Clin. Cardiol. 5, 556-568 (1992)
Review
Magnesium Disorders and Cardiovascular Diseases
JOHN R. PURVIS, M.D., ASSAD MOVAHED, M.D.*
Department of Family Medicine and *Department of
Medicine/Section of Cardiology, East Carolina University, School
of Medicine, Greenville, North Carolina, USA
Summary: The evidence linking magnesium
disorders with the pathogenesis and treatment of various
cardiovascular diseases will be reviewed.
Key words: magnesium deficiency, magnesium
supplementation, cardiomyopathy, ischemic heart disease,
hypertension, arrhythmias, digitalis toxicity
Introduction
Magnesium is critical to the proper functioning of many
physiologic reactions, including those that are critical to the
cardiovascular system.1 There is growing evidence that
magnesium status is important in pathogenesis and treatment of
cardiovascular disease.2-5 Magnesium activates
adenosine triphosphatase (ATPase), which is essential for normal
cell membrane function and is the energy source for Na-K
pump.6 Intracellular magnesium deficiency may cause an
increase in intracellular Na and Ca and a loss of K.6
Despite the importance of this cation, physicians frequently fail
to consider magnesium status when managing a patient. In a recent
study of hospitalized patients, 5.7% of the patients were
hypermagnesemic and 42.2% were hypomagnesemic.7
Physicians initiated requests for magnesium measurements for 7.4%
of these patients.7
Serum magnesium, like serum potassium, is often normal despite
depletion of total body magnesium.8 Retention of an
oral or intravenous magnesium load is a good estimate of the
total body magnesium, but usually requires urine collection of 24
hours.9,10 Intracellular levels of magnesium are more
accurate measures11 but there is often poor
correlation of intracellular red blood cell and intracellular
mononuclear cell magnesium,12,13 and these may
correlate poorly with the magnesium content of muscle in
different disease states.14,15 Of the two,
intracellular mononuclear cell magnesium is a better indicator of
the magnesium status of the heart. For example, in a recent study
of coronary care unit patients, only 7.7% were hypomagnesemic,
but 53% showed low levels of mononuclear cell
magnesium.8
Yet, neither serum nor intracellular levels of magnesium may
give as accurate a picture of physiologic activity as the level
of free magnesium,16,17 which may best be determined
by nuclear magnetic resonance (NMR)
spectroscopy.9,16-18 Obviously, except for serum
magnesium, it is impractical for clinicians to determine
magnesium status. However, magnesium abnormalities may be
important in pathogenesis and magnesium replacement may be
necessary for treatment of ischemic heart disease,
cardiomyopathy, congestive heart failure, and some
arrhythmias.
Epidemiology
Epidemiologic evidence linking magnesium deficiency to
ischemic heart disease and sudden death has been investigated for
more than three decades. One area of interest is the possibility
that people living in areas with magnesium-low water have more
heart disease than those living in areas with magnesium-rich
water. The hypothesis is that because modern western diets
contain less magnesium than needed according to the recommended
dietary allowance and magnesium balance studies,19 the
marginal difference in magnesium intake occurs from the water
supply.20 Therefore, people living in magnesium-low
water areas have increased cardiovascular mortality because the
total intake is insufficient.
This is referred to as the "water story" and is supported by
numerous studies showing an inverse relationship between
cardiovascular mortality and water hardness.21-27
Others have found good correlation between heart disease and the
ratios of calcium to magnesium28 or
sodium29 to magnesium in the water supply. In
addition, areas switching to soft water from hard water have had
increased mortality, while mortality decreased when the opposite
change was made.30 Autopsies of patients in soft-water
areas who died from noncardiac causes have shown lower levels of
magnesium in cardiac tissue than those who had lived in
hard-water areas.31 Finally, autopsies of men less
than 45 years old who had lived in soft-water areas showed more
coronary atheromata and evidence of myocardial infarction than
similar men from hard-water areas.32
However, not all evidence supports this hypothesis. Many other
elements are also found in hard water. Other researchers have
found correlations between increased calcium,25,3
copper,34 potassium,35
lithium,25 and a host of other trace
elements,25 and diminished heart disease. Other
studies have shown no increased cardiac mortality with hard
water.36-40 Reviews of the subject have been unable to
demonstrate a conclusive association between magnesium content of
water and ischemic heart disease.34,36,41 Some of the
confusion may be due to the fact that "hard water" has varying
amounts of calcium and magnesium.42,43
Nonetheless, it is important to remember that intake from food
and water determines whether magnesium deficiency exists.
