In: Molecular biology of atherosclerosis. Proceedings of
the 57th European Atherosclerosis Society Meeting. Edited by MJ
Halpern. John Libbey & Company Ltd. Ch 114, pp
513-521
Magnesium and the cardiovascular system: II. Clinical data. A
critical review
J. Durlach1, V. Durlach2, Y.
Rayssiguier3, M. Bara1 and A.
Guiet-Bara1
1SDRM, 64 rue de Longchamp, F-92200 Neuilly,
France; 2CHU, Reims 51092, France; 3INRA
Centre de Recherches Clermont-Fd, Theix 63122, France
Introduction
Magnesium is an important factor in physiology of the
cardiovascular apparatus, and the pathogenesis of cardiovascular
diseases. However several methodological errors are definitely
misleading. Extrapolation from pharmacological effects to
physiological properties is obviously erroneous. Many papers
consider as a proof of the importance of magnesium deficit in the
pathogenesis of cardiovascular diseases the effects of parenteral
magnesium or of high oral doses of magnesium (greater or equal to
2 Mg RDA, i.e. 12 mg/kg/d) which are only
pharmacological data. The physiological properties of magnesium
can only be demonstrated by the occurrence of symptoms due to
in vivo magnesium deficiency subsequently followed by
its specific control with supplementation through physiological
oral doses of magnesium (usually 5 mg/kg/d, always less than 2 Mg
RDA, i.e. 12 mg/kg/d)1,2,3. The
physiopathological role of magnesium deficit is shown by the
parallel correction of this magnesium deficit and of its related
symptomatology.
Control of magnesium deficit depends on the nature of the
magnesium deficit1,2. The difference between magnesium
deficit, magnesium deficiency and magnesium depletion should not
be overlooked. In the case of magnesium deficit it is very
important to distinguish between magnesium deficiency where the
disorder corresponds to an insufficient magnesium intake and
which merely requires simple oral physiological magnesium
supplementation, and magnesium depletion where the disorder is
related to a dysregulation of the control mechanisms of magnesium
metabolism and which requires appropriate
correction1,2.
The main expression of primary magnesium deficit is closely
linked with the consequences of long term chronic magnesium
marginal deficiency. Experimental and clinical forms of chronic
magnesium deficiency are better and better identified and differ
from overt signs of acute deficiency1,2,3.
Coexistence of a symptomatology and a marker of magnesium
deficit even though it was correlated should not be mistaken for
a causality link. Parallel control of both is necessary to prove
this connection. This shows the importance of the magnesium oral
loading test1,4,5. At a physiological dose level (5
mg/kg/day) of a well absorbed salt for at least 1 month, oral
magnesium is totally devoid of the pharmacodynamic effects of
parenteral magnesium. Correction of biological and clinical
symptoms checked after 1 month constitutes the best proof that
these were due to magnesium deficiency. Reversely it is
ineffective in magnesium depleted patients1,6,7,8,9.
The more delicate diagnosis of magnesium depletion rests on the
control of the magnesium metabolism dysregulating
factors1,4,5.
We will firstly discuss epidemiological data, secondly the
role of magnesium deficit in cardio-vascular risk, its
correlation with blood pressure and dyslipidaemias particularly,
lastly its role in the physiopathology of some cardio-vascular
diseases.
Epidemiological data
Magnesium level in drinking water
Among the numerous variables involved in the significant
inverse correlation between cardio-vascular morbidity and
mortality and drinking water hardness, magnesium appears
pre-eminent (see review in (10). The critical quantitative intake
of water magnesium may palliate the absolute marginal magnesium
deficit--usually found in developed countries4--and
its multiple consequences on the nephrocardiovascular apparatus
particularly. Even in the case of balanced daily magnesium
intake, water magnesium may qualitatively act on the
nephrocardiovascular apparatus by palliating a genuine
qualitative magnesium deficit due to a deficient amount of the
highly bioavailable water magnesium 4,10,11,12,13. It
is able to reduce the activation of the neuroendocrine regulatory
mechanisms of magnesium homeostasis which also controls the
metabolism of Cl, Na, K, P and Ca and the regulation of vasomotor
tone1,10. Corrosivity is the other main factor of the
role of drinking water in cardiovascular risk. The noxiousness of
corrosive waters is mainly due to two toxic metals Pb and Cd
which have cumulative toxicity on the nephrocardiovascular system
particularly. Magnesium appears as a competitive inhibitor of
both polluting metals on different sites and particularly during
combined intoxication 1,10,14. It seems advisable to
have 30 mg/l of magnesium in drinking water 1,10.
