Magnesium in Health and Disease: Y. Itokawa & J. Durlach,
eds. © 1989 John Libbey & Co Ltd. pp 191-197.
Myocardial injury in magnesium deficiency
Sherman Bloom, MD
Professor and Chairman, Department of Pathology, The
University of Mississippi Medical Center, 2500 North State
Street, Jackson, Mississippi 39216-4505 USA.
The reason we are interested in dietary magnesium is that
reduced intake, primarily in the drinking water, is associated
with an increase in the myocardial infarction death rate. There
may also be an association with cardiac arrhythmias,
hypertension, toxemia of pregnancy, and possibly some neoplastic
diseases. Animal models of magnesium deficiency appear to be
suitable for study of this condition. Much useful information has
been obtained from such models, and we can expect much more to
come. It is worth noting that a wide variety of animals,
including cattle, dogs, rats, mice, and hamsters have been found
to be vulnerable to magnesium deficiency in ways that are
apparently similar to humans. The ease of producing deficiency,
however, varies considerably among the species and also varies as
a function of age. It is presumed, but not established, that the
effects of species and age reflect differences in magnesium
reserves and the kinetics of exchange between compartments. Most
of the work that is discussed here has been carried out with
hamsters. This shows its effects with clarity. We have used the
dog for studies on myocardial infarction because the surgical
procedures and other aspects of the methodology for the study of
myocardial infarction are well established for this species.
While an adult hamster shows severe signs of magnesium deficiency
after 2 weeks on a diet devoid of added magnesium, adult dogs
show only minimal signs after 3 months on such a diet.
MAGNESIUM DEFICIENCY LEADS TO INCREASED MYOCARDIAL LEVELS OF
SODIUM AND CALCIUM
It has been known for some time that severe magnesium
deficiency in animals is associated with focal myocardial
necrosis and decalcification (Heggtveit, 1969). Perhaps the
intuitively most likely mechanism for this effect is depletion of
tissue magnesium, which would lead to serious deleterious
consequences because of the role of magnesium in many enzymatic
reactions, especially those involving nucleotides. While
depletion of tissue magnesium may be an important mechanism of
injury in some tissues, it does not appear to be the case for
heart muscle. We have shown (Chang and Bloom, 1985) that
myocardial levels of magnesium are not affected by reduced
dietary levels, even if the deficiency is severe enough to
greatly lower the serum magnesium level, and even lead to death
of the animal. Because of the methodology used (determination of
magnesium levels in bulk myocardium), it is possible that changes
in a small intracellular magnesium pool were missed. However,
such an event remains to be demonstrated.
While consumption of a magnesium deficient diet may not lead
to reduced myocardial levels of magnesium, it does lead to an
increase in myocardial levels of both sodium and calcium. These
changes area observed even in moderate magnesium deficiency, in
the absence of myocardial necrosis (hamster on Mg10, dog on Mg0).
Furthermore, it appears that the rise in sodium may precede the
rise in calcium (Chang and Bloom, 1985). It has been inferred
from the above observations that magnesium deficiency leads to
reduced activity of the myocyte (Na,K)-ATPase, leading to an
accumulation of sodium in cardiac myocytes (Bloom, 1988}, and
that the high level of intracellular sodium potentiates
sodium-calcium exchange, resulting in an increased level of
intracellular calcium as well. This conclusion is also supported
by studies on the kinetics of potassium flux across heart muscle
cells (Madden et al, 1982). It must be emphasized that the degree
of calcium accumulation can be great enough to cause
morphologically obvious cardiac myocyte calcification, usually
associated with cell death. The influx of calcium is presumably a
critical event, since high levels of cytosolic calcium are
associated with deleterious metabolic effects, including impaired
ATP production (Bloom, 1981). Increased calcium influx therefore
increases vulnerability of cells to injury. Sodium may be
important in the same way, but the metabolic basis by which
accumulation of sodium ions could be deleterious is not
clear.
