In American Journal of Cardiology 63:4G-21G, 1989
The section headers of this paper are as follows:
Dietary magnesium (Mg) deficiency is more prevalent than generally suspected, and can cause cardiovascular lesions leading to disease at all stages of life. The average American diets is deficient in Mg, especially in the young, in alcoholic persons, and in those under stress or with diseases or receiving certain drug therapies, who have increased Mg needs. Otherwise normal, Mg deficient diets cause arterial and myocardial lesions in all animals, and diets that are atherogenic, thrombogenic and cardiovasopathic, as well as Mg-deficient, intensify the cardiovascular lesions, whereas Mg supplementation prevents them. Diuretics and digitalis can intensify an underlying Mg deficiency, leading to cardiac arrhythmias that are refractory unless Mg is added to the regimen. Potassium (K) depletion in diuretic-treated hypertensive has been linked to an increased incidence of ventricular ectopy and sudden death. K supplementation alone is not the answer. Mg has been found to be necessary to intracellular K repletion in these patients. Because patients with congestive heart failure and others receiving diuretic therapy are also prone to chloride loss, leading to metabolic alkalosis that also interferes with K repletion, the addition of Mg and Cl supplements in addition to the K seems prudent.
It is paradoxical that many physicians do not consider magnesium (Mg) a nutrient, inadequacy of which has many overt consequences (Table I),
precisely because it has long been recognized as a very effective drug for the treatment of convulsions and hypertension of eclampsia,(1-3), and for cardiac arrhythmias, including those that are refractory without Mg therapy.(1,4-9) Realization that its efficacy in these life-threatening conditions might be a reflection of repair of its deficiency, as well as of its pharmacologic activity, has been gradual. Basic studies have clarified mechanisms by which Mg deficiency can disrupt arterial and cardiac integrity; Mg plays many roles at the mitochondrial level, activating numerous enzymes and preserving both function and structure. (10,11) The heart, with its dense mitochondrial structure and high enzymatic activity,(12) is particularly vulnerable to Mg loss. There is substantial evidence that long-term Mg deficiency in animal species, including monkeys, causes cardiovascular histologic and functional abnormalities.(13) Whereas Mg deficiency in all experimental models increases vulnerability to cardiotoxic agents, and intensifies arterial and cardiac damage caused by other dietary factors (such as excesses of fat, calcemic agents and inorganic phosphate) Mg supplementation has a protective effect.(1,13,14) The epidemiologic evidence that populations consuming more Mg from hard water or diet are less prone to cardiovascular disease and sudden death, than those with lower Mg intakes,(15-19) substantiates the relevance of the animal findings to human atherosclerosis, hypertension and its treatment, myocardial infarction, and sudden cardiac death.(1,20) Both Mg loss and hypochloremic alkalosis interfere with potassium (K) repletion(21-24) and contribute to the risk of sudden death among hypertensive and cardiac patients treated with Mg- and K-losing diuretics.(25)
It is widely assumed, especially in the United States where the food intake is generally ample, that Mg inadequacy is unlikely. However, the foods that are highest in Mg - vegetables (especially legumes and dark green leafy vegetables), fish (including shellfish, and whole grains and nuts (Table II(26))
are not major constituents of the average American diet. Nutrients that are high in the American diet, such as fat, sugar, salt, vitamin D, inorganic phosphate, proteins and more recently supplemented calcium (Ca) and fiber, all increase the dietary requirement of Mg.(26,27)
Recommended dietary allowances for adults: The recommended dietary allowance is defined as: the amount of a nutrient that maintains a balance of intake and output in healthy adults, and is sufficient to assure health - as determined from studies performed long enough for adjustment to be made to altered intakes.(26) Analysis of worldwide metabolic balance studies of free-living young adults, showed that when 4-<5 mg/kg/day of Mg (the content of typical American diets) is taken, men tended to be in negative Mg balance, whereas women remained in equilibrium(26). (Figure 1)
The analysis also disclosed that in countries (i.e. in the Orient) where the Mg intake is higher (6>8 mg/kg/day), both men and women were in positive Mg balance during the studies. The decision that the recommended dietary allowance for Mg in the stable adult should be 5 mg/kg/day(28) was derived from the finding that maintenance of Mg equilibrium was unreliable on lower intakes.(28)
However, many factors: dietary imbalance, normal anabolism as during growth and development, and psychologic and physical stress, including that of athletic training and competition, all increase the need for Mg. Diseases and drugs that decrease Mg absorption or increase renal Mg loss increase vulnerability to Mg deficiency(27). (Figure 2)
To assure adequacy of Mg to meet increased needs, the optimal intake of adults may be 6-8 mg/kg/day.
Dietary surveys - magnesium intakes below recommended dietary allowance: Large scale dietary surveys have disclosed that the dietary Mg intake of most Americans falls below the recommended dietary allowance.(27,29-31) Vegetarians' Mg intake is much higher, which could be a factor in their lower incidence of cardiac and vascular disease. Self-selected meals of students in American and Canadian high schools and colleges were found to provide less than the recommended dietary allowance for Mg, but more than the recommended dietary allowances for Ca and phosphate(27,32-34). (Figure 3)
Overconsumption of saturated fat, which is accepted as a key factor in the high morbidity and mortality from cardiovascular disease, increases the need for Mg. Mg deficiency alone has been shown to cause cardiac and arterial pathologic changes in every species of animal in which it has been induced.(1,13,35-38) High fat/low Mg intakes appear to be conjoint pathogenic factors. The arterial lesions of high fat diets in several species are intensified by simultaneous Mg deficiency, and protected against by Mg repletion.(1,13,35-42)
Fats form soaps with Ca and Mg, in the gut, thereby decreasing absorption both of fat and divalent cations. However, the protection afforded by high oral Mg intake, against both hyperlipidemia and cardiovascular lesions, entails more than diminution of fat absorption. Mg supplementation decreases the enhanced thrombogenesis caused by high fat intake(36,43) (see later).
