINA. 24. CLARK. 8 . 8 .. J. R. CUMMINGS AND E. Electrolyte changes in the ventricular myo SI\IITH. The intluence of electrolyte changes on cardium foUowing experimental hemorrhagic the .:ffcl'ls uf antiarrhythmic dru!!s: some pre hypotension in the dog. Surg. Res. 3: 335, 1965. liminary observations. J. New Entrl. Cardiovascu 10. ISERI. L. T ., L. C. ALEXANDER, R. S. larSo..:. l4 : '!.7.1956. MCCAUGHEY, A. J. BOYLE AND G. B. 25. GOLDSMITH. N. f ., H. HUGGEL AND H. K. MYERS. Water and electrolyte content of UR Y. Serum electrolytes and clotting factors in cardiac and skeletal muscle in heart failure and rats during blood loss by cardiac puncture: myocardial infarction. Am. Heart J. 41 : 215, dfe~:t of norethvnodrclwith mestranol on serum 1952. magne~ium . Rc~ . Suisse Zool. 76: !!49. 1969. 11. MEISTER. H. • AND H. J. SCHUMANN. Unter 26. HARRIS. A . S .. A. ESTANDIA. H. SMITH. R. suchufll.len uber den Calcium und Magnesium W. OLSEN. T . J. FORD. JR. AND R. F. gehalt und leil:henberzen bei Herzinsoffizienz TILLOTSON. :\lal!ncsium sulfate and chloride in und Myoc:ardinfarkt. Beitr. Pathol. Anal. 126: suppression of ectopic ventricular tachycardia 486, 1962. a..:companyinJ!! a~:utc myocardial infarction. Am. 12. RAAB . W. Myocardial electrolyte derangement: J. Physiol. 172: .!51. 1953. crucial feature of pluricausal so-~.:alled coronary 27. CLARK. B. B. . AND J. R. CUMMINGS. Ar heart disea»e. Ann. N.Y. Acad. Sd. 147: 627, rhythmias foUowin~ experimental coronary oc 1969. clusion and their response to druf!s. Ann. N.Y. 13. RAAU. W. Cardiotoxic effects of emotional. Acad. Sci. 64 : 543. 1956. socioeconomic and environmental ~t resses. In: 28. CARDE!-1. N. L.. AND J . R. STEINHAUS. Role MyocardioiOf!Y, edited by E. Bajusz and G . of ma!!ne~ium ion in the initiation of ventricular Rona. Baltimore: University Park. 1972. vol. I. librillation produ~:ed by acute coroll:lrY occlu p. 707. . sion. Circulatio n Res. 5 : 405. 1957. 14. HEGGTVEIT. H. A .• P. TANSER AND B. 29. BAJUSZ. E.. AND H. SELYE. The chemical HUNT. Magnesium content of normal and prevention of cardioa•· necroses foUowing occlu ischemic human heart~ . 7th Intern. Congr. of sion of coronary vessels. Can. Med. Assoc. J. 82: Clinical Pathology, Montre:al, July JJ-19, 1969, 212.1960. p. 53. 30. WEBER. B.. H. LABORIT. J . M. JOUANY. P. 15 . LAURENDEAU, E., AND J. P. DURUISSEAU. NIAUSSAT AND C . BARON. Modifications des Electrolytes in aging human and animal normal signes electrocardiographiques de l'infarctus du and pathologic:al heart. Memorias l V Congress myocarde experimental chez le lapin per l'injec Mundial De Coardiologia 5 : 245. 1963. tion de dcis de l'acide :JSpartique. Compt. Rend. 16. DURUISSEAU. J . P. Mat~nesium ..erique et Soc. Bioi. 152 tPart II: 431. 1958. tis.~ulaire. First Intern. Symp. on ~al!nesium 31. LAMARCHE. M .. AND R . ROYER. Aspartic Deticit in Human Pathology. edited by J. add salts and the cardiovascular diseases. In: Durl;ach. Paris: Vittel. 1971 . Vol. Communicoa Elcl'trolytes and Cardiovascular Diseases, edited tions: 357, 1973. by E. Bajusz. Basel: S. Karger. 1965, vol. I. p. 11. SINGH, C. H .• C. T. G. FLEAR. A. NANDRA 104. AND D. N. ROSS. Electrolyte choanges in the 32. LA:'.IARCHE. M .• AND ~1. TAPIN. Action d'un human myocardium. Cardiology 56: 128, 1971- melange de sels de l'a~:ide aspartique sur le coeur 1972. isole de cobaye. Compt. Rend . Soc. Bioi. 155 18. HOLTMEIER, H. J. Magnesiumsoffwechselsstoy (Part I 1: 377. 1961. und Herzintarkt. In: Herzinfarkt und Schoch, 33. LAMARCHE. ~.. ~f . TAPIN AND R. edited by L. Heilmeyer and H. J . Holtmeier. ROYER. A..:tivite pharmacodynamique cardi Stullgart: GeoiJ!e Theim Verlag. 1969, p. 110. aquedes:~sp:~rtates . Therapie 17: 935.1962. 19. HUGHES, A., AND R. S. TONKS. Platelets. 