MAGNESIUM DEFICIENCY INCREASES VULNERABILITY TO MYOCARDIAL
NECROSIS, AND THIS IS COUPLED TO ITS EFFECT ON SODIUM AND CALCIUM
LEVELS
There are several possible tests of our basic hypothesis that
consumption of a moderately magnesium deficiency diet leads to
increased vulnerability to injury, and that such an increase is
secondary to changes in sodium or calcium metabolism. We can ask,
for example, if controlled amounts of ischemia produce more
myocardial necrosis in magnesium deficient animals than in
control animals. We have, in fact, found this to be the case
(Chang et al, 1985). Furthermore, the amount of myocardial
necrosis that was observed, per unit of muscle made ischemic,
varied directly with the level of myocardial sodium as well as
with the level of myocardial calcium, strongly implicating these
in the pathogenesis of the increased vulnerability.
The basic hypothesis could also be tested by determining if
magnesium-deficient animals are more vulnerable to the necrogenic
effects of isoproterenol. As with myocardial infarction, this was
found to be the case (Bloom, 1988). Since isoproterenol-induced
myocardial necrosis is thought to occur through a calcium
overload mechanism (Bloom and Davis, 1972; Bloom, 1981), the
synergism of magnesium deficiency and isoproterenol in producing
myocardial necrosis attains additional significance.
The efficacy of administered magnesium to patients with
toxemia of pregnancy has implicated magnesium in the control of
hypertension. Recent studies in which reduced levels of magnesium
in serum or red blood calls correlated with the occurrence of
hypertension (Dyckner and Wester, 1983; Resnick at al, 1984)
further suggest that this is the case. We can hypothesize that
consumption of a low dietary magnesium level leads to increased
levels of calcium in vascular smooth muscle, just as it does in
myocardium. The vasodilator actions of magnesium (Overbeck at al,
1969) also support this conclusion. Measurement of the vascular
smooth muscle electrolyte levels has not been made. Such
measurements are technically difficult, but not impossible. Our
general theory regarding the relationship between dietary
magnesium, tissue electrolytes, and vulnerability to injury leads
us to hypothesize that magnesium deficiency might increase the
tone of vascular smooth muscle, its vulnerability to injury, and
if sufficiently severe, cause necrosis of vascular smooth muscle.
The hamster is particularly sensitive to magnesium deficiency and
might therefore ha particularly valuable as an indicator of
vascular smooth muscle injury in this condition. We have examined
severely magnesium deficient hamsters for arterial vascular
lesions and found that these are indeed present. The most
striking lesion found was fibrinoid necrosis of arteries and
arterioles (Bloom, 1985). This lesion in hamsters was similar to
that found in human toxemia of pregnancy.
CARDIOTOXICITY OF MAGNESIUM DEFICIENCY IS AUGMENTED BY
INHIBITION OF (NA,K)-ATPASE AND REDUCED BY CALCIUM CHANNEL
BLOCKADE
If it is true that the mechanism by which MD leads to
increased vulnerability to injury is through inhibition of
(Na,K)-ATPase, leading to sodium accumulation, then the
pathologic changes caused by magnesium deficiency should be
aggravated by the administration of an (Na,K)-ATPase inhibitor
during. Furthermore, if the importance of sodium accumulation is
the rise in intracellular calcium it engenders, then the
pathologic changes caused by magnesium deficiency should be
reduced by the administration of a calcium channel blocking
agent. We have found both of these to be true. Digoxin, an
inhibitor of (Na,K)-ATPase, increased both the abundance and size
of myocardial lesions due to magnesium deficiency. Nifedipine, a
calcium channel blocker, had the opposite effect (Ahmad and
Bloom, unpublished observations).
DOES CALCIUM OVERLOAD OCCUR IN HUMANS WHO CONSUME REDUCED
MAGNESIUM LEVELS?
Experimental animals provide considerable evidence implicating
increased levels of intracellular sodium and calcium in the
pathogenesis of the effects of magnesium deficiency on the
cardiovascular system. By extension, we predict that calcium
overload is also important in humans suffering from magnesium
deficiency. What has not bean demonstrated, however, is the
occurrence of increased levels of sodium or calcium in the
vascular smooth muscle or myocardium of humans consuming a
suboptimal level of dietary Mg. For obvious reasons, it may not
be possible to make such measurements. However, it may be
possible to obtain some information on this point indirectly.