Clinical studies looking at the importance of magnesium
supplementation often do not consider environmental levels of
magnesium. This may account for differences found between studies
investigating the link between magnesium disorders and
cardiovascular disease.
Ischemic Heart Disease
There is growing evidence that magnesium deficiency is
important in the pathogenesis of ischemic heart
disease.44-48 In addition to the indirect
epidemiologic evidence already discussed, there is experimental
evidence that supports the role of magnesium deficiency in
ischemic heart disease.
Autopsies of patients who died from ischemic heart disease
have shown lower cardiac magnesium levels than autopsies of those
who died from other causes.49-51 In addition, patients
with ischemic heart disease retain more magnesium than those
without the disease, which points to a relative magnesium
deficiency.52
Magnesium supplementation has been used to diminish the
symptoms of ischemic heart disease for more than 50
years.53,54 Malkiel-Shapiro reported that 125 patients
with angina improved with magnesium
supplementation.54
Recently, Goto et al. showed increased magnesium
retention in patients with variant angina.55 Calcium
channelblocker therapy completely relieved symptoms in these
patients, and magnesium retention decreased to the levels of
control subjects.55 Other antianginal medications have
been shown to affect magnesium levels as well. Unstable angina
patients treated with nitrates and calcium channel blockers or
nitrates alone have shown improved serum magnesium
levels.56 Cohen et al showed that beta
blockers also have a beneficial effect on serum magnesium in
patients after myocardial infarction.57
There are physiologic reasons that magnesium may be important
in the pathogenesis of ischemic heart disease. Magnesium
deficiency has been associated with most of the major risk
factors for atherosclerotic coronary artery disease, coronary
artery spasm, and coronary artery disease, coronary artery spasm,
and coronary artery thrombosis.
Atherosclerosis
There is considerable evidence linking magnesium deficiency to
atherosclerosis and the major risk factors for coronary artery
disease. Several studies on different species have shown that
animals given magnesium supplementation have less
atherosclerosis58-65 when given atherogenic diets than
those not supplemented, even without a change in serum
cholesterol.62 In fact, Resnick and
associates66-68 have postulated that several coronary
artery disease risk factors including hypertension, obesity, and
insulin resistance have the common denominator of magnesium
deficiency.69-70
Diabetes
The level of diabetic control has been shown to be inversely
related to magnesium deficiency.71-73 In addition,
diabetic retinopathy has been correlated to magnesium deficiency,
irrespective of diabetic control in two different
studies74-75
Both insulin-dependent and noninsulin-dependent diabetic
patients have been shown to have increased urinary
losses76 and reduced serum77,78 and
intracellular levels of magnesium.77,79-81
However, not all diabetics have deficiencies of both serum and
intracellular magnesium,73,82,83 and the levels differ
depending on the type of diabetes and the gender of the patient.
Nevertheless, oral magnesium supplementation has improved control
in insulin-dependent84 and noninsulin-dependent
diabetics.79
Magnesium deficiency could be important in diabetes for
several reasons. Many of the enzymes involved in glycolysis are
magnesium dependent.85 Increased insulin
resistance86 has been found in patients with reduced
free magnesium levels,70 and animal studies have shown
increased glucagon stimulation,86 decreased insulin
secretion87 and reduced insulin uptake88
with magnesium deficiency.89
Dyslipidemia
The importance of magnesium deficiency in dyslipidemia
has been suggested for some time.90-95 Experiments in
rats have shown that magnesium deficiency produces
hypertriglyceremia,96,97
hypercholesterolemia,96-99 increased low-density
lipoproteins (LDL),97 and reduced high-density
lipoprotein (HDL)95 through reduced triglyceride
clearance,100 diminished activity of lecithin
cholesterol acetyltransferase (LCAT)96 and lipoprotein
lipase, and increased activity of HMG-COA
reductase.101 The association between hypomagnesemia
and hypertriglyceremia has been confirmed in studies of
pigs.102
The association between lipid abnormalities and hypomagnesemia
has not been as clear in human studies. Population studies have
shown positive,103 inverse,91 or
no104 correlation between serum magnesium and
cholesterol levels.