Recent demonstration of the importance of Mg in fat metabolism in rats(36-38,44,45) suggests that increased Mg intakes may also exert a favorable influence on adverse effects of diets too high in fat, even in humans. The increase in low-density lipoproteins, very low density lipoproteins, and decrease in high-density lipids seen in Mg deficient rats - on a diet providing 20% casein, that was relatively low in fat (5% corn oil), but high in sucrose (70%) (Table III),
was reversed with Mg supplementation.(38,44) Triglyceride plasma levels were also higher in Mg deficient rats than in controls (same diet, but with adequate Mg) - an effect that was shown to be caused by its impaired clearance.(38,44,45) A marked decrease in esterified cholesterol (but no change in total cholesterol) was reported in Mg deficient dogs on a high butter fat diet in a 1933 study.(46) Fifty years later, the reduction in esterified cholesterol of rats maintained on the aforementioned high sucrose/5% oil/Mg deficient diet was shown to be caused by decreased activity of lecithin-cholesterol acyl-transferase.(38) It may be the subnormal lecithin-cholesterol acyl-transferase activity that is responsible for the depression of high-density lipoproteins in Mg deficiency - the high-density lipoproteins being the major substrate for esterification by this enzyme.(47)
A pilot clinical study of the effect of oral supplements of MgCl2 on blood lipoproteins of 16 patients with abnormally low high-density lipoprotein/very low density + low densitylipoprotein ratios, showed that a mean daily dose of 17.9 mM for a mean period of 118 days significantly raised the ratio.(48)
Sugar: These animal studies showing the effects of Mg deficiency on lipoproteins were with high sucrose diets.(36-38,44,47) In humans, sugar loading causes magnesiuresis,(49) possibly converting a marginal intake to a deficient one. Diabetes mellitus, which causes Mg wasting, especially during periods of decompensation,(50,51) is marked by hyperlipidemia and lesions of small blood vessels,(52,53) that resemble those seen in experimental Mg deficiency.(1,13)
Calcemic Agents and Phosphates: Among the other nutrients, of which the usual diet is likely to provide more than is required, and excesses of which increase Mg needs and are cardiovasopathic, vitamin D is of interest as both a calcemic and hyperlipidemic sterol,(54-59) that has been shown to be a steroid hormone.(60) Its requirements are individually variable, and the amount provided to prevent rickets (in milk, by addition to many foods, and in multivitamins), is enough to cure rickets, even in those with high requirements, and is close to the toxic dose for those whose need is low.(56-58) Vitamin D is often one of the components of experimental cardiovasopathic diets against which Mg is protective.(61) Inorganic phosphate which is plentiful in the American diet (though cola beverages and processed foods) is another component of cardiovasopathic regimens.(16,62) Excess Ca is included in some of the cardiovasopathic models, and elevated myocardial Ca is characteristic of cardiac damage.(1,13,14) Finland, with the world's highest dietary Ca/Mg ratio, has the world's highest cardiovascular morbidity and mortality and incidence of sudden death among young men.(16,63) A similar ratio may become a problem in the United States, where Ca supplementation is increasing. Similarly, unsupervised excess intake of fiber (organic phosphate), which can reduce availability of Mg, as well as of other divalent cations, may require mineral supplementation to correct fiber-induced losses.(27)
Alcohol: Ethyl alcohol increases Mg needs, even when taken in moderate quantities, through its enhancement of renal Mg excretion.(64-66) The efficacy of Mg treatment of neuromuscular and cardiac disorders of alcoholism was early attributed to correction of the Mg deficiency.(67) Chronic alcoholics become profoundly Mg depleted as a result of long-term magnesiuresis, superimposed on poor intake; those with cirrhosis also lose Mg as a result of secondary aldosteronism.(68,69) During the stress of alcohol-withdrawal, the fatty acids released as a result of catecholamine-induced lipolysis magnify the problem by binding serum and cellular Mg.(70) Unless the concomitant Mg deficiency is repaired during treatment of alcoholism (which entails repair of thiamin deficiency) there may be faulty response to administered vitamin B1 because of the Mg-dependence of thiamin-activated enzymes.(71-74) In thiamin- and Mg deficient rats, thiamin administration without correction of the Mg deficiency intensifies tissue Mg depletion.(73)
Pregnancy, growth and development: Studies show that Mg intake in pregnant women has been falling, while their intakes of Ca, phosphate, and vitamin D have risen(1). (Figure 4)
The lowest reported Mg intake and repeated negative Mg balances during a long-term study of a pregnant woman were in Finland,(75) (the country with the lowest Mg intake and the highest Ca/Mg dietary ratio, as well as the highest cardiovascular morbidity and mortality rates in relatively young men.(16,63) Mg intakes of white, middle class pregnant American women have disclosed that low dietary Mg results in negative Mg balance during pregnancy.(76,78,79) This is a potentially dangerous situation during a time when new tissue formation in mother and fetus mandates an adequate supply. It is possible that Mg deficiency may be a factor in peripartal cardiomyopathy and arrhythmias, which often occur in women with conditions that increase Mg requirements: maternal immaturity, multiple births, high parity especially when rapidly successive, and diabetes mellitus. The lesions resemble those of Mg deficiency.(1) That Mg inadequacy during pregnancy might cause fetal arterial injury is suggested by reports of coronary arterial lesions and generalized arteriosclerosis, detected at autopsy in infancy and atherosclerosis and cardiac damage early in childhood.(1,59) A few studies of Mg requirements of very young children and adolescents suggest that Mg needs during growth and development are higher than they are in adults. Might inadequate Mg intakes at times of high need contribute to cardiovascular disease?
