Magnes Res 1992 Jun;5(2):147-53
Summary: Magnesium deficit may be considered as a cardiovascular risk because of its aetiopathogenic role in the genesis of atherogenous dyslipidaemias and the so-called "idiopathic" mitral valve prolapse. It does not, however, constitute a major antihypertensive factor, though it may sometimes be an accessory co-factor. Plasma magnesium is generally normal in untreated hypertensive patients and normotension is the rule during magnesium deficit. An inverse relationship between magnesium and renin in the plasma of hypertensives has not been confirmed. In practice, plasma magnesium seems to be related to the evolution of the disease. An inverse correlation between blood pressure and erythrocyte total and free magnesium levels has been observed in diverse selected populations but no adjustment has been made in these studies for important covariables. A weak positive association between blood pressure and erythrocyte free magnesium was lost in a multivariate regression analysis. As a rule there is no difference between erythrocyte, leucocyte, and lymphocyte magnesium in hypertensives and controls. More often no relation between urinary magnesium and blood pressure is observed. Daily urine magnesium may be increased with increased excretion of urine adrenaline. Epidemiological data on dietary magnesium, particularly in drinking water, should be carefully scrutinized: these studies do not establish a major role for magnesium as an antihypertensive factor but confirm the importance of magnesium deficit as a nephrocardiovascular risk factor and sometimes gives support for a role of magnesium as an antihypertensive cofactor. The use of magnesium-depleting drugs in hypertensive patients may induce magnesium depletion which must be palliated. In none of the double blind placebo-controlled studies of magnesium therapy in hypertensive patients was a significant fall in systolic or diastolic blood pressure observed. Monotherapy with oral magnesium cannot be considered as an efficient treatment of hypertension or be used as a substitute for drugs of proven efficacy. However, in some hypertensive patients with magnesium deficit, its deleterious effects on the nephrocardiovascular apparatus must be controlled. The well known pharmacological hypotensive action of parenteral magnesium may be used in hypertensive patients --in pre-eclampsia particularly--but the pharmacological mechanisms are observed irrespective of magnesium status. Such effects should not be used as a diagnostic tool in the investigation of magnesium deficit.
Key words: Blood pressure, diabetes mellitus, dyslipidaemias, magnesium, mitral valve prolapse.
Magnesium is an important factor in the physiology of the cardiovascular apparatus and the pathogenesis of cardiovascular disease. However several methodological errors are definitely misleading.
Extrapolation from pharmacological effects to physiological properties is obviously erroneous. Many papers consider that proof of the importance of magnesium deficit in the pathogenesis of cardiovascular diseases is provided by the effects of parenteral magnesium or of high oral doses of magnesium (equal to twice the RDA or more, ie 12 mg/kg/d), but such data are purely pharmacological. The physiological properties of magnesium can only be demonstrated by the occurrence of symptoms due to in vivo magnesium deficiency, followed subsequently by its specific control with supplementation through physiological oral doses of magnesium (usually 5 mg/kg/d, always less than twice the RDA, ie 12 mg/kg/d)1-3. The pathophysiological role of magnesium deficit is shown by the parallel correction of the 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 magnesium deficit, it is very important to distinguish between magnesium deficiency, where the disorder corresponds to an insufficient magnesium intake 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 which requires appropriate correction1,2.
The main expression of primary magnesium deficit is closely linked with the consequences of long term chronic marginal magnesium deficiency. Experimental and clinical forms of chronic magnesium deficiency are now more and more easily identified and differ from overt signs of acute deficiency1-3.
Coexistence of symptoms with markers of magnesium deficit, even though correlated, should not be mistaken for causality. 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/d) of a well absorbed salt for at least one month, oral magnesium is totally devoid of the pharmacodynamic effects of parenteral magnesium. Correction of biological and clinical symptoms after one month of such treatment constitutes the best proof that these were due to magnesium deficiency. Conversely, physiological doses are ineffective in magnesium-repleted patients1,6-9. The more precise diagnosis of magnesium depletion rests on the identification of dysregulating factors concerned with magnesium metabolism1,4,5. <./P>
Experimental studies on magnesium and blood pressure have showed that in vivo chronic marginal magnesium deficiency either did not affect blood pressure or initially decreased and subsequently increased it3,10.
The aim of the present study was to establish the importance of magnesium in hypertensive disease. We shall first discuss the epidemiological and biological data; second, evaluate the role of magnesium deficit in various cardiovascular risk factors: dyslipidaemias, diabetes mellitus, and mitral valve prolapse; and third, show the importance of magnesium supplementation as an adjunct to the treatment of hypertensive patients.