Supplementation has had variable results. Healthy volunteers
have shown no improvement in lipid panels with magnesium oxide
supplementation.105 Studies in patients with lipid
disorders have shown both no effect106 and a
statistically significant improvement107 in
cholesterol and triglycerides. The latter study showed reductions
in total cholesterol from 297 mg/dl to 257 mg/dl and improvements
in HDL levels from 35 mg/dl to 47 mg/dl with magnesium
supplementation.
The earlier suggestion that patients with ischemic heart
disease had improvement in cholesterol levels with parenteral
magnesium supplementation108 has been confirmed in a
short-term follow-up of a relatively small group of patients with
oral magnesium supplementation93 Other studies also
have shown a beneficial decrease in beta-lipoprotein
levels,93,108,109 which would reduce risk of coronary
artery disease. 110
Hypertension
Magnesium deficiency has been linked to the pathogenesis of
another coronary artery disease risk factor,
hypertension.111,112 Magnesium is important in
activating the Na-K-ATPase pump, which in turn expedites the
movement of potassium into the cell and sodium out of the cell.
1 112,113 Magnesium is important in
decreasing the entry of calcium into the cell as
Well.112,113 Therefore, magnesium deficiency can lead
to increased intracellular sodium and calcium,114
increased peripheral resistance, and vasospasm,115,116
which have been observed experimentally in animals.117
A decrease in retinal spasm with magnesium supplementation has
also been noted in a group of eight hypertensive patients with
elevated renin levels although the systemic arterial pressure did
not change. 118
A number of studies report the relationship between
hypertension and intake of a variety of cations.
119-127 The importance of magnesium in the
pathogenesis of hypertension is not clear. For instance, the
Honolulu heart study 126 found that total magnesium
intake was strongly and inversely related to systolic and
diastolic arterial pressure, but other studies have found varying
relations.119-125,127 One Belgian study showed an
inverse relationship between systemic arterial blood pressure and
24-h magnesium excretion, 120 and another did not.
119
Likewise, evaluations of magnesium status in untreated
hypertensives have found increased, 128 decreased,
129,130 or the samel3l-132 levels as in
normotensive patients. Furthermore, studies have shown no overall
improvement in the systemic arterial pressure of otherwise
untreated hypertensivel33-135 patients with magnesium
supplementation. A comprehensive review of the epidemiologic and
clinical evidence linking magnesium deficiency and hypertension
concluded that the evidence was insufficient to prove a link
between magnesium status and hypertension. 136
However, there is evidence to suggest that magnesium status
may be important in some hypertensive patients. Studies of junior
high school students found that patients with a family history of
hypertension did have an inverse relationship between systemic
arterial pressure and intracellular magnesium levels, which was
not found when there was no family history. 137,138
One study which showed no difference between serum magnesium
values of normotensive and hypertensive patients did show that
hypertensive patients excreted less urinary magnesium due to
depleted magnesium stores. 132 A very recent study
found that magnesium supplementation had no benefit in unselected
mild hypertensive subjects or in subjects with a high-normal
arterial pressure,134 although, in subjects with a low
urinary excretion of magnesium, a hypotensive effect was seen.
134 Others have shown that hypertension response to
magnesium is dependent on intracellular sodium concentration.
139 It has been shown that high-renin hypertensive
patients have lower serum magnesium levels and respond better to
magnesium supplementation, and low-renin hypertensives have
higher serum magnesium levelsl40 and may have a
pressor response with supplementation. 141 An inverse
correlation between plasma aldosterone and serum magnesium has
also been found,142 suggesting that low magnesium
levels are associated with elevations of the entire renin
angiotensin-aldosterone system. 141
Magnesium supplementation has been shown to benefit some
patients receiving other antihypertensives. Patients on
traditional non-potassium-sparing diuretics tend to have a
potentially dangerous magnesium deficiency, 143-147
and have had particular benefit from the addition of oral
magnesium supplementation. Studies have shown that magnesium
supplementation in these patients will lower systolic arterial
pressure by approximately 10 mmHg,148-150 although
another study could find no benefit. 151 It is of
interest that Resnick et al found that, as hypertension
was controlled, the levels of intracellular free magnesium rose,
regardless of which antihypertensives was used. 16
Other Coronary Artery Disease Risk Factors
Less is known about the relationship of other coronary
artery disease risk factors and magnesium deficiency. It is
interesting that Type A patients may have magnesium deficiency.