Aging: The Mg intake of the elderly tends to be low, and their susceptibility to Mg deficiency is intensified by diminished intestinal absorption and increase urinary output of Mg.(80-83) Elderly persons, who are subject to disorders that impair absorption and renal function, and who may be taking Mg-wasting medications, are likely to be particularly vulnerable to Mg deficiency.(80)
Whether long-standing Mg deficiency affects the health of the aged, and increases their susceptibility to adverse cardiac reactions to disease and drugs that cause Mg-wasting deserves investigation. Transient ischemic cerebral attacks, to which the elderly are particularly prone, might be intensified by Mg deficiency. Subjects who have Mg added to their diets have been reported to be less likely to have transient ischemic events,(84)
That the tolerance of old subjects to stress might be improved by Mg supplementation is suggested by a study of rats maintained on diets low in Mg from the time of weaning to death from old age.(85) They adapted to the deficiency and ceased to show the acute signs, that occurred at the outset (which caused death in convulsions in some). However, the Mg-depleted survivors had shorter lives and died with cardiac damage under conditions of stress tolerated by controls.
Stress: A variety of stresses, both psychological and physical, increase Mg requirements and cause increased cellular Mg loss(27). (Figure 5)
Stress and Mg deficiency are mutually enhancing. Experimental Mg deficiency has been shown to cause hypertrophy of the juxtaglomerular index,(86) which results in mineralocorticoid secretion, which in turn increases Mg loss.(69,87) In vitro studies have shown that catecholamine secretion is increased by low Mg/Ca ratios, and decreased by high Mg/Ca ratios in suspensions of catecholinergic cells of the adrenal cortex(88) and of ganglionic nerve endings(89. (Figure 6)
In vivo rat studies have shown that hypomagnesemic noise-stressed rats excrete more catecholamines than do control-fed stressed rats.(90,91)
A vicious cycle can thereby develop, because exogenous or endogenous catecholamines secreted as a result of stress cause mobilization of cellular Mg, particularly from the myocardium - from which 12-39% losses have been reported, in association with uptake of Ca.(91-96) The loss of myocardial Mg precedes cardiac damage and Ca accumulation.(14,93-95) It has been postulated that catecholamines also block Mg ingress across a proposed Mg-channel.(97,98) This theory is in accord with data suggesting that catecholamines block Mg-uptake via a Mg-channel by lymphoma cells.(99) The highly protective effect of verapamil, the Ca-channel blocking agent, against catecholamine-induced cardiac necrosis, has been associated both by reduction of Ca-uptake and of Mg-loss.(92,97)
These effects may explain the transitory increase in serum Mg that has been shown in noise-stressed rats and in guinea pigs stressed by overcrowding. They exhibited decreased erythrocyte Mg and increased serum Mg that derived from released intracellular Mg, and then increased urinary excretion of Mg.(90) The longer-term fall in Mg levels during the stress of exposure to cold of ruminants transferred from barn to early spring pasture,(100) alcohol withdrawal,(70) and myocardial infarction(101) has been attributed to stress hormone induced release of fatty acids, with resultant inactivation of Mg in the serum and tissues. Another interpretation is that epinephrine, which increases Mg-binding in adipocytes,(102) a reaction that is coupled to adrenergic lipolysis,(103) might be responsible for the reduction in serum Mg.
Subjects with Type A personalities, who have increased urinary catecholamines and circulating free fatty acid levels, been shown to have lower erythrocyte Mg levels than do those with more phlegmatic Type B personalities, who are less vulnerable to stress-related cardiovascular disease.(104-107) Patients with latent tetany associated with Mg deficiency - may be especially vulnerable to stress-induced catecholamine release. This condition is diagnosed more frequently in Europe than in the United States, and has received detailed consideration.(108) Whether those presenting with nervous complaints, with or without latent tetany, might be especially vulnerable to heart disease as a result of catecholamine induced increase of Mg requirements (as are Type A subjects) is moot. Among (130) children with "nervous" complaints related to psychosocial and school stresses 16% had hypomagnesemia, and 41.5% had hypocalcemia; 62% improved with oral Mg aspartate HCl supplementation.(109) Among 842 children, diagnosed as having latent tetany and respiratory alkalosis, who had comparable complaints, satisfactory improvement was achieved in 56% by oral treatment with MgCl2, and there was partial amelioration in 32%.(110)
Stresses to which normal young people are subject include those experienced during competition (athletic and career-oriented), crowding and subjection to flickering lights and vibration - as in subways or discoteques. Those with genetic predisposition to poor tolerance of psychological stress,(104-109), or others exposed to physical or psychological stress, are at particular risk of Mg inadequacy.(1,27,74,78) The close interrelations of suboptimal Mg intake, coupled with the Mg loss induced by excess release of stress-hormones, suggest the desirability of Mg supplementation, as a reasonable means of reducing the risk of cardiovascular disease culminating in chronic disease, myocardial infarction, or sudden unexpected death from cardiac arrhythmia.