34. HOCHREIN, H. A .. AND K. LOSSNITZER. The magnesium iind myocardial infarction. lancet I : interrelation b.:tween myocardial metabolism 1044, 1965. and hcoart failure. Ann. N. Y. Acad. Sci. 156: 20. NATH . K .. K. K. SIKKA. B. K. SUR. C'. P. 3117, 1969. SAXENA AND S. SRI VASTAVA . S.:rum mal!- 35 . ROSEN. H .. J. ~IcC ALLUM. A. BLUMENTHAL nesium in clinical and experintental myo..:ardial AND H. P. K. AGERSBORG. Effects of infarction. Indian J. Med. Res. 57: 317. 1969. potassium and ma~ne si um aspartatcs on the 21. BROWN . D. F .• R. 8 . MC'GANDY. E. GILLIE isolated guinea pig heart. Arch. Intern. Pharma- '· SEELIG AND HEGGTVEJT ~od y n. 147: 476, 1964. N. MORRIS. Mortality and hardness of local J6. TRZEIJSKI. A.. AND B. LEWARTOWSKI. w:~ter supplies. L:~n.:e t I : 827, 196H. I n~rc:~scd :~no x ia resistan ~c of the heart perfused 54. CRAWFORD. T .• AND M. D. CRAWFORD. with :~sp:~rtic acid s:~lt s. Bull. Ao.::~d . Pol. So.:i. 7 : Prevalence :~ nd pathological changes of ischaemic 2R3, 1959. hearHlisease in a hard-w;~tcr :~nd in a soft-water 37. IJASS. P. . I. MAXURKIEWICZ AND K. I. area. Lan~-et I : 229, 196 7 . MELVILLE. Effect~ of magnesium o n ~o r o nar y 55 . MORRIS J. N .. M. D. CRAWFORD AND J. A. llow :~nd heart :~o.:ti on and it s inllueno.:c on the HEADY. Hardness of local water-supplies and responses to :~drenaline and noradrenaline. Arch. mortality from cardiov.rscular disease. Lancet 2: Intern. Pharmacodyn. 117: 9 , 1958. 506, 1962. JR. SMITH. P. K., A. W. WINKLER AND H. E. 56. MORRIS. J. N., M. D. CRAWFORD AND J. A. HOFF. The pharmat:ologit:al actions of HEADY. H a rdne~ of local water-supplies and parenterally administered magnesium salts. A mortality fro m card iovascular disease in the review. Anesth6io logy J : 323. 1942. county boroughs of England and Wales. Lancet 39. SCOTT, J. B.. E. D. FROHLICH. R. A. I: H60. 1961. HARDIN AND F. J. HADDY. N:~'. I<'. :~nd Mg .. 57. PETERSON. D. R .. D. 1. THOMPSON AND J-M. :~.:tio n un coronary vascular resistance in the dog NAN . Water hardness, ;~rtcriosclerotic heart hc:~rl. Am. J. Physiol. 20 I : 1095, 196 1. disease and sudden death. Am. J. Epidemiol. 92: 40. KOBA YASHJ. J. On geogr:~phi.::~l relationship 90, 1970. between the chemic:~l n:~ture of river water and SR. ROBERTSON. J. S . Mo rtality and hardness of death rate from apoplexy. Her. Ohara lnst. II : water. Lancet 2 : 34M, 196M. 12. 1957. 59. ROBERTSON. J. S. The water story. Lancet I : 41. SCHROEDER. H. A. Munidpal drinking water 1160. 1969. and cardiovascular death rates. J. Am. Med. 60. UNSIGNED EDITOR lA L. Hardness of water Assoc. 95 : 125, 1966. and cardiovascular disease. Brit. Med. J. I: 1429, 42. SCHROEDER, H. A. 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Lancet I : I 171 , 1961 . quality and de:~ths from cardiovascular disease. 46. PHILLIPS, J. H .• AND G . E. I:IURC'H. C:~ rdio J. Am. Waterworks 54: 1371, 1962. vascular disease in the white and Negro ra.:es. 64b.LEVERTON. R. M. • J. M. LEICHSENRJNG, H. Am. J. Med. Sci. 238: 97, 1959. LINKSWJLER AND F. MEYER. Magnesium 47. BERSOHN, I. Atherosclerosis :~nd coronary requirement of young women receiving con heart disease: possible incrimination of m :~g tro lled intakes. J. Nutr. 74 : 33. 1961. ncsium dcfio.:icn.:y in their promotio n. Mcd. 65. MARIER. J . R. Tht! importance of d ietary Pruc.4: 62,1951!. magnesium with particular reference to humans. 48. BERSOHN. 1., AND P. J. OELOFSE. Correia· Vitalstoffe Zivilisation skrankh. 13 : 144, 1968. tion of serum-m;agnesi um and serum,ho lesterol 66. NERI, L. C .. D. HEWITT AND I . S. MANDEL levels in South African Bantu and European Risk of sudden death in soft water areas. Am. J. subj.:.:ts. Lancet I : I 020. I 95 7. 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