At the time of myocardial infarction, there is a systemic
surge of sympathetic activity. One of the effects of adrenergic
stimulation of the heart is an increase in cardiac myocyte
calcium levels, leading to a positive inotropic effect. This may
contribute to the metabolic demands on the heart and may, for
this reason, actually be harmful. The protective effects of
calcium channel blockers and beta adrenergic blockers in patients
with myocardial infarction are presumably due, at least in part,
to their effects in counteracting this sympathetic surge. The
important point for the present discussion, however, is that this
increase in the cardiac myocyte calcium level could lead to
morphologically demonstrable deposits of calcium in myocytes,
especially if the heart muscle was previously loaded with an
abnormally large burden of calcium, as might be the case among
people drinking water containing a low level of magnesium. The
is, if humans are similar to animals in the effects of dietary
magnesium on cardiac myocyte calcium metabolism, then we might
expect to find myocyte calcification in the hearts of patients
who die of acute myocardial infarction in regions where the
drinking water contains low levels of dietary magnesium. The
frequency of such myocyte calcification should be lower,
according to this line of reasoning, in regions where the
drinking water contains large amounts of magnesium.
To determine if this is the case, we have examined the hearts
obtained at autopsy of patients dying with acute myocardial
infarction, and scored them as positive or negative for
myocardial calcification (Bloom and Peric-Golia, unpublished). We
have done this for patients dying at the Veterans Administration
Medical Center in Salt Lake City, Utah, and for patients dying at
the George Washington University Hospital in Washington, DC. We
selected these areas because published values for the water
composition in these areas showed that the Salt Lake City water
supply contains a much higher level of Mg than does the District
of Columbia water supply, furthermore, in agreement with other
data on the association between magnesium content of drinking
water and the myocardial infarction death rate, the myocardial
death rate has been found to be much lower in Utah than in the
District of Columbia (Moriyama et al, 1971).
We examined autopsy material of patients who died with
microscopically demonstrable acute myocardial infarcts. We took
all such cases at the George Washington University Hospital for
the year 1986. There were 23 such cases. We then took 23
consecutive cases at the Salt Lake City Veterans Administration
Medical Center, beginning January 1, 1986, in which there was
microscopically demonstrable acute myocardial infarction. Cases
were examined in a double blind fashion.
The results were very clear. There were no cases of cardiac
myocyte calcification among the 23 cases from the Salt Lake City
area, while there were 15 such cases among the 23 from the
Washington, DC area. This difference was highly significant. Of
course there may be confounding factors. The Salt Lake City
population was from a Veterans Administration hospital, and all
were white males. The Washington, DC population, on the other
hand, was composed of both men and women, white and black. Among
the 8 white males that were in the Washington, DC group there
were 5 cases in which cardiac myocyte calcification was found,
and was significantly different from the Salt Lake City
cases.
CHARACTER OF CALCIUM DEPOSITS IN CARDIAC MYOCYTES OF PATIENTS
WITH ACUTE MYOCARDIAL INFARCTS
Several specific morphologic features of the calcium deposits
in cardiac myocytes in the Washington, DC population are worthy
of note. In all situations, the calcification was limited to
cells. That is, there was no interstitial deposition of calcium
which might suggest an artifact of processing. Some examples of
calcification of old scar tissue were noted, but these were not
scored as positive, since our criteria specified calcification of
heart muscle cells. The most striking of our observations was the
occurrence of calcification of myocytes both outside the area of
infarction, as well as within the area of infarction. The is,
apparently normal ('viable') cardiac myocytes, sometimes some
distance from the area of infarction, showed dense accumulations
of calcium in a granular form scattered throughout their
cytoplasm. The granules of calcium were often distributed in such
a way as to accentuate the cross striations of the myocytes.
Within the area of infarction, calcification was noted as
accumulations of granular calcium in necrotic myocytes. These, of
course, showed no cross striations, and no nuclei. The granules
of calcium were randomly distributed within these necrotic
myocytes.
In addition to these two patterns of calcification, there were
two cases in which granular calcium was found within the walls of
small blood vessels. Some of these blood vessels were
capillaries, and the calcium was present in the endothelium.