152 Experimental evidence suggests that Type A
patients may produce more catecholamines when exposed to stress.
This would result in increased free fatty acids and diminished
intracellular and plasma magnesium stores. 153
One investigator has linked decreased free intracellular
magnesium to obese patients,69 even though total
intracellular magnesium is normal in obese
patients.154 In addition, it is known that patients
have hypomagnesemia after jejuno-ilial bypass surgery,
154,155 but not with newer methods of
gastric bypass surgery. Obese patients on diets supplemented by
protein, 156 diets high in saturated fat, or high in
polyunsaturated fats,157 have shown diminished levels
of intracellular magnesium.
Coronary Artery Spasm
There is considerable evidence that magnesium deficiency can
induce coronary artery spasm. It seems that magnesium can control
the movement of calcium into and out of smooth muscle cells.
115,116 In fact, magnesium may be considered a
naturally occurring calcium channel blocker. 158 In
vitro experiments on coronary arteries of dogs have shown that
the arteries are more likely to go into spasm if they are
incubated in solutions with low concentrations of magnesium.
159 Low-magnesium solutions significantly increased
the potential for contractile responses of both small and large
coronary arteries to norepinephrine, acetylcholine, serotonin,
angiotensin, and potassium.159 Experiments on intact
dogs l60 and isolated coronary arteries of pigs show
the same tendency.89 Furthermore, vulnerability of
human coronary arteries to spasm increases with magnesium
deficiency.161 Variant angina has been treated
successfully by intravenous magnesium sulfate, 162
which also points to the importance of magnesium deficiency in
coronary spasm.
Thrombosis
The efficacy of parenteral magnesium in reducing coronary
thrombosis has been suspected since 1954. In an uncontrolled
study, Parsons and associates found that patients admitted with
angina or myocardial infarction had a reduced death rate, from
approximately 30 to 1%, with treatment by 2cc of 50% magnesium
sulfate intramuscularly every 5 days for a total of 60 days.
108 The improvement in mortality was thought to be due
partly to favorable effects on reducing the inhibition of
plasmin.108
Recent animal experiments have shown that magnesium
halogenates inhibit adenosine diphosphate (ADP)-induced platelet
aggregation. 163 In 1986, a study demonstrated that
bleeding time increased with magnesium infusion in postmyocardial
infarction patients.164 Magnesium infusions have been
shown to reduce clotting in preeclamptic patients by reducing
certain clotting factors.165 Paolisso and colleagues
have been able to reduce the increased platelet aggregation of
diabetic patients by oral supplementation of magnesium.
166 This evidence suggests that magnesium
supplementation can reduce thrombosis in some patients.
Myocardial Infarction
Magnesium deficiency appears to be extremely important in the
peri-infarction period.167 In addition to previous
uncontrolled studies,54,108 several more recent
controlled studies have evaluated the effect of magnesium
infusion in the peri-infarction period. 168-175 When
findings from all studies were analyzed, only 3.8% of the
patients in the treated group died, compared with 8.0% of the
control group.174 The primary benefit of magnesium
therapy has been the reduction of malignant
arrhythmias.171-176
Magnesium infusion in patients with suspected myocardial
infarction could reduce myocardial oxygen demand45 and
limit the infarct size. 171 The preinfarction
magnesium status is unclear, because serum and intracellular
magnesium levels have been found to be decreased,
177-180 no different from,181-185 or
increased, compared to patients without myocardial
function.186-187 However, a study of magnesium
retention after myocardial infarction showed magnesium
deficits,164 and patients have been found to be
hypomagnesemic up to 6 months after a myocardial
infarction.56 The differences in these findings may be
due in part to the cation shifts which occur after myocardial
infarctionl88-190 and which correspond with the size
of the infarct.187 These changes resolve over
time,177,188,191 resulting in different magnesium
values at different times after infarction. 191
A correlation between hypomagnesemia and postinfarction
ventricular arrhythmias has been shown in
most,178,181,183 but not all, studies.184
Supraventricular tachycardia and atrial fibrillation have been
found more frequently in hypomagnesemic patients, and
atrioventricular blocks and supraventricular bradycardias have
been found more frequently in hypermagnesemic
patients.178
Cardiomyopathy
Magnesium deficiency has been suggested as the cause of
cardiomyopathy.4,192 Pathologic associations as well
as epidemiologic, histological, and animal studies, have
implicated magnesium deficiency in a variety of
cardiomyopathies.