Diets delivering amounts of Mg sufficient to prevent death in experimental animals but insufficient for optimal growth and development, have caused arterial and cardiac lesions, the nature of which differs depending on other dietary factors.(1,13,35) In animals fed Mg deficient, but otherwise acceptable diets, early myocardial lesions develop predominantly in the small coronary and intramyocardial arteries.(1,13,35,111,112) There are pathologic sarcosomal and mitochondrial alterations, with Ca accumulation before the cell dies and multifocal necrosis develops.(111,112) There are many Mg-dependent processes in the heart that entail interactions with Ca.(10,11) Mg modulates Ca uptake by myocardial mitochondrial,(113,114) thereby protecting against conditions and drugs that increase Ca ingress and damage to the heart.(1,93,113,114) The lesions of the mitochondria of the heart caused by Mg deficiency resemble those of myocardial ischemia and of catecholamine induced cardiopathy; in experimental models, and in fatal clinical ischemic heart disease, the first alteration is loss of Mg from the heart.(1,13,14,93,95,111,115-119)
Intensification of Atherogenesis by Mg Deficiency: Atherosclerosis is frequently produced by feeding animals diets high in fat/cholesterol. The Mg deficiency induced lesions of the small and medium sized arteries in several animal species are characterized by edematous and thickened intima, and thinned, split, and fragmented internal elastica sometimes with lipid droplets(1,13,35). (Figure 7)
Coronary arteriopathy: hyperplasia of smooth muscle cells, fibrinoid necrosis, and chronic medial and adventitial inflammation develop in the hamster, a rodent that is particularly vulnerable to Mg deficiency, when fed a Mg deficient diet.(120) When, in addition to low Mg the diet includes excesses of saturated fat and/or calcemic agents, or both, larger arteries are affected, and atherosclerosis develops(1). (Figure 8)
The lesions are intensified over those seen in the absence of Mg deficiency.(1,13,35,39-41)
Coagulation, and Thrombosis: The possibility that early lesions of atherosclerosis are mediated by organization and fatty changes in mural thrombi at sites of arterial damage(121) calls attention to the possible role of Mg deficiency, which increases intra-arterial coagulation. Mg deficient animals had significantly shorter thrombin clotting time than did controls.(122) Hypercoagulability caused by a thrombogenic diet rich in fat was counteracted by oral supplements of MgCl2.(43) Most of the in vitro studies showing that Mg inhibits coagulation factors: prothrombin, thrombin, and Factors V, VII, and IX, have been with unphysiologically high Mg concentrations.(1,108)
The anti-thrombotic effect of high concentrations of Mg has been investigated in animals receiving standard diets, with artificially induced intimal lesions. The suppression of platelet aggregation by local application of a MgSO4 solution (6%) was demonstrated at areas of arterial injury caused by holding or pinching with a forceps.(123) Repeated intravenous infusions of isotonic MgCl2 also suppressed thrombus formation(123). (Figure 10)
The effect of high doses (50 mg/kg) of intravenously administered MgSO4 (25%) on platelet deposition in arteries with suture ligation of arteries causing 40-60% constriction has been reported.(124) (Dogs) with a narrowed major coronary artery, and rabbits with a narrowed carotid artery, pretreated with Mg, showed marked diminution of platelet aggregation at the site of constriction, and absence of microthrombi in the arteries distal to the ligation. It has been suggested that these findings have potential therapeutic or prophylactic implications - in Prinzmetal's variant angina where arterial spasm is the principal factor, and in coronary thrombosis.(124) There is some evidence that these findings may be applicable to the clinical situation.
Patients with thromboembolic disease, associated with latent tetany, have responded to Mg therapy by correction of hypercoagulability caused by excess adenosine diphosphate-induced platelet aggregation.(125,126) Increased platelet aggregability has been demonstrated in myocardial infarction patients, in association with decreased serum Mg levels.(127) In addition, Mg therapy has yielded benefit in patients with Prinzmetal angina(128) and in post-myocardial infarct patients (see later).
Fibrotic Changes in Thrombi and Myocardium: Fibrosis constitutes a large portion of the occlusive thrombi, examined from cases of fatal myocardial infarction.(129). Since increased fibrosis and slowed collagen resorption has been reported in tissues damaged by experimental Mg deficiency,(36,37) it is plausible that Mg deficiency may be a factor in clinical cardiomyopathies. Fibrotic cardiomyopathy has been associated with abnormalities during the perinatal period (in mother as well as infant) alcoholism, protracted diarrhea, protein calorie malnutrition, in hypercalcemic states, such as hyperparathyroidism and vitamin D hyperreactivity or toxicity, and in congestive heart failure.(130) All are conditions associated with Mg deficiency, as a result of the disease, or of treatment.