Other blood vessels were larger but could not be identified with
certainty as to type. In these, calcium granules were present
both in the intima and elsewhere in the wall, possibly in
vascular smooth muscle cells.
IMPLICATIONS OF ACUTE MYOCARDIAL INFARCTION-ASSOCIATED
CARDIAC MYOCYTE CALCIFICATION
The finding of acute myocardial infarction associated
calcification in myocytes of patients in the Washington, DC area,
but not in the Salt Lake City, Utah area, implies that dietary
magnesium affects the deposition of calcium in heart muscle. Of
course other confounding factors may explain this finding, but no
such confounding factor is apparent. For example, the difference
in myocyte calcification could be related to the elevation above
sea level, which is much greater in the Salt Lake City area than
in the Washington, DC area, but there is no basis for such a
belief. Nevertheless, such a possibility must be considered.
The significance of calcification of myocytes that are not
necrotic must be addressed. It would be expected that if enough
calcium were deposited in a myocyte to make it morphologically
obvious, then it should be sufficient to produce a lethal
metabolic perturbation. This is obviously not the case. It is
concluded that these calcium deposits are sequestered in a
compartment that prevents them from exerting their deleterious
consequences. It is likely that such sequestration could only
occur if the calcium influx occurred gradually, since rapid of a
large amount of calcium appears to rapidly produce necrosis
(Bloom, 1981). Thus, we conclude the patients in the Washington,
DC area have baseline calcium myocyte levels that are elevated.
This support the basic hypothesis that the increased myocardial
infarction death rate in the Washington, DC population is due to
reduced dietary intake of magnesium, that this relative magnesium
deficiency exerts its deleterious effect through action on
calcium metabolism.
One other thing that this finding suggests, is that animal
models of magnesium deficiency are, indeed, appropriate, and that
we say learn more about the human condition by studying them.
BIBLIOGRAPHY
Bloom, S. and Davis, D (1972): Calcium as mediator of
isoproterenol-induced myocardial necrosis. Am. J. Path. 69,
459-470
Bloom, S. (1951): Reversible and irreversible injury: Calcium
as a major determinant. In: Cardiac Toxicology, ed T. Balazs, pp.
179-199 Boca Baton: CRC Press
Bloom, S. (1985): Coronary arterial lesions in Mg-deficient
hamsters. Magnesium 4, 82-95
Bloom, S (1988): Mg deficiency cardiomyopathy. Am. J.
Cardiovasc. Path. 2, 7-17
Chang, C. and Bloom, S. (1985): Severe Mg deficiency,
electrolyte homeostasis, and myocardial necrosis in hamsters. J.
Am. Coll. Nutrition 4, 173-185
Chang, C., Varghese, J., Downey, J. and Bloom, S. (1985):
Magnesium deficiency and vulnerability to myocardial infarction.
J. Am. Coll. Cardiol. 5, 280-289
Dyckner, T. and Wester, P. (1953): Effect of magnesium on
blood pressure. Brit. Med. J. 286, 1847-1849
Heggtveit, HA. (1969): Myopathy in experimental Mg deficiency.
Ann. NY Acad. Sci. 162, 758-765
Madden, J.D., Smith, G.A. and Llaurado, J.G. (1982):
Myocardial K kinetics in rats on Mg deficient diet. J. Am. Coll.
Nutr. 1, 323-329
Moriyama, I., Krueger, D. and Stamler, J. (1971):
Cardiovascular Diseases in the United States. pp 49-118.
Cambridge: Harvard University Press
Overbeck, H.W., Daugherty, R.M. and Haddy, P.J. (1989):
Continuous infusion indicator dilution measurement of limb blood
flow and vascular response to magnesium sulfate in normotensive
and hypertensive men. J. Clin. Invest. 48, 1944-1956
Resnick, L.M., Gupta, R.K. and Laragh, J.H. (1984):
Intracellular free magnesium in erythrocytes of essential
hypertension: Relation to blood pressure and serum divalent
cations. Proc. Natl. Acad. Sci. USA 81, 6511-6515
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