For instance, patients with hypoparathyroidism can manifest a
cardiomyopathy which responds to calcium and magnesium
replacement. 193 Alcoholic patients are known to have
both cardiomyopathy and magnesium deficiency.4 People
living in low-magnesium equatorial areas, and who have
magnesium-deficient diets, develop spontaneous endomyocardial
fibrosis of undetermined etiology.194,195 Postmortem
heart examinations have shown low concentrations of magnesium and
high concentrations of thorium and cerium which are thought to be
cardiotoxic.194,195
Several different experimental animal models have shown that
magnesium deficiency is cardiotoxic, resulting in gross
pathologic changes and histologic changes from
injury.196-198 Postmortem evaluation has shown that
with a variety of insults, magnesium and potassium leave cardiac
tissue and calcium and sodium accumulate in cardiac tissue. Any
of these changes could cause necrosis.196,199-201
However, magnesium is the first ion to shift in the myocardial
necrosis of parathyroidectomized rats. 199 The
necrosis in parathyroidectomized rats was partially prevented by
parenteral, but not oral, magnesium
supplementation.199 Other animal studies have
suggested that preventing magnesium loss can protect the heart
against cardiotoxic agents. In vitro experiments show that
dopamine-induced postischemic injury is attenuated by
magnesium-rich perfusate solutions.202 Spironolactone,
which spares both potassium and magnesium, prevents calcium
accumulation in spontaneously cardiomyopathic
hamsters,203 although potassium may be more
protective.204 The cardiomyopathy in hamsters given
magnesium-deficient diets is reduced with
nifedipine,205 pointing to the importance of magnesium
and calcium disturbances in cardiomyopathy in these animals. An
infusion of potassium, magnesium aspartate prevents and reverses
isoproterenol-induced cardiomyopathy in dogs, again suggesting a
protective effect of magnesium.206 The relevance of
magnesium deficiency to cardiomyopathy in humans is yet to be
determined.
Congestive Heart Failure
Patients with congestive heart failure (CHF) frequently have
magnesium deficiency207 due to increased urinary
excretion.208 There is decreased tubular absorption of
magnesium due to increased extracellular volume and the effects
of the secondary hyperaldosteronism found in CHF.209
Diuretics that do not spare
potassium210-213 and digitalis can worsen
the problem of diminished tubular
resorption.209,214
Other neurohumoral transmitters may also be at work. The
renin-angiotensin 11 system may stimulate an already
elevated aldosterone.209,215 Norepinephrine may reduce
magnesium through increased fatty acids.216
Angiotensin converting enzyme (ACE) inhibitors, which conserve
magnesium,217 have resulted in diminished mortality in
patients with CHF.
Magnesium deficiency worsens hyperaldosteronism, which may
lead to fluid retention.209,218 Magnesium loss also
compounds hypokalemia, which could theoretically produce
ventricular arrhythmias and hemodynamic deterioration in
CHF.214 Magnesium depletion may worsen cardiac
function by diminishing contractility, increasing
vasoconstriction,207,218 or by depleting energy
stores.207
Patients with CHF and magnesium abnormalities whereas
hypomagnesemic patients 45 and 42%, and
hypermagnesemic patients 37 and 30%,
respectively.219 The hypomagnesemic patients probably
died as a result of ventricular arrhythmias. The increased
mortality of patients with hypermagnesemia was thought to be a
reflection of poorer renal perfusion associated with more serious
CHF, since these patients had fewer arrhythmias than patients
with low or normal levels of serum magnesium.219
The potential value of correcting electrolyte imbalance in
CHF-associated ventricular arrhythmias is evident because it is
difficult to predict which arrhythmias may result in sudden
death.215,220 Conventional antiarrhythmic drugs also
are notoriously ineffective in reducing sudden death in these
patients and patients with cardiomyopathy.215 In a
study of 10 patients with ischemic dilated cardiomyopathy without
CHF who received magnesium infusions, the number of premature
ventricular contractions and couplets decreased 95% and runs of
ventricular tachycardia stopped.221 It is interesting
that all patients had normal levels of magnesium before and after
infusions.
Not all evidence supports the importance of magnesium in CHF.