Among the numerous variables involved in the inverse correlation between cardiovascular morbidity and mortality and the hardness of drinking water, magnesium appears pre-eminent11. The critical quantitative intake of water magnesium may palliate the absolute marginal magnesium deficit commonly found in developed countries4 and its multiple consequences, particularly on the nephrocardiovascular apparatus. Even in the case of a balanced daily magnesium intake, water magnesium may act qualitatively on the nephrocardiovascular apparatus by palliating a magnesium deficit resulting from an inadequate intake of this highly bioavailable source of magnesium4,11-14. It can reduce the activation of the neuroendocrine regulatory mechanisms of magnesium homeostasis which also control the metabolism of Cl, Na, K, P and Ca and the regulation of vasomotor tone1,11. Corrosivity is the other major factor in the role of drinking water in cardiovascular risk. The harmful effects of corrosive waters are mainly due to two toxic metals, Pb and Cd, which have cumulative toxicity on the nephrocardiovascular system particularly. Magnesium appears to be a competitive inhibitor of these two polluting metals at different sites, particularly during combined intoxication1,11,15. It seems advisable to have at least 30 mg/litre of magnesium in the drinking water1,11.
The data concerning the links between magnesium intake and cardiovascular diseases are scanty and contradictory. Among other multiple dietary factors, magnesium intake shows either an inverse association or none at all with blood pressure(reviews 11,16-18). 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 in the light of well established physiological principles. On the basis of our present knowledge of the physiological relationship between magnesium and blood pressure, magnesium does not appear to be a major antihypertensive factor, but only a possible antihypertensive cofactor in particular cases. Thus, by using the interesting concept of multicollinearity, the same epidemiological studies concerning magnesium and other nutrients with better established links with blood pressure could be differently interpreted11,16. In any case coexistence does not mean causality and we shall see that controlled magnesium supplementation studies are always ineffective.
Various studies have examined the possible correlation between urinary magnesium level and blood pressure. When renal function is efficient, these levels should reflect the dietary intake of magnesium; sometimes an inverse correlation between daily magnesuria and blood pressure is observed19, but more often no relation is found16.
A study of the relationship between daily magnesuria and several hormones which regulate blood pressure in mild essential hypertension has shown that daily urine magnesium significantly increases but only in the group with comparatively increased excretion of urine adrenaline20.
Plasma magnesium is generally normal in hypertensive individuals and normotension is the rule during magnesium deficit11,19. An inverse correlation between serum magnesium and blood pressure is sometimes observed16,21 but it is not the rule16,22 and it may depend on the concomitant use of magnesium-depleting drugs1,22. An inverse relation between magnesium and renin in plasma23 was not confirmed in other studies19,24,25, in agreement with our recent experimental data10. In fact serum magnesium seems related to the evolution of the disease. A positive correlation has been observed in moderate hypertension which tended to disappear when hypertension became more severe17,24. An early clinical study of patients who had severe hypertension with end organ disease demonstrated high serum magnesium concentrations16.
An inverse correlation between erythrocyte magnesium levels, and free magnesium in particular, and blood pressure has been observed in diverse selected populations of hypertensive patients but no adjustments were made for important covariables16. A weak positive association was found between free magnesium and mean blood pressure. This relationship was lost in a multivariate regression analysis25. As a rule there is no difference between erythrocyte magnesium concentrations in hypertensive patients and controls26. There have been similar observations relating to leucocyte magnesium27,28.
To sum up, these epidemiological and biological magnesium data do not yet allow final conclusions to be drawn, but they do not seem to support the notion that there is an important link between magnesium deficit and the hypertensive state.
Parallel control of both magnesium deficit and cardiovascular risk is necessary to establish a causality link: some magnesium supplementation trials have appreciated the role of magnesium deficiency in dyslipidaemias, and of magnesium deficit in mitral valve prolapse where depletion appears more frequent than deficiency, showing its aetiopathogenic importance. However, studies on the control of magnesium depletion in hyperglycaemias are very scarce or lacking.
Correlation studies have indicated a positive correlation between serum magnesium and HDL cholesterol and a negative correlation between serum magnesium and total cholesterol29. Epidemiological studies point to the fact that high dietary magnesium is correlated with high serum HDL cholesterol and low serum total lipid concentrations30. Thus several open studies were carried out to study the effects of oral magnesium supplementation of at least one month's duration in physiological doses, in addition to the usual dietary measures31. There were no positive effects of these interventions on blood pressure7,32,33, and the effects on the lipid profile were either positive or negative7.
The beneficial effects mainly concerned serum triglycerides33, with no significant effects33 or with significant effects33 on the cholesterol fractions (observed after the longest supplementation - 118 d). In a double blind placebo-controlled study in a group of patients with ischaemic heart disease, oral magnesium supplementation controlled the deleterious lipid profile33a. Another double blind study included 2 months of placebo, 2 months of oral physiological magnesium supplementation, and a final 2 months of placebo; triglyceride concentration decreased during magnesium treatment by 30% and increased by 18.1% after switching over to placebo34. Activation of serum lipoprotein lipase activity may be involved since this is also observed in parallel with a decrease in triglyceride levels following the pharmacological intravenous infusion of MgSO4.35 The observed data36 suggest that the subjects tested (with hyperlipoproteinaemia types IIa, IIb, or IV) presented magnesium deficiency, since they were diagnosed through a positive oral magnesium load test5. These common types of dyslipidaemia may thus depend on magnesium deficiency.