Dietary magnesium
The data concerning the links between magnesium intake and
cardiovascular diseases are scarce and contradictory. Among other
multiple dietary factors, magnesium intake shows either an
inverse association or not with blood pressure (see review in
(10,15,16,17). These studies do not establish a major role of
magnesium as an antihypertensive factor. People eat food not
nutrients and it may be difficult to demonstrate an independent
effect of a single nutrient in observational studies.
Epidemiological studies are necessarily interpreted on the ground
of well established physiological bases. In the light of our
present knowledge of the physiological relationship between
magnesium and blood pressure magnesium does not appear as a major
antihypertensive factor, but only as a possible antihypertensive
cofactor in particular cases. Thus by using the interesting
concept of multicollinearity, the same epidemiological studies
concerning magnesium and other nutrients whose links with blood
pressure are better established, could be differently interpreted
10,15. In any case coexistence does not mean causality
and we will see that controlled magnesium supplementation studies
are always ineffective.
Magnesium in urine
A variety of studies have examined the possible correlation
between urinary magnesium level and blood pressure. When the
renal function is efficient, these levels should reflect dietary
intake of magnesium: sometimes an inverse correlation between
daily magnesuria and blood pressure is observed18, but
more often no relation was found(see review in 15).
A study of the relationship between daily magnesuria and
several hormones which regulate blood pressure in mild essential
hypertension showed that daily urine magnesium significantly
increased but only in the group with comparatively increased
excretion of urine epinephrine19.
Serum or plasma magnesium
Plasma magnesium is generally normal in hypertensive
individuals and normotension is generally the rule during
magnesium deficit(see review in 10,18). An inverse correlation
between serum magnesium and blood pressure is sometimes
observed15,20 but it is not the rule15,21
and may depend on the use of concomitant magnesium-depletive
drugs1,21. An inverse relation between magnesium and
renin in plasma22 was not confirmed 18,23.
In fact serum magnesium seems related to the evolution of the
disease. A positive correlation was observed in moderate
hypertension which tended to disappear when hypertension became
more severe16,22. An early clinical study of patients
who had severe hypertension with end-organ disease demonstrated
high serum magnesium concentrations15.
Intracellular magnesium: magnesium in erythrocyte and
leucocyte
An inverse correlation between erythrocyte magnesium levels
and free magnesium particularly and blood pressure was observed
in diverse selected populations of hypertensive patients, but no
adjustments were made concerning important covariables(see review
in 15). A weak positive association was found between
free magnesium and mean blood pressure. This relationship was
lost in a multivariate regression analysis23. As a
rule there was no difference between erythrocyte magnesium
concentrations in the hypertensives and controls23a.
Same data concerned magnesium in leucocytes24 or
lymphocytes25. To sum up, these epidemiological and
biological magnesium data do not allow final conclusions yet.
Magnesium deficit and cardiovascular risk
Parallel control of both magnesium deficit and cardiovascular
risk is necessary to establish a causality link: some magnesium
supplementation trials appreciated the role of magnesium
deficiency--negative in hypertension and positive in
dyslipidaemias particularly,--but studies on the control of
magnesium depletion inducing cardiovascular risk--i.e.
in hyperglycaemias--are very scarce or lacking.
