Am Heart J, 102 Aug;124(2):544-9
Magnesium deficiency and sudden death
Mark J. Eisenberg, MD, MPH San Francisco,
Calif.
Over the past three decades, a variety of epidemiologic,
autopsy, clinical, and animal studies have suggested an
association between magnesium (Mg) deficiency and sudden death.
This association may have far-reaching implications, because
sudden death continues to be a major cause of cardiovascular
mortality in the United States and accounts for over 300,000
deaths per year.1, 2 Early studies showed an inverse
relationship between drinking water content and cardiovascular
disease incidence,3, 4 but much of this relationship
was subsequently shown to be the result of an association between
water hardness and sudden death.5 A number of
water-borne minerals were examined as potential cardiotoxic or
cardioprotective factors, and over the past few decades a
consensus has emerged that low Mg content in drinking water is
associated with high rates of sudden death.
Magnesium metabolism
Distribution and measurement. After potassium, Mg is
the most common intracellular cation. It is an important
component in a variety of biologic processes, and it is critical
for the actions of many enzymes. Mg is distributed throughout the
body as follows: approximately two thirds is located in bone,
close to one third is intracellular, and the rest is
extracellular.6, 7 A 70 kg adult contains about 2000
mEq of Mg (1 mEq = 0.5 mmol = 12 mg), and normal serum values
vary between 1.5 and 2.5 mEq/L.8
Because the blood contains less than 1% of total body Mg
stores, serum Mg is poorly reflective of whole body levels.
However, although normal serum levels may be seen in the setting
of Mg deficiency, if serum levels are low, Mg deficiency is
usually present.7-9 Sophisticated means have been
developed to assess total body Mg stores,7, 10 but
these techniques are not commonly available, and they have been
used in very few studies.
Nutritional sources. The body’s Mg requirements
have been estimated to range from 18 to 33 mEq/day, while average
intake in the United States has been estimated to range from 20
to 30 mEq/day.6-7, 11 Because average intake is so
close to requirement levels, nutrition surveys suggest that
dietary Mg is often barely adequate to meet daily
requirements.11, 12 Foods rich in Mg include nuts,
cereals, seafoods, and green leafy vegetetables.8, 13
Boiling these foods in Mg-deficient soft water may leach out Mg,
while boiling in Mg-rich hard water may prevent its
loss.14 In addition, gut absorption of water-borne Mg
may be more efficient than that of food-borne Mg. Consequently,
Mg bioavailability may be greater from water than from food
sources.15 Because of the marginal intake and
absorption of Mg from food sources, it has been estimated that in
hard water areas, 20% to 40% of a person’s daily Mg
requirements may be provided by the Mg contained in drinking
water.16
Water hardness. Magnesium and calcium (Ca) are the
principal minerals that determine water hardness, but the
proportions of these minerals may vary
substantially.17 In North America, Mg:Ca ratios
generally range from 1:1 to 1:5, but in certain areas of Western
Europe, they may be two orders of magnitude lower.18
Knowledge of Mg and Ca contributions to water hardness is
important when assessing studies relating Mg deficiency and
sudden death. In many of the early epidemiologic studies, exact
mineral content was not reported, and this presents a problem
when trying to evaluate these studies.
Magnesium deficiency and sudden death
Epidemiologic studies. In the late 1950s and early
1960s, evidence began to accumulate documenting striking
geographic differences in the incidence of cardiovascular
disease. Cardiovascular disease was shown to be more common in
areas with increased mineral content in drinking water. The
relationship was first described by Kobayashi3 in
Japan, and shortly thereafter by Schroeder4 in the
United States. Kobayashi’s findings related stroke
incidence and the acidity of river water. Schroeder subsequently
analyzed regional incidences of cardiovascular disease and found
an inverse relationship with water hardness.
In the 1960s and early 1970s, Anderson et al.5, 19
conducted a series of studies in Ontario, Canada. Since there is
a gradient of water hardness across Ontario, these investigators
examined the incidence of acute and nonacute ischemic heart
disease in hard and soft water areas. Little relationship was
found with nonacute heart disease, but an inverse relation ship
was found between water hardness and sudden death. In hard water
areas (water hardness >200 ppm), the standardized death rate
from ischemic heart disease was 365 in 100,000, and 120 in
100,000 of these deaths were sudden. In soft water areas (water
hardness <100 ppm), the death rate was 416 in 100,000, and 195
deaths in 100,000 were sudden. Among deaths ascribed to heart
disease, the proportion of sudden deaths was 20% to 30% higher in
soft water areas compared with death rates in hard water
areas.
Following these early reports, epidemiologic studies in a
number of countries confirmed the inverse relationship between
drinking water hard ness and sudden death, while a few reports
found no correlation.20-27 (The lack of correlation
between water hardness and sudden death in several reports was
later explained by the inclusion of hard water areas with
unusually low Mg concentrations.) Although analytical techniques
were different among the studies, several found similar
correlation coefficients between water hardness and
cardiovascular disease (-0.59 to -0.70), and others found that
cardiovascular mortality or sudden death was at least 10% more
common in soft water areas than in hard water areas.
