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 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.
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.
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.
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.
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.
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.
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.
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.
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 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.
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.
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.
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.
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.
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.
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.
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.
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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