The so-called idiopathic mitral valve prolapse (IMVP) is merely one form or aspect of latent tetany due to magnesium deficit (MDLT)1,17,37-40. The prevalence, latent nature, and symptomatology of these two conditions appear to be strictly similar. Routine examination reveals the auscultatory and echocardiographic findings of IMPV combined with clinical and electromyographic data compatible with latent tetany. 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 dosage, 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 to be usually a benign condition (95% of cases) and even capable of recovery, though in a minority of cases it may be a risk factor. It is thus essential to identify adverse prognostic factors such as very marked symptomatology and in particular ventricular arrhythmias, low body weight, evidence of mitral regurgitation, hyperechogenic mitral valves, especially in elderly men, prolongation of the QTc interval, a high "excitability index", thrombogenic disorders, particularly of platelet origin, immunological disorders, constitutional factors such as the presence of HLA Bw35 antigen, rarely a family history of sudden death, and finally a magnesium depletion requiring difficult and sometimes chronic treatment. The aetiology of magnesium deficit covers mesological factors (e.g., inadequate magnesium intake, in particular during weight-reducing diets, stress etc.) together with constitutional factors(e.g., HLA Bw35 antigen, behavioural type A, etc.). The latent or symptomatic state depends on the efficiency of magnesium homeostasis. Magnesium deficit 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 in the majority of cases due to depletion it must be combined with magnesium-sparing diuretics, pharmacological doses (of between 0.75 and 1.0 g/d) of pyridoxine hydrochloride, or physiological doses of vitamin D (e.g., 5 micrograms of 25-OHD/d). Propanolol, verapamil and phenytoin may sometimes prove useful partial "magnesium analogues". In cases 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 (one case out of five) leading to complete recovery. Early treatment of MDLT should prevent the development of mitral valve prolapse. Comparison of the well known prevalence of IMVP (5% of the population) and our magnesium concept of its aetiology (a complication of 1/4 or 1/3 cases of MDLT) implies the high prevalence of MDLT (15 to 20% 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 founded1,17,37,38,41,42.
Magnesium deficit in the diabetic patient represents a typical example of deficit where depletion is mainly involved. It cannot be explained by an insufficient intake (ie, magnesium deficiency controlled by simple magnesium supplementation) but derives from complex dysregulation which differs according to the various clinical forms of diabetes mellitus (for example a negative correlation between glycosylated haemoglobin was found in some studies but not in others 1,17,39). 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 appears to be an important inducing factor of atherogenous dyslipidaemia and mitral valve prolapse, two well defined cardiovascular risk factors, and may be linked with cardiovascular complications of hyperglycaemia through complex dysregulations.
Several uncontrolled trials of long term magnesium supplementation have been performed in mild to moderate hypertension. For instance the study subjects were being treated concurrently with antihypertensive drug therapy inducing magnesium leakage1,7,16,18. The results were not consistent. They appeared to be better when magnesium deficit was observed and perhaps in particular selected subgroups6-9,16-18,40,43,44. But in none of the double blind placebo-controlled studies was a significant fall in systolic or diastolic blood pressure observed16,18,45,46. Monotherapy with oral magnesium cannot be considered as an efficient treatment of hypertension or be used as a substitute for a drug of proven efficacy11,40,47. In some hypertensive patients, however, magnesium deficit must be controlled because of its numerous harmful effects on the nephrocardiovascular apparatus7,9,10,11,67, and because it may sometimes behave as a cofactor of constitutional or acquired hypertensive factors11. This seems to be particularly the case for stress-sensitive patients with labile hypertension because of the close links between magnesium deficit and stress1,8,10,11,30,48.
The vasodilator action of parenteral magnesium has been well known for over a century49. The hypotensive action of parenteral magnesium may be used in hypertensive patients, particularly in pre-eclampsia but its pharmacological mechanisms are observed irrespective of magnesium status. Therefore such pharmacological effects should not be used as a diagnostic tool in the investigation of magnesium deficit because its pharmacological actions are observed irrespective of magnesium status1,5,11,17,50,51.
Magnesium deficit may be considered as a cardiovascular risk on account of its aetiopathogenic role in the genesis of atherogenous dyslipidaemias and of "idiopathic" mitral valve prolapse.
Magnesium supplementation does not constitute a major antihypertensive treatment and cannot be used as a substitute for drugs of proven efficacy. However, in some hypertensive patients magnesium deficit must be controlled because of its numerous harmful actions on the nervous system and on the nephrocardiovascular apparatus, and because it is sometimes a cofactor of constitutional or acquired aetiological factors for hypertension.
The well known hypotensive action of parenteral magnesium may be used in hypertensive patients, ie in pre-eclampsia, but its pharmacological effects, which are observed irrespective of magnesium status, should not be used as a diagnostic tool for magnesium deficit.
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