Magnesium deficiency and hypertension
Several trials of longterm magnesium supplementation, not
placebo controlled, were performed in mild to moderate
hypertension. For instance the study subjects were being treated
concurrently with antihypertensive drug therapy inducing
magnesium leakage1,7,15,17. The results were not
consistent. They appeared to be better when magnesium deficit was
observed and perhaps in particular selected
subgroups6,7,8,9,15-,16,17,26,27,28. But in none of
the double-blind placebo controlled studies was a significant
fall in systolic or diastolic blood pressure
observed15,17. Monotherapy with oral magnesium cannot
be considered as an efficient treatment of hypertension and be
used as a substitute for a drug of proven
efficacy10,26. But in some hypertensive patients
magnesium deficit because of its numerous noxious actions on the
neprocardiovascular apparatus must be controlled7,9,10
and may sometimes behave as a cofactor of constitutional or
acquired hypertensive factors10. This seems to be
particularly the case with stress-sensible patients with labile
hypertension because of the tight links between magnesium deficit
and stress1,8,10,19,29. The well-known hypotensive
action of parenteral magnesium may be used in hypertensive
patients in preeclampsia particularly but its pharmacological
mechanisms are observed irrespective of magnesium status.
Therefore such pharmacological effects should not be used as a
diagnostic tool attesting magnesium
deficit1,5,10,16,30,31.
Magnesium deficiency and dyslipidaemias
Correlation studies indicated a positive connection between
serum magnesium and HDL cholesterol and a negative correlation
between serum magnesium and total cholesterol32.
Epidemiological studies pointed to the fact that high dietary
magnesium was correlated with high serum HDL cholesterol and low
serum total lipid concentrations33. Thus several open
studies were carried out in order to study the effects of
magnesium oral supplementation at physiological doses inefficient
in healthy subject33a, during 1 month at least in
addition to the usual dietary measures. The results did not bring
any positive action on blood pressure7,34,35 and
either positive or non positive7 effects on lipid
profile. These beneficial effects mainly concerned serum
triglycerides35 with no significant35 or
significant effects34 on cholesterol fractions
(observed after the longest supplementation: 118 days). A double
blind study included 2 months of placebo, 2 months of oral
physiological magnesium supplementation, then again 2 months of
placebo. Triglyceride concentration decreased during magnesium
treatment by 30 percent and increased by 18.1 percent after
switching over to placebo36. The hypothesis of an
activation of serum lipoprotein lipase activity should be invoked
since it is observed simultaneously with a decrease of
triglyceride levels by the pharmacological intravenous infusion
of MgSO4 2 g.36a The observed
data37 suggest that the tested
subjects(hyperlipoproteinaemia type IIa, IIb, or IV) presented
magnesium deficiency, since diagnosed through a positive
oral magnesium load test5. This frequent type of
dyslipidaemia may depend on magnesium deficiency.
Magnesium depletion and diabetes mellitus
Magnesium deficit in the diabetic patients represents a
typical example of deficit where depletion is
largely involved. It cannot be reduced to insufficiency in the
intake (i.e. magnesium deficiency controlled by simple
magnesium supplementation) but comes from complex dysregulation
which differs according to the various clinical forms of diabetes
mellitus, for example a negative correlation between glycosilated
haemoglobin was found in some studies but not in others
1,16,38). The relationship between diabetic macro and
microangiopathy (retinopathy mainly) and magnesium deficit will
only be explained by further understanding of the mechanisms
involved in diabetic magnesium depletion, a requirement
for its control.
To sum up, magnesium supplementation is not a major
antihypertensive factor but appears as an important inducing
factor of atherogenous dyslipidaemia.
Magnesium and aetiopathogeny of cardiovascular diseases
The aetiopathogenic importance of magnesium deficit in
cardiovascular diseases has been closely studied in idiopathic
mitral valve prolapse with major practical consequences, in
several arrhythmias, in some cardiomyopathies and
phlebothromboses, coronary diseases and lastly in cerebrovascular
attacks.