Ralston et al, have shown that in ambulatory patients
with dilated cardiomyopathy and CHF, the prevalence of
hypomagnesemia is relatively low (9%) and serum, circulating
mononuclear cell, skeletal muscle, and myocardial magnesium
concentrations correlate poorly with each other.15
Another study indicated that CHF per se and treatment with
digoxin were not the causes of magnesium depletion.222
Pronounced diuresis by diuretics and increased renal excretion of
magnesium was the cause of magnesium deficiency in 55% of their
patients.222
Arrhythmias
The value of magnesium supplementation in arrhythmias
associated with CHF and myocardial infarction has been discussed.
The importance of magnesium in ventricular-, supraventricular and
digitalis-related arrhythmias has been the subject of
considerable interest.223-232
Magnesium deficiency which is often accompanied by hypokalemia
produces prolongation of QT interval,233-234
ST-segment depression,235 and low-amplitude T waves.
1
Increased magnesium levels lead to bradycardia,236
increased conduction time, and diminished
automatism.231 Magnesium probably influences transport
of potassium,235-237 sodium,238 and calcium
across the cell.237 Magnesium may abolish ventricular
arrhythmia during acute myocardial ischemia due to prevention of
conduction slowing by an anti-ischemic action.239
Although hypomagnesemia is associated with hyponatremia,
hypocalcemia, and hypophosphatemia,3 the association
with hypokalemia is the best known association.240-241
Both potassium and magnesium tend to be depleted with thiazide
diuretics240-243 and spared with potassium-sparing
diuretics.244 This is particularly true for the
elderly245 and for patients on high doses of
diuretics, 243 and may be true for others already at
risk for electrolyte abnormalities, including
alcoholics,1,11 diabetics,11 those with
congestive heart failure, 11 or those with a recent
myocardial infarction. 11 It has been shown that
although serum potassium rises with replacement therapy, the
level of potassium in muscle will not increase unless magnesium
is replaced as well.230,241,246 The benefit of
replacing potassium and magnesium in patients with deficits in
both seems to be larger than for either alone, particularly in
patients treated with non-potassium-sparing
diuretics.243,247 Patients on non-potassium-sparing
diuretics have more frequent ventricular
arrhythmias.243,247 Even more ominous is the finding
in a recent prospective study that 66% of patients in cardiac
arrest had magnesium abnormalities and none of these patients
were successfully resuscitated.241
Ventricular Arrhythmias
Some studies have shown that intravenous replacement of
magnesium is essential in reducing ventricular extrasystoles in
patients with combined magnesium and potassium
deficits246 or those with magnesium deficits
alone.249,250 Even patients who have normal levels of
magnesium may benefit from magnesium infusions after other
antiarrhythmics have failed,224,251,252 particularly
if the patient is also on quinidine or digoxin.251,252
Doses of 2-3 g MgSO4 over 1 min,224,251,212
followed by 10 g of MgSO4 over five hours, are usually
given in life-threatening situations. The antiarrhythmic effects
are perhaps in part due to supraphysiologic doses of magnesium
resulting in increased blood levels 252,253 rather
than due to simple replacement.253 Fortunately,
intravenous magnesium is well tolerated except in those with
renal failure226,235 or preexisting bundle-branch
blocks.227 However, the loading dose should not be
given faster than over one min, since cardiac arrest may
occur.254,255
Recent investigation has cast doubt on the value of magnesium
in some ventricular arrhythmias. Ralston et al. reported
no statistical association between ventricular arrhythmias and
magnesium levels of serum, mononuclear cells, skeletal muscle, or
cardiac muscle of ambulatory patients with CHF.256 In
addition, a recent study found magnesium infusion to be of
limited effect in suppressing inducible, sustained, monomorphic
ventricular tachycardias in a group of 11
patients.257
Torsade de Pointes
In patients with torsades de pointes (polymorphous ventricular
tachycardia associated with marked QT prolongation), when treated
with magnesium sulfate, arrhythmia episodes would be
abolished.258-261 A variety of dosages have been used,
from continuous infusions of 50 mg/min258 to a bolus
of 1 g to 2 g within 1 to 2 min.259-261
Tzivoni and associates259 reported 12 patients with
torsade de pointes and marked QT prolongation who responded to
intravenous magnesium sulfate. In eight of their patients
magnesium was the only therapy given, while in four others,
initial therapy failed and therefore magnesium sulfate was given.
Tzivoni et al.259 recommend that intravenous
magnesium should be used as the first line of therapy in patients
with torsade de pointes and marked QT prolongation.
