In American Journal of Cardiology 63:4G-21G, 1989
CARDIOVASCULAR CONSEQUENCES OF MAGNESIUM DEFICIENCY AND LOSS:
PATHOGENESIS, PREVALENCE AND MANIFESTATIONS. MAGNESIUM AND
CHLORIDE LOSS IN REFRACTORY POTASSIUM REPLETION
Mildred S. Seelig, M.D., M.P.H.
New York Medical College, Valhalla, and the American College
of Nutrition, Scarsdale, New York
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)
Diets high in saturated
fat:
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.
Histologic
Lesions:
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)
(Figure 9)
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)
Digitalis:
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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