Idiopathic mitral valve prolapse
So-called idiopathic mitral valve prolapse (IMVP) is merely
one form or aspect of latent tetany (LT) due to magnesium deficit
(MDLT)1,16,39,40,41,42. The prevalence, latent nature,
or symptomatology of these two conditions would appear to be
strictly similar. Routine examination reveals the auscultatory
and echocardiographic findings of IMPV combined with clinical and
electromyographic data compatible with LT. Clinical chemical
evaluation must involve at least the examination of plasma and
erythrocyte magnesium, plasma calcium and 24-h urinary calcium.
These should be assessed during dynamic testing with an oral
magnesium load in physiological doses, with, in addition, the
measurement of 24-h urinary magnesium. Other more sophisticated
tests may be necessary in certain special clinical forms. Like
MDLT, IMVP would appear usually to be a benign condition (95
percent of cases) and even capable of recovery, though in a
minority of cases it may be a risk factor. It is thus essential
to elucidate pejorative prognostic factors such as very marked
symptomatology and in particular a ventricular arrhythmia, low
body weight, evidence of mitral regurgitation, hyperechogenic
mitral valves, in particular in elderly men, prolongation of the
QTc interval, a high "excitability index", thrombogenic
disorders, notably of platelet origin, immunological disorders,
constitutional factors such as the presence of HLA Bw35 antigen,
rarely a family history of sudden death, and finally the
depletive nature of MD requiring difficult and sometimes chronic
treatment. Aetiology of MD covers mesological factors
(e.g. inadequate magnesium intake, in particular in
weight-reducing diets, stress etc.) in combination with
constitutional factors(e.g. HLA Bw35 antigen,
behavioural type A, etc.). The latent or symptomatic state
depends on the efficiency of magnesium homeostasis. MD may cause
abnormalities in collagen as well as in the myocardium capable of
inducing mitral dyskinesia. Magnesium therapy is an essential
specific feature in IMVP. A simple increase in magnesium intake
is required in the minority of cases due to deficiency, but must
be combined in the majority of cases due to depletion either with
magnesium-sparing diuretics, pharmacological doses (of between
0.750 to 1 g/d) of pyridoxine hydrochloride, or physiological
doses of vitamin D (e.g., 5 micrograms of 25-OH-D/day).
Propanolol, verapamil and phenytoin may sometimes prove useful
partial "magnesium analogues". In case of mitral insufficiency
and/or thickened hyperechogenic valves, antibiotics must be
prescribed in the presence of any circumstances likely to result
in bacteraemia. Such treatment is capable of controlling symptoms
and more rarely echographic abnormalities, sometimes (1 case out
of 5) leading to complete recovery. Early treatment of MDLT
should prevent the development of MVP. Comparison of the
well-known prevalence of IMVP (5 percent of the population) and
our magnesium concept of its aetiology (complication in 1/4 to
1/3 cases of MDLT), implies the high prevalence of MDLT (15 to 20
percent of the population). The prevalence of this condition is
an epidemiological feature still underestimated in many countries
and in particular in the USA. However, recent international
studies would appear to confirm that these magnesium data are
well founded1,16,38,40,41,42.
Arrhythmias
Both primary and secondary magnesium deficit may induce
cardiac arrhythmias. They are more often ventricular--torsades de
pointe particularly--than supraventricular1,43,44.
They may be the cause for sudden death. Cardiac arrhythmias are
observed in some cases of primary magnesium deficiency, but they
are of great importance in various aetiologies of secondary
magnesium deficit not only in some cardiac disorders such as
congestive heart failure and myocardial infarction, but also in
other causes of secondary magnesium deficit i.e.
alcoholism, diabetes mellitus and magnesium depleting treatments:
i.e. cardiac glycosides and diuretics. The lifespan of
patients under long term-treatment with these drugs may depend on
the control of their magnesium status1. The well-known
antiarrhythmic effects of parenteral magnesium
therapy1,43,44,45 cannot be considered as a diagnostic
tool of magnesium deficit, but arrhythmias due to magnesium
deficit constitute the type of "mixed"
indications--pharmacodynamic and aetiopathogenic--of parenteral
magnesium therapy1.