Supraventricular Arrhythmias
Magnesium also has been shown to be of benefit in
supraventricular tachyarrhythmias.223,224,249,262
Magnesium infusion has been shown in some patients to convert
atrial tachycardia,249,262-264 multifocal atrial
tachycardia,224,263 and reentrant junctional
tachycardia264 to sinus rhythm. Most of these patients
had low serum magnesium224,249,262 or were on digoxin,
furosemide, or aminoglycosides, which may have depleted magnesium
stores.224,263 However, magnesium infusion has been
shown to be effective in supraventricular
tachycardia264 and reentrant junctional
tachycardia,265 even with normal serum magnesium, when
the atrioventricular node is a part of the reentrant
circuit264 Magnesium sulfate was usually given by 2 g
infusion over a period of one min224,263 or
less.264,265
Digoxin Related Arrhythmias
Magnesium status is probably important in digoxin-related
arrhythmias. In one study, hypomagnesemic patients in atrial
fibrillation required twice the amount of intravenous magnesium
to control atrial fibrillation than those who were
not.266 Unfortunately, patients on digoxin therapy may
tend to be hypomagnesemic.209 One study of
hospitalized patients who received digitalis found 19% to be
hypomagnesemic.267
Hypomagnesemia has been shown to lower the ventricular
premature contraction threshold and the ventricular fibrillation
threshold in dogs receiving digitalis.268 Some
investigators have found hypomagnesemia in patients with atrial
fibrillation.269,270 Singh et al. found
hypomagnesemia in 5 of 9 children with a variety of digoxin-toxic
dysrhythmias, and in 3 of 10 children on digoxin but without
toxicity.271 Decreased lymphocyte magnesium and
potassium were found in a series of seven patients on digoxin
with idionodal tachycardia who were successfully treated with
magnesium repletion alone.272
Supplementation has been used successfully in patients with
decreased 269-271 or normal 272 serum
magnesium. The mechanism of magnesium's effect on
digitalis-induced arrhythmias remains unclear.273-276
Magnesium may work by blocking potassium274 or
calcium275 fluxes across the cell or even through the
central nervous system.276 However, magnesium
supplementation has some risk in patients with renal
insufficiency. A prospective study 277 in patients
with cardiac digitalis toxicity and in digitized patients without
toxicity showed that hypomagnesemia was present in 21% of
patients with and 10% of those without digitalis toxicity. The
presence of hypermagnesemia was significantly greater in patients
with toxicity (18%) than in those without toxicity (5%) and
appeared to be related to a significantly greater prevalence of
abnormal renal function in the former group.277
Magnesium infusion does seem to have a role in the treatment
of ventricular arrhythmias associated with digitalis
overdose,278 including in patients with
hyperkalemia279 or with life-threatening ventricular
arrhythmias refractory to lidocaine and
diphenylhydantoin278,279 Usually, 2-3 g of
MgSO4 are given intravenously over one min, followed
if needed by a continuous infusion sufficient to reach a serum
level of 4-5 mEq/l. Serum magnesium levels should be monitored
every two h and the infusion should stop immediately at the onset
of respiratory depression or if deep tendon reflexes are
diminished.279
Conclusion
Magnesium deficiency may play a critical role in the
pathogenesis of ischemic heart disease, cardiomyopathy, and
certain arrhythmias. How a clinician should use this information
in treating his or her patients is still not clear. It is
important to be aware that patients may have magnesium
deficiency, even with serum magnesium levels within the normal
range. 11 Because many of these patients are taking
diuretics for associated hypertension or congestive heart
failure, it may be prudent to use potassium-sparing diuretics,
which also spare magnesium.241
In the hospital setting, it is particularly important to check
serum magnesium in patients with cardiovascular
disease.7 In patients with documented hypomagnesemia,
the magnesium may be given orally, intramuscularly, or
intravenously depending on the urgency of the
situation.280,281
In patients with severe deficits or life-threatening
situations, intravenous magnesium supplementation is
preferred.280,281 Fortunately, magnesium infusion is
well tolerated, even in patients with ischemic heart
disease.282
Magnesium infusion is indicated in patients with torsade de
pointes associated with marked QT prolongation.259
Patients with life-threatening digitalis-related ventricular
arrhythmias refractory to other therapy should be considered for
intravenous magnesium administration.228 Caution
should be exercised in the administration of magnesium sulfate to
azotemic patients who may already be
hypermagnesemic.277
Acknowledgments
The authors would like to acknowledge Jerri Harris, Alicia
Harris, and Sharon Lindsay for preparation of the manuscript.