Myocardial Ischemia of Coronary Insufficiency or Occlusion: Ischemic heart disease, which is responsible for about a third of all deaths in the Western world, is caused by coronary atherosclerosis with or without thrombosis that gives rise to myocardial infarction, arteriospasms, and resultant arrhythmias. Many theories have been propounded as to the pathogenesis of this widespread disease-complex.(118,131) Inadequacy of Mg is a common denominator in some of the proposed mechanisms. The cited damaged intima, and lipid infiltration of Mg deficient animals, and their increased blood coagulability bear on the endothelial injury/lipid infiltration/mural thrombosis theory of atherogenesis.(132) The cited role of Mg in reversing low high-density/high-density ratios may also be germane to that theory. The importance of optimal Mg levels in counteracting arteriospastic agents - neurohormonal and electrolyte ultimately affects angina pectoris and peripheral arterial spastic disease.(118,119)
Pertinent to the effect of Mg on the damage to the myocardium caused by coronary occlusion, are the demonstrations in rats that its extracellular depletion causes impaired postischemic cardiac function and metabolism,(133) and its dietary inadequacy in dogs results in increased infarct size after coronary artery occlusion.(134) It has been proposed that the protective effects of Mg during myocardial ischemia entails not only its limiting the loss of cellular Mg and K, and militating against Ca-overload, but restricting the cellular loss of Mg-adenosine triphosphate the essential substrate for many cellular reactions.(135-137) The experimental findings suggest that early myocardial changes after an ischemic event (perhaps during the first 20-30 minutes) might be reversible, and that applying the findings to patients with a recent MI might result in better preservation of the ischemic myocardium and limitation of the size of the infarct.(137)
Electrophysiologic Cardiac Findings: With Mg deficiency severe enough to produce convulsions in rats, the electrocardiogram first disclosed tachycardia, followed by marked arrhythmia and then bradycardia just before the seizures started.(46) During post-convulsive unconsciousness, a sinoauricular block developed, with occasional skipped or ectopic ventricular beats.(138) In young dogs with average serum Mg of 0.4 mEq/liter, the PQ interval and QRS were markedly shortened, with lesser shortening of the QT interval, and an increased incidence of negative T waves.(139) With a semisynthetic diet that lowered the serum Mg to < 0.5 mEq/liter without seriously affecting serum K or Ca, there was sinus tachycardia, but little change in PR, QRS or QT intervals.(140) Less severe Mg deficiency in dogs and monkeys produced changes like those of extracellular hyperkalemia (as K shifted out of cells): marked sinus tachycardia, peaking of T waves, and ST depression.(41,141)
Electrocardiographic similarities among magnesium, potassium and calcium abnormalities - experimental and clinical: The electrocardiographic changes of Mg deficiency differ, depending on the degree of the deficiency which further influences K and Ca intracellular and extracellular levels. Therefore, it is not surprising that there are similarities between the electrocardiograms of Mg deficiency and those of Ca or K abnormalities(1,142), (Figure 11).
The loss of myocardial K (with transitory elevation of extracellular K) that results from myocardial Mg loss can contribute to electrophysiologic changes of Mg deficiency that resemble that of moderate hyperkalemia: a T-wave that is peaked but narrower than that of Mg deficiency.(1,142,143)
The common pushing of K therapy to overcome the (often undiagnosed) hypomagnesemia-associated refractory hypokalemia(21,22) can intensify Mg deficiency(144) and be associated with the electrocardiogram of K-depletion. With long-standing Mg deficiency, the electrocardiogram with its flattened T-wave (and sometimes a U-wave) is more similar to that of hypokalemia, with which it is associated.(142-144)
Early hypomagnesemia can be accompanied by hypercalcemia that may be caused by transient hyperparathyroidism(145) and that might contribute to the broader T wave peak (than that of hyperkalemia) seen with moderate Mg deficiency. More severe Mg deficit is associated with hypocalcemia, in association with both impaired release of parathyroid hormone and blunting of the target organs to its action.(145) At that stage, the electrocardiogram of Mg deficiency also resembles that of Ca deficiency. However, at that stage, there is a shift of Ca into the myocardium. Much of the protective effect of Mg against arrhythmic stimuli is being attributed to its being a physiologic Ca blocker.(118,119,146)
Many of the clinical conditions, in which electrocardiographic changes of hypomagnesemia have been reported, have been associated with electrocardiograms characteristic of hypokalemia or hypocalcemia. Basic to the role of Mg in maintaining or restoring cardiac rhythmicity is its role in maintaining K and Ca homeostasis. In brief, the electrocardiogram associated with clinical hypomagnesemia is usually characterized by increased sino-atrial discharge rate, with a tendency towards abnormal impulse formation, and ventricular ectopic beats.(8,147) Prolongation of the PR and QT intervals reflect the arrhythmogenic potential of Mg deficiency. Widening of the QT may indicate a lengthened repolarization phase, caused by altered membrane transport of K, associated with aberrant conduction, reentry, and lowered threshold for ventricular fibrillation.
Arrhythmias: The efficacy of intravenously administered Mg in control of clinical arrhythmias has been reported at intervals during the past half century. Since the early 1970s when this effect was associated with correction of Mg deficiency, (6,7) a variety of dysrhythmias incompletely responsive or refractory to conventional treatment have been controlled by parenteral Mg therapy (Table IV).(8)
Although the Mg-responsive arrhythmias are often not associated with low serum Mg levels, better tests for Mg deficiency(42) have shown it to be implicated in the conditions in which cardiac dysrhythmias develop.(6-9,148-159)
Dysrhythmias responsive to Mg occur in alcoholism - particularly during alcohol withdrawal,(6,8,64,65,154-159) during long-term administration of parenteral fluids lacking or inadequate in Mg, or in those undergoing postsurgical drainage of gastrointestinal fluids, or a combination of all 3.(1,65,154,160-162) They have been reported in patients with Mg deficiency caused by chronic diarrhea or short bowel.(7,160-163) The diarrhea of protein calorie malnutrition can be a predisposing factor to the arrhythmias seen in victims of starvation, especially during refeeding with formulas inadequate in Mg.(164).
The arrhythmias during exchange transfusions(165,166) and after open-heart surgery are partially caused by hypomagnesemia resulting from the use of anticoagulants such as acid-citrate-dextrose, that bind Mg as well as Ca (only Ca usually being repleted)(167). (Figure 12)
The use of Mg in the postcardiotomy period has decreased the incidence of arrhythmia.(168-171) Addition of Mg to cardioplegic solutions used in the pump-prime during cardiac surgery has proved to be the single most effective component of the protective infusates tested(172), (Figure 13)
Myocardial Infarction: Treatment of myocardial infarct patients with parenteral Mg salts was reported to decrease arrhythmias and improve survival in uncontrolled studies in South Africa, Australia and Europe from 1958 through the 1960s.(1) Recent controlled studies have verified the improvement in management and survival after acute myocardial infarction achieved by intravenous Mg therapy.(173-177) There is growing evidence that Mg deficiency may be a predisposing factor for myocardial infarction and subsequent complications,(8,23,91,147-153,178) Addition of Mg to the postmyocardial infarction regimen parenterally in the early phase, and orally subsequently - needs serious consideration.