Idiopathic dilated cardiomyopathics (IDC)
In comparison with controls patients with idiopathic dilated
cardiomyopathy (IDC) had a highly significantly increased
concentration of cadmium in whole blood (+173 percent) and a
lower concentration of magnesium (-11 percent). In daily urine
there was a higher concentration of cadmium and a lower
concentration of magnesium (-36 percent)46. Antagonism
between magnesium and cadmium1,10,14 and the well
known cardiac consequences of both magnesium deficit and cadmium
intoxication1,10,14,46 supports the hypothesis of
their role in pathogenesis of IDC. High alcohol consumption
constitutes a major risk factor in this specific
disease47 and an important cause for secondary
magnesium deficit1. Heavy drinkers are usually big
smokers but in the studied IDC group the smoking habit alone does
not appear to be responsible for the higher cadmium levels. It
would be interesting to assess the corrosivity in drinking water
which might increase cadmium concentration in tap
water1,10.
Phlebothrombosis
In 1967, we described the first case of phlebothrombotic form
of primary magnesium deficit: a major case of phlebothrombosis
which combined reoccurring episodes of profound thrombophlebitis
in the jugular, portal, mesenteric and iliac veins. The magnesium
deficit is verified by a series of indisputable criteria:
negative magnesium balance, low intra-cellular magnesium
concentrations in erythrocytes and platelets, considerable
alterations in exchangeable magnesium and disorders in calcium
distribution. Oral intake of physiological doses of magnesium
confirmed the role of magnesium deficit in the origin of this
whole syndrome by controlling the entire group of clinical and
paraclinical symptoms. In contrast two untimely interruptions in
the magnesium therapy brought on two types of relapse: phlebitis
of the lower limbs and mesenteric phlebitis that required a
resection of the small intestine. The follow-up of this
observation now for more than 25 years verifies the fact of its
magnesium-related aetiology.
This indisputable clinical entity has however given rise to
only a very small number of observations1. No
systematic study has yet tried to define the possible role of
magnesium deficit in the aetiopathogenesis of idiopathic
thrombosis1.
Coronary diseases: angor pectoris and myocardial
infarction
Data on magnesium status in angina are scarce and
contradictory in myocardial infarction. In angina, signs of
magnesium deficit appear more often in vasospastic and unstable
anginas than in common angina.
Myocardial infarction is the typical example of a painful
illness where stress induces magnesium
depletion1,16,48,49,50,51,52,53. In double blind
vs placebo studies on oral magnesium supplementation for
angina pectoris, beneficial effects were shown: either through a
lesser requirement or nitroglycerin54,55 or in a group
of patients with ischaemic heart disease through control of the
deleterious concomitant dyslipidaemia56.
Although the use of intravenous magnesium therapy in acute
myocardial infarction seems justified--namely as pharmacological
antistress therapy--its beneficial effects do not constitute a
proof of magnesium deficit. Moreover the usual doses would be
insufficient to balance it. Several double blind controlled
trials showed that acute mortality and incidence of arrhythmias
were more than halved. In this "mixed" indication of parenteral
magnesium, the beneficial effect is due mainly to its
pharmacological action rather than to a repletion of a deficit:
direct depressive effect on the cardiac conducting system,
peripheral dilatory effect on the arteries, reduced infarct size,
ion stabilizing effect, improved energy generation in the
myocardium and inhibitory effect on platelet
aggregation1,11,44,49,50,52,53,57,58,59,60,61.
Transient ischaemic cerebral attacks and sudden deafness
One should make the greatest reservations on the possible but
unproved role of magnesium in the aetiology of
strokes1. Its "demonstration" relies on dubious
extrapolations from epidemiological, in situ, in vitro,
infusion data and on the so-called major antihypertensive role of
magnesium62,63.
Reversely magnesium deficit could play an important role in
transient ischaemic cerebral attacks until the age of fifty
particularly. They seem in any case to be favoured by the two
major forms of primary deficit: mitral valve prolapse and latent
tetany. Both respond to magnesium supplementation. Some cases of
sudden deafness may have the same magnesium dependent
mechanism1,39,40,42,64,65,66.