References
1. Seelig M: Cardiovascular consequences of magnesium
deficiency and loss: Pathogenesis, prevalence and
manifestations-magnesium and chloride loss in refractory
potassium repletion. Am J Cardiol 63, 4G-21G (1989)
2. Sjogren A, Edvinsson L, Fallgren B: Magnesium deficiency in
coronary artery disease and cardiac arrhythmias. J Int
Med 226, 213-222(1989)
3. Altura BM, Altura BT: New perspectives on the role of
magnesium in the pathophysiology of the cardiovascular system.
Magnesium 4, 226-244 (1985)
4. Seelig MS: Magnesium Deficiency in the
Pathogenesis of Disease: Early Roots of Cardiovascular Skeletal,
and Renal Abnormalities. Plenum Medical Book Company, New
York (1980),1-24,141-266
5. McCarron DA: Calcium, magnesium, and phosphorus
balance in human and experimental hypertension. Hypertension
4, (suppl 111);III-27-III-33 (1982)
6. Rardon DP, Fisch C: Electrolytes and the Heart. In The
Heart, 7th edition (Ed. Hurst JW). McGraw-Hill Book Co., New
York (1990),1567
7. Whang R, Ryder KW: Frequency of hypomagnesemia and
hypermagnesemia: Requested vs. routine. J Am Med Assoc
263, 3063-3064(1990)
8. Ryzen E, Elkayam U, Rude RK: Low blood mononuclear cell
magnesium in intensive cardiac care unit patients. Am Heart
J 111,475-480(1986)
9. Elin RJ: Assessment of magnesium status. Clin Chem
33, 1965-1970(1987)
10. Ryzen E, Elbaum N, Singer FR, Rude RK: Parenteral
magnesium tolerance testing in the evaluation of magnesium
deficiency. Magnesium 4, 137-147 (1985)
11. Reinhart RA: Magnesium metabolism. Arch Intern
Med 148, 2415-2420(1988)
12. Ryan MF, Ryan MP: Lymphocyte electrolyte alterations
during magnesium deficiency in the rat. Irish J Med Sci
148, 108-109 (1979)
13. Elin RJ: Status of the determination of magnesium in
mononuclear blood cells in humans. Magnesium 7, 300-305
(1988)
14. Lim P, Jacob E: Magnesium deficiency in patients on term
diuretic therapy for heart failure. Br Med J 3, 620-622
(1972)
15. Ralston MA, Murnane MR, Kelley RE, Altschuld RA,
Unverferth DV, Leier CV: Magnesium content of serum, circulating
mononuclear cells, skeletal muscle, and myocardium in congestive
heart failure. Circulation 80, 573-580 (1989)
16. Resnick LM, Gupta RK, Laragh JH: Intracellular free
magnesium in erythrocytes of essential hypertension: Relation to
blood pressure and serum divalent cations. Proc Natl Acad
Sci 81,6511-6515(1984)
17. White RE, Hurtle HC: Magnesium ions in cardiac function:
Regulator of ion channels and second messengers. Biochem
Pharmacol 38, 859-867 (1989)
18. Elin RJ: Magnesium metabolism in health and disease. In
Disease-a-Month. (Ed. Bone RC). Year Book Medical
Publishers, Inc. (1988)
19. Lichton IJ: Dietary intake levels of requirements of Mg
and Ca for different segments of the U.S. population.
Magnesium 8, 117-123(1989)
20. Marier JR: Magnesium content of the food supply in the
modern-day world. Magnesium 5,1-8 (1986)
21. Bierenbaum ML, Fleischman Al, Dunn JP, Hayton T, Pattison
DC, Watson PB: Serum parameters in hard and soft water
communities. Am J Public Health 63, 169-173 (1973)
22. Crawford MD, Gardner MJ, Morris IN: Changes in water
hardness and local death-rates. Lancet 2, 327-329
(1971)
Address for reprints:
Assad Movahed, M.D.
East Carolina University
School of Medicine
Section of Cardiology
Greenville, NC 27858-4354, USA
This page was first uploaded to The Magnesium Web Site on June
19, 1999
http://www.mgwater.com/
Healthy Water
Association--USA