Congestive Heart Failure: The most arrhythmogenic disease, congestive heart failure,(179-182) is responsible for many unexpected sudden deaths - not from progressive circulatory failure, but suddenly and unexpectedly, at a rate even higher than among patients in the first 12 months after myocardial infarction.(179) This has been attributed to the dysrhythmias caused by the electrolyte disturbances produced both by compensatory mechanisms and by treatment of the disease. (Figure 14)
The compensatory mechanisms resulting from reduced cardiac output cause increased secretion of vasoconstrictor and volume regulating hormones: catecholamines, renin-angiotensin-aldosterone, and anti-diuretics,(180,183) Catecholamine and aldosterone secretion is increased by underlying Mg deficiency - which is increased by both diuretic and digitalis therapy (see before), which further stimulate the neurohormones.(180,183) Loss of K and Mg, caused by diuretics and aldosterone, increases arrhythmias, which are intensified by angiotensin's stimulation of aldosterone secretion and potentiation of the sympathetic nervous system.(180,183)
Correction of secondary aldosterone- andtreatment-induced losses of both K and Mg is responsible for the favorable immediate response of heart failure patients with digitalis arrhythmias. When both cations are deficient, repletion of Mg is necessary for the repair of Mg and K tissue levels and the dysrhythmias.(23,180-182) Infusion of K before Mg infusion had a much weaker anti-arrhythmic effect than did Mg infusion alone; in several patients, the K infusion actually caused more ectopic beats, that were largely corrected by the Mg infusion.(184)
Rapid electrolyte depletion might explain the precipitation of lethal arrhythmias in patients with left heart failure with myocardial fibrosis, ventricular wall stress and elevated circulating neurohormones.(182) Hypokalemia is most often recognized in this condition, and in patients with congestive heart failure resuscitated after in-hospital cardiac arrest. It has been suggested that the only antiarrhythmic intervention needed to prevent recurrence of cardiac arrest may be repletion of K and Mg.(182)
Mitral Valve Prolapse: The electrocardiogram patterns and arrhythmias of mitral valve prolapse that are like those seen in Mg deficiency(185) are those present in a condition frequently seen in many patients with latent tetany of Mg deficiency.(108,185,186) The finding of decreased red blood cell Mg levels in patients with the human leukocyte antigen haplotype HLA haplotype HLA-Bw35,(187) has been associated with mitral valve prolapse,(188) supports the premise that there is a relation. Additional theories as to how Mg deficiency might participate in the pathogenesis of this disease have been considered.(108,186)
Hypertension: Hypertension is the most prevalent risk factor for premature cardiovascular diseases in the United States; it is estimated that over 30 million are affected.(189) Reviews of the dietary changes recommended for its prevention and treatment summarize strengths and weaknesses of past and current recommendations: caloric and sodium (Na) restriction, and K, Ca, and Mg supplementation.(189,190) The premise that dietary Ca deficiency is an important factor in the pathogenesis of hypertension,(190) and the evidence as to the proposed mechanisms that might be involved have been analyzed and found questionable.(191)
Unlike Ca, high serum levels of which increase blood pressure,(191) hypermagnesemia produced by Mg administration in pharmacologic doses has long been found efficacious in the treatment of severe hypertension, as in toxemias of pregnancy,(2,3) There is substantial experimental evidence that dietary Mg deficiency increases arterial contractility, and that elevating Mg decreases blood pressure.(1,118,192-194) However, severe experimental Mg depletion reduces the activity of vasopressive neurohypophyseal peptides.(1,192) This may explain the hypotension of patients with renal Mg wasting.(195)
The fact that hypertensive patients with low plasma renin activity (who have higher than average serum Mg levels) respond to administration of Ca, while those with high renin activity (who have lower serum Mg levels) respond to Mg treatment(196) does much to clarify the roles of Mg and Ca in hypertension. Of particular interest is the evidence of low levels of free Mg in erythrocytes in both forms of hypertension.(197,198)
It was found that Mg infusions - in patients with congestive heart failure and with hyponatremia, increased muscle Na and Cl, and subnormal muscle K and Mg and with increased resistance to diuretics - corrected the electrolyte abnormalities.(199) Comparable results were obtained with oral Mg supplements in CHF and hypertensive patients taking long-term diuretics.(200)
The first demonstration of the anti-arrhythmic effects of Mg was in the treatment of digitalis toxicity, more than 50 years ago.(201) Almost 30 years later, low serum Mg levels (1.38 mEq/liter +/- 0.13) were found in patients with arrhythmias of digitalis toxicity.(202) These findings have been repeatedly confirmed.(5,203,204) Patients with normal serum Mg levels, but decreased lymphocyte Mg, have also been shown to respond to intravenous Mg therapy by correction of the arrhythmias.(205) Hypomagnesemia has been reported more frequently than hypokalemia in patients with digitalis toxicity.(206) Among patients with symptomatic atrial fibrillation 20% were found to be hypomagnesemic; these required twice as much digoxin to control the arrhythmia as did those with normal serum Mg.(207)
The mechanisms by which Mg deficiency increases digitalis toxicity and by which Mg administration protects against digitalis arrhythmias, have been elucidated by animal and in vitro experiments. In vitro studies of isolated calf cardiac Purkinje fibers(208) suggested that excess digoxin poisons the membrane Na and K-adenosine triphosphatase with resultant inhibition of the Na-K pump, which is Mg dependent.(10,11). As a result, there is a reduction in the intracellular K/Na ratio that causes phasic movement of Ca in and out of the myoplasm, and transient inward current and spontaneous depolarizations. Low Mg levels potentiate these currents, while high Mg levels block them.(8.208) A study of digitalis-induced arrhythmias in dogs did not confirm the hypothesis that Mg reactivated digoxin-inhibited Na-K adenosine triphosphatase, suggesting that Mg directly affects Ca and K fluxes across the cell membrane.(209) A study of the efficacy of repeated intravenous infusions of MgCl2 in intact dogs given doses of digitalis that induced ventricular tachycardia showed that Mg corrected the arrhythmia, or when given before the digitalis, prevented it.(210)