Conclusion
Magnesium deficit may be considered as a cardiovascular risk,
though its aetiopathogenic role in the genesis of atherogenous
dyslipidaemias and of "idiopathic" mitral valve prolapse. In
these frequent indications, long term oral magnesium
supplementation is needed. This latter does not constitute a
major antihypertensive factor but sometimes may be an accessory
cofactor. In some arrhythmias, cardiomyopathies,
phlebothrombosis, angina, transient ischaemic attacks, sudden
deafness, investigation of magnesium status is necessary to
appreciate the aetiopathogenic importance of magnesium deficit.
Several causes of secondary magnesium deficit are suggestive:
treatments with salidiuretics and cardiac glycosides, alcoholism,
cadmium intoxication. Diabetes mellitus induces magnesium
depletion whose the control is yet very uncertain. The
pharmacological properties of parenteral magnesium may be used in
some hypertensions (i.e. during pregnancy), arrhythmias
and in coronary infarction, but their efficiency does not
constitute a diagnostic tool for magnesium deficiency. Further
research is still required to determine the exact part played by
magnesium in cardiovascular diseases.
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38. Speich, M., Murat, A., Arnaud, P. & Pineau, A. (1988):
Plasma and erythrocyte magnesium in diabetes mellitus: more on
the correlation and regression studies between several variables.
Magnesium-Bull. 10, 19-21.
39. Durlach, J. & Durlach, V. (1986): Idiopathic mitral
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40. Durlach, J. (1988): Les rapports entre le magnesium et le
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41. Cohen, L., Laor, A., Schnaider, H. & Palant, A.
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42. Zeana, C.D. (1988): Recent data on mitral valve prolapse
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43. Surawicz, B. (1989): Is hypomagnesemia or magnesium
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44. Sjogren, A., Edvinsson, L. & Fallgren, B. (1989):
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45. Iseri, L.T., Allen, B.J. & Brodsky, M.A. (1989):
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46. Smetana, R.H. & Glogar, D.H. (1986): Role of cadmium
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49. Ising, H., Bertschat, F., Ibe, K., Stoboy, V., Goosen, C.
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50. Abraham, A.S. (1988): Potassium and magnesium status in
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51. Speich, M., Auget, J.L. & Arnaud, P. (1990): Analysis
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52. de Valk, H.W., Halboon, J.R.E., Sruyvenberg, A., Grobbee,
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53. Thiele, R., Schuffenhauer, M., Winnefeld, K., Dawczinski,
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55. Ziskoven, R. (1981): Magnesium ions as a natural calcium
antagonists in the therapy of coronary heart.
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56. Rasmussen, H.S., Aurup, P., Goldstein, K., McNair, P.,
Mortensen, P.B., Larsen, O.G. &: Lawaetz, H. (1989):
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57. Classen, H.G., Classen, O., Fischer, G., Fisher, H.,
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58. Rasmussen, H.S. (1988): Justification for intravenous
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59. Schecter, M. (1990): Beneficial effect of magnesium in
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60. Golf, S.W., Graef, V., Temme, H., Mobius, T., Katz, N.,
Roka, L. & Homann, J. (1990): Magnesiumbehandlung beim akuten
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61. Schechter, M. &: Hod, H. (1991): Magnesium therapy
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62. Altura, B.T. & Altura, B.M. (1982): The role of
magnesium in etiology of strokes and cerebrovasospasm.
Magnesium 1, 277-291.
63. Altura, B.T. & Altura, B.M. (1984): Interaction of Mg
and K on cerebral vessels. Aspects in view of stroke.
Magnesium 3, 195-211.
64. Fehlinger, R., Mielke, U., Fauk, D. & Seidel, K.
(1986): Rheographic indications for reduced cerebral
vasoconstriction after oral magnesium medication in tetanic
patients; a double blind, placebo controlled trial.
Magnesium 5, 60-65.
65. Fehlinger, R. (1989): Accelerated aging in magnesium
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4, 1.
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