Once a relationship between water hardness and sudden death
was established, investigators examined whether it was the result
of a cardiotoxic factor in soft water or a cardioprotective
factor in hard water. Initially, a cardiotoxic factor was
suspected, because it was known that soft water can leach out
undesirable minerals from pipes and geologic layers.28
No strong correlations were found when a variety of minerals was
examined, however, and a cardioprotective factor began to be
suspected. Many elements were investigated, with attention
focusing on Mg and Ca because of their importance in deter mining
water hardness. Mg was found to correlate most closely (in an
inverse fashion) with sudden death rates.29, 30
Autopsy studies. Autopsy data were next examined in
an effort to link intracellular Mg levels with drinking water
intake and sudden death. Investigators were particularly
interested in myocardial Mg content. Anderson et al.31
examined myocardial tissue from people dying of trauma in hard
and soft water areas. Myocardial Mg content was significantly
lower in people living in soft water areas compared with levels
in people living in hard water areas (207 versus 222 µg/gm
wet weight, respectively). These differences in Mg content were
only found in myocardial tissue samples; they were not present in
serum samples or in tissue samples from diaphragm or pectoralis
muscle.16
A series of studies also examined myocardial Mg content in
people dying of sudden death and in controls who died of trauma
(Table I).32-37 These studies consistently showed
depressed levels of myocardial Mg in people who died suddenly.
Although it is clear that myocardial Mg content is decreased
after sudden death, it is still unclear whether this is a cause
or an effect.
Animal and clinical studies. In conjunction with
epidemiologic and autopsy studies, animal and clinical studies
were also conducted. These studies suggest two possible
mechanisms for the association between Mg deficiency and sudden
death: arrhythmogenesis and coronary artery vasospasm. According
to the arrhythmogenesis theory, Mg deficiency in creases cardiac
irritability and facilitates cardiac arrhythmias.38
Experimental studies show that Mg is an essential cofactor for
Na-K adenosine triphosphatase (ATPase), an enzyme that influences
cardiac irritability by regulating ion fluxes across myocardial
cell membranes. Clinical reports40-42 suggest that Mg
deficiency is linked with cardiac rhythm disturbances including
premature ventricular beats, ventricular and supraventricular
arrhythmias, and torsades de pointes. These studies also suggest
that Mg deficiency lowers the threshold for digitalis-toxic
arrhythmias,43 and that intravenous Mg can acutely
reverse cardiac rhythm disturbances in some
situations.44-46
A second proposed mechanism is that Mg deficiency causes
coronary artery vasospasm, leading to myocardial ischemia and
sudden death. Evidence comes from several animal
studies47-49 in which vasospasm was induced by
Mg-deficient solutions and vasospasm subsequently resolved with
the addition of Mg. Other studies50, 51 have
documented pathologic changes in the heart associated with Mg
deficiency, and these changes have been linked with chronic
myocardial ischemia. Although these studies suggest that coronary
artery vasospasm induced by Mg deficiency may be responsible for
sudden death, complementary clinical data are lacking.
Magnesium
supplementation. The large number of studies that
suggest an association between Mg deficiency and sudden death
raise the issue of whether Mg supplementation can be used for the
primary prevention of sudden death. Several methods of
supplementation have been proposed including: public education to
change dietary habits, addition of Mg to community water
supplies, fortification of foods, and oral supplementation.
Before supplementation can be considered, however, several
questions need to be answered: (1) Will Mg supplementation reduce
the risk of sudden death? (2) How much time is required before
the effects of such supplementation are evident? (3) What is the
optimal method of supplementation? and (4) Is supplementation
technically and financially feasible?
Risk reduction. Can Mg supplementation be used for
the primary prevention of sudden death? Although no studies have
addressed this question directly, a number of double-blind,
placebo-con trolled trials have examined the use of Mg
supplementation for secondary prevention. These studies examined
the efficacy of intravenous Mg supplementation in patients
hospitalized after myocardial infarction (Table II).52,
58 Most of these studies indicate that intravenous Mg
decreases the incidence of cardiac arrhythmias and overall
mortality after acute myocardial infarction. Although intravenous
Mg supplementation may be useful in patients at high risk for
ventricular arrhythmias, little research has been directed at
supplementation in people with long standing but mild Mg
deficiency (as might be expected in people living in soft water
areas). Nevertheless, results from the early epidemiologic
studies5, 22 suggest that sudden death rates in soft
water water areas are at least 10% greater than sudden death
rates in hard water areas. If Mg supplementation causes even a
modest decrease in sudden death rates a substantial number of
lives might be saved.