Digitalis toxicity has also developed in patients with congestive heart failure who had hypermagnesemia as a result of concomitant renal impairment.(203) This seems contradictory to the evidence that Mg deficiency increases digitalis toxicity. However renal failure patients may have Mg deficiency, despite their higher than normal serum Mg levels, as indicated by subnormal skeletal muscle Mg concentrations.(211-213)
Diuretics: With regard to the risk of arrhythmia, most classes of diuretics have long been known to cause Mg as well as Na and K loss. Although the loop diuretics are the main offenders in treatment of congestive heart failure, patients receiving long-term treatment with such agents as the thiazides, are at risk, especially the elderly,(214-216) Serum Mg determinations are less reliable than tissue values.(42) In a study of muscle and serum Mg and K levels in 34 patients in whom ventricular ectopic beats developed while taking long-term diuretic therapy, Mg infusions more effectively reduced the ectopic beats than did K infusions.(184) In a larger study among 297 patients with congestive heart failure who had received long-term diuretic treatment, serum Mg was subnormal in 37%, and skeletal muscle Mg was subnormal in 43% (almost all of whom also had low muscle K(23)).
The increase of mortality among those participants, receiving diuretics, in large-scale anti-hypertension studies has called attention to the possibility that Mg loss, as well as K loss (which is usually watched for and corrected) may be at fault. Mg loss, in contrast, is usually undetected. In the extensive randomized Multiple Risk Factor Intervention Trial (MRFIT), that was sponsored by the National Institutes of Health, there was poorer survival in a subgroup who had had baseline electrocardiogram abnormalities and had been treated with thiazide diuretics, than in those not so treated.(217,218) In a study of mildly hypertensive patients 165 of whom (n = 287) had ambulatory electrocardiography, ventricular ectopic beats occurred more frequently in thiazide-treated patients than in placebo-treated controls.(219) A higher mortality rate due to fatal myocardial infarction and sudden deaths had been reported earlier in elderly hypertensive men, treated with diuretics, than in comparable patients treated only with salt restriction or beta-adrenergic blocking agents.(220) This is contrast to the European double-blind multicenter study, in which the study group was given diuretics plus Mg and Ksparers; survival of that group of subjects was 15% better than it was in the control groups.(221)
In two of the Multiple Risk Factor Intervention Trial centers, the serum Mg levels of 300 participants, aged 35-57 years, were analyzed after 4 to 5 years of treatment with relatively low dose chlorthalidone or hydrochlorthiazide.(222) About 15% of these had persistently lower Mg levels on 2 samples taken 4 months apart, than did those not taking diuretics. The investigators noted that the small differences might reflect the inadequacy of serum Mg as an index of Mg loss, and that further study is indicated, using better indices of the Mg status.
Hypochloremic metabolic alkalosis interferes with potassium repletion: Diuretic-induced Cl loss is less frequently noted than is hypokalemia, with or without Mg loss. Metabolic alkalosis can develop, especially in patients with congestive heart failure, but also appears in hypertensive patients receiving long-term diuretics. In an update of complications of thiazide diuretic therapy, in which the above disappointing results in large scale antihypertensive intervention trials were summarized, emphasis was placed, not only on Mg and K losses, but on the metabolic alkalosis caused by diuretic- and aldosterone induced Cl loss as a contributory factor in intracellular K depletion, and refractoriness to K repletion.25 Patients with metabolic alkalosis, associated with volume contraction and Cl loss induced by diuretics and secondary aldosteronism, require large doses of KCl to repair the cellular K deficit. A patient with renal Mg wasting developed hypokalemic hypochloremic alkalosis while being treated with a diuretic for edema of unknown derivation, despite administration of KCl.(195) Only when MgCl2 was added was normal electrolyte status restored.
Reports, in which the importance of Mg in repleting intracellular K is considered, sometimes refer to the concomitant existence of metabolic alkalosis, that intensifies K loss, but usually only in passing.(23,180,181,204) Problems of metabolic alkalosis are usually considered in reports on acid/base disorders.(24) The diuretics in common use promote cation excretion almost exclusively in association with Cl. Because patients receiving diuretics are often advised to consume low salt diets, that are thus also low in Cl, metabolic alkalosis - often not diagnosed - may exist. At first, the alkalosis was considered the result of K depletion; however, subsequent studies showed the K deficit often encountered in metabolic alkalosis (as high as 300 to 500 mEq) is a consequence of the alkalosis rather than its cause.(24) In 1955, acute metabolic alkalosis induced by removal of Cl was shown to increase K excretion in rats.(223) In a study of dogs made alkalotic by a diet low in K and Cl, and by administration of a mineralocorticoid and sodium bicarbonate, Cl was shown to be critical in repair of alkalosis.(224) Full correction of the hypokalemia required sufficient Cl to repair the hypochloremia. The importance of Cl in repair of hypokalemic alkalosis in humans was then shown by balance studies performed in normal human volunteers with alkalosis induced by Na nitrate, and in patients with diuretic-induced metabolic alkalosis.(225) Both in the experimentally induced and the diuretic induced alkalosis, liberal intakes of K had no effect on plasma bicarbonate and little effect on body K, if the Cl deficiency was not corrected.
One of the patients with metabolic alkalosis studied by metabolic balance(225) had chronic obstructive pulmonary disease. A series of such patients, who had a tendency towards metabolic alkalosis, rather than respiratory acidosis, had multifocal atrial tachycardia that responded to Mg sulfate infusions.(226) Four of the 9 patients with chronic pulmonary disease had serum Mg levels below 1.5 mEq/ liter and 5 had levels higher than 1.8. Even those with normal serum Mg retained substantial amounts of infused Mg, indicating deficiency. Possibly, their respiratory insufficiency might have caused sufficient hypoxia to mobilize tissue Mg, raising serum levelsas has been shown to result from too long application of a tourniquet, while withdrawing blood samples,(227), and as has been seen in birth asphyxia.(228)
Alkalotic patients had greater vulnerability to digitalis toxicity, even though they had therapeutic digitalis blood levels lower than the nonalkalotic patients.(229) They improved with KCl treatment, even though they were normokalemic, an effect that was attributed to correction of decreased intracellular K that had been caused by metabolic alkalosis. Their serum Mg levels were not reported.
Risk of intensifying alkalosis by repletion of non-Cl salts: Among the studies that showed that Cl is critical to repair K loss and alkalosis, were case studies that showed worsening of alkalosis when buffered K rather than KCl was provided,(225) In another instance, a patient who abused Mg cathartics, developed hypochloremic, hypokalemic metabolic alkalosis, believed to have resulted from conversion of the Mg oxide to MgCl2 in the stomach, and fecal excretion of endogenous Cl.(230)
Animal studies of the intestinal absorption of different Mg salts have shown a tendency towards hypochloremic alkalosis with all of the Mg organic compounds and inorganic salts, except those containing Cl (Table V).(231)
Rats fed MgCl2 had a slight tendency towards hyperchloremic acidosis, which might be useful in subjects with diuretic induced hypochloremic alkalosis.
Improvement in intestinal absorption of Mg, and correction of extracellular alkalosis, with use of Cl-containing Mg compounds was credited with the greater cardioprotective effect of MgCl2 and Mg aspartate hydrochloride in adrenergic cardiopathy (Table VI).(231-234)
The experimental model employed a mixed gluco-mineralcorticoid, that is a very potent agent for inducing hypochloremic alkalosis and marginal Mg deficiency, and that in combination with epinephrine or with dietary Mg deficiency, or both, lowers the myocardial Mg and raises the myocardial Ca before development of necrosis.(234) Feeding a Cl containing Mg compound (Mg aspartate hydrochloride) protected against cardiac electrolyte changes and necrosis.
Early studies of the electrolyte-steroid-cardiac necrosis and stress rat models showed that MgCl2 and KCl were the most potent protectors against cardiac damage.(62) In a comparative study of old and young stressed rats, it was found that Cl-deficiency particularly intensified the risk of cardiac necrosis in old rats.(235)
Repair of intracellular potassium deficits associated with deficiencies of magnesium and chloride: Most of the foregoing data deals with evidence that when Mg and K deficiencies coexist, repletion of Mg is necessary for repair of the cellular K loss. Since hypochloremic alkalosis has also been shown to interfere with K repletion, it seems appropriate to provide Mg and Cl, as well as the K that is usually provided, to patients with diseases and those subjected to treatments that cause loss of all 3 ions (Table VII).
Because of the hygroscopic nature of MgCl2, it must either be supplied as a solution for oral use or in protectively coated tablets.
In addition to the response of a patient with Mg-deficient latent tetany to elixir of MgCl2,(195) there is a report of satisfactory improvement of most of 842 children diagnosed as having latent tetany and respiratory alkalosis on treatment with orally administered MgCl2.(110) There are several preliminary reports on the efficacy of an enteric coated MgCl2 preparation in cardiovascular disorders.(48,236,237) Doses of 4-6 tablets, each containing 0.5 g MgCl26H20, given for 6 weeks to 2 years, were effective in decreasing QTc and QUc intervals in 25 patients.(236) The same preparation was found to improve the antihypertensive response to a thiazide diuretic of 21 hypertensive patients aged 42 to 82 years.(237) Abnormally high low-density lipoprotein levels were reduced in 16 patients given 6-10 coated MgCl2 tablets daily for a mean period of 118 days.(48)
There is substantial experimental evidence of the vital role of Mg in maintaining cardiovascular integrity and normal function. Large-scale dietary surveys have shown that American diets are usually Mg deficient, inadequately meeting requirements under conditions of growth and development, stress, or disease and drug therapy that cause Mg loss. Mg has long been used for parenteral treatment of convulsions and hypertension of eclampsia, and more recently, as a therapeutic modality in refractory cardiac arrhythmias (although usually as a last resort). Mg has potential value in the management of cardiovascular diseases treated with Mg-wasting drugs that intensify Mg deficiency. Such diseases and treatment also predispose to Cl loss induced metabolic alkalosis, which with Mg deficiency, contribute to refractory cellular K depletion.
The fact that chronic Mg deficiency is silent and difficult to diagnose - serum Mg levels being an unreliable index of the cellular Mg status, has militated against early treatment or supplementation with Mg. Studies should further assess the Mg status in persons with conditions that may cause Mg deficiency or those being treated with Mg- and K-wasting drugs. All of the ions that are lost should be repleted - Mg, K, and Cl (to prevent or correct metabolic alkalosis). It is further proposed that optimal Mg intake throughout life, and especially under conditions of normal anabolism and stress, may reduce the risk of cardiovascular disease, and even of sudden unexpected cardiac death.
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