Timing of supplementation. If Mg supplementation
decreases the risk for sudden death, how long will it take before
the effects are seen? Then answer to this question will have an
impact on the choice of supplementation methods and the length of
time supplementation will need to be maintained. If sudden death
is related to intracellular Mg depletion, then supplementation
might be able to reverse the situation rather quickly. If sudden
death is related to pathologic changes caused by chronic Mg
deficiency, then supplementation may have to be given for many
years before a change in death rates is observed. One
study59 addressed this question tangentially by
observing changes in death rates following a change in the source
of community water supplies and coincidental increases in
drinking water hardness. Within a few years of drinking water
changes, reductions in death rates were evident. This study did
not quantify the Mg content of the drinking water, however, and
overall cardiovascular mortality was assessed rather than sudden
death. No interventional trials have yet addressed this
issue.
Methodology. What is the best method of increasing Mg
intake? One method is public health education to increase the use
of Mg-rich hard water for drinking and cooking. Health education
could be used to discourage the use of water softeners to treat
water used for drinking and cooking. (Conventional water
softeners remove natural Mg.) At the same time, the consumption
of Mg-rich food and water could be encouraged.
A second method of supplementation is the addition of Mg to
community water supplies, similar to fluoridation. If Mg content
in soft water areas could be raised to levels found in hard water
areas, a drop in sudden death rates would be strong evidence that
supplementation makes a difference.
A third method of increasing Mg intake involves the
fortification of foods. In Finland, substitution of Mg for part
of the sodium in table salt was shown to be a safe way of
increasing Mg intake, and this substitution was associated with
an increase in serum Mg.60 Sudden death rates could
not be examined in this study because of the small number of
patients investigated.
Finally, oral Mg supplementation has been suggested for people
at high risk of sudden death. This type of supplementation would
be similar to potassium supplementation for cardiac patients who
are receiving diuretics. The advantages of oral supplementation
over other methods are that it is cheap and that it can be easily
targeted at high-risk groups. In addition, oral Mg has long been
prescribed by clinicians who were influenced by the early
epidemiologic studies. With the exception of hypermagnesemia in
patients with renal failure, few adverse effects have been
reported. Although large-scale clinical trials have not yet been
attempted, the long history of oral Mg supplementation testifies
to its safety.
Feasibility. Is Mg supplementation feasible? Public
health education to increase Mg intake is unlikely to be
controversial, but the questions of how to supplement Mg and in
whom remain unanswered. Large-scale Mg supplementation of
community water supplies is impractical because of technologic
and political obstacles.18, 61 Fortification of foods
is technically feasible and would be less controversial, since
many foods are now fortified with vitamins and minerals. To date,
however, oral Mg is the best studied of the alternatives and
might well be the most feasible initial intervention. Patient
acceptability, low cost, and the possibility of targeting
high-risk groups make this an easy method to implement and
monitor.
Conclusions.
Substantial evidence suggests that Mg deficiency is associated
with sudden death, but most data come from observational rather
than interventional studies. Proof that Mg supplementation
reduces the risk of sudden death is needed before efforts to
increase Mg intake are undertaken. Sufficient data have
accumulated to justify a large, randomized, placebo-controlled
trial for the primary prevention of sudden death. If such a study
demonstrates that Mg supplementation reduces both sudden death
and overall mortality rates, then large-scale efforts may be
warranted.
Summary.
A link between Mg deficiency and sudden death is suggested by a
substantial number of studies published over the past three
decades. Data come from epidemiologic, autopsy, clinical, and
animal studies. They suggest that: (1) Sudden death is common in
areas where community water supplies are Mg-deficient. (2)
Myocardial Mg content is low in people who die of sudden death.
(3) Cardiac arrhythmias and coronary artery vasospasm can be
caused by Mg deficiency and (4) Intravenous Mg reduces the risk
of arrhythmia and death immediately after acute myocardial
infarction. Because of these data, Mg supplementation has been
proposed as a possible method of reducing the risk of sudden
death. Suggested ways of supplementing Mg include public
education to change dietary habits, addition of Mg to community
water supplies, fortification of foods, and oral supplementation.
Despite the substantial number of studies linking Mg deficiency
with sudden death, no prospective studies have yet investigated
whether large-scale Mg supplementation is useful for the primary
prevention of sudden death.
I thank Mr. John Marier (National Research Council of Canada),
Dr. Dade Moeller (Harvard School of Public Health), and Dr.
Kenneth Flegel (Royal Victoria Hospital, McGill University) for
many helpful suggestions.
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From the Cardiology Division of the Department of Medicine,
University of California, San Francisco.
Received for publication Dec. 30, 1991; accepted March 3,
1992.
Reprint requests: Mark J. Eisenberg, MD, Moffitt-Long
Hospital/Box 0214, University of California, 505 Parnassus Ave.,
San Francisco, CA 94143.
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