Magnesium deficiency in coronary artery disease and cardiac arrhythmias

Magnesium deficiency may be of importance for the pathogenesis and the clinical outcome of several cardiac disorders, including coronary artery disease and cardiac arrhythmias 1-7. Magnesium deficiency is frequently found 8-10, and the administration of magnesium has proved to be of therapeutic value 5, 8, 9, 11-16 in subjects with cardiac diseases. Magnesium is the fourth most plentiful cation in the body 4. Intracellularly. the concentration of magnesium is only exceeded by that of potassium. The level of free intracellular magnesium is, however, low and varies with time, conditions, and subcellular structure 17. The myocardial content of magnesium is comparatively high; the concentration in the ventricles is somewhat higher than in the atria 4, 18-20. It has been shown that the ability of cardiac muscle (and vascular smooth muscle) to retain magnesium when placed in a magnesium deficient solution is high compared with other types of muscle tissue 4, 7, 21. The myocardium is nevertheless vulnerable to magnesium deficiency, i.e. heart muscle cell degeneration, fibrosis, necrosis and calcifications may be seen in conjunction with magnesium depletion 4, 22, 23. In heart tissue magnesium stimulates oxidative phosphorylation, Na-K-ATPase, adenylatecyclase, and myofibrillar contraction 17, 24. Furthermore, the complex of MgATP2+ is the substrate of a number of enzymatic reactions, including those noted above 17. A vasodilator action of magnesium was first observed in 1932 by Hazard whether this effect of magnesium deficiency is also valid for chronic forms of ischaemic heart disease remains to be evaluated. The addition of magnesium to isolated arterial segments rapidly results in relaxation. This has been demonstrated for many types of vessels from several species 2, 25-28, 44-47; e.g. both intramyocardial and epicardial coronary arteries from rat, guinea-pig, rabbit, cat, canine, and man (Fig. 1A, B). It has also been shown that magnesium may, uniformly to verapamil and diltiazem 2, 48, abolish rhythmic contractions of human coronary arteries taken postmortally (Fig. 1C). The effect on the vascular tone of shifting the extracellular medium to a magnesium-free buffer solution is the opposite (Fig. 1D), i.e. a contraction is promptly established 26, 27, 44, 45. The effect of magnesium on isolated segments from a human coronary artery after precontraction with 124 mM potassium (A), without precontraction (B), with spontaneous rhythmic contractile activity (C). and by shifting the extracellular medium to a magnesium-free buffer solution (D). The methods are described in papers by Sjögren however, both receptor-and potential-operated calcium channels are involved, the former type of calcium channel to a greater extent than the latter 46, 47. The contractile responses to the cumulative addition of calcium to feline coronary arteries (n = 10) incubated in a high potassium (124 mM) and calcium-free buffer solution containing 10 μM EGTA, in the presence of 1.2. 4.4 or 13.2 mM magnesium. The open symbols indicate contraction produced by 124 mM potassium in the absence of calcium. Adopted with permission from Catherine Press Ltd. Brugge. Belgium (Sjögren in some situations there may in addition be an involvement of depolarization-induced release of noradrenaline from sympathetic nerve terminals 53, 56. It has been demonstrated that magnesium 51 and nifedipine 54 inhibit this action of potassium. The addition of prostaglandin F2α or noradrenaline to arterial segments incubated in a calcium-free buffer solution results in strong contractions which correspond to the release of calcium from stores located within or on the inner surface of the sarcolemma, and/or from intracellular sites 54, 57, 58. The magnitude of these contractions is attenuated by raised extracellular concentrations of magnesium 59. Consequently, it may be suggested that magnesium can interfere with the release of calcium from cellular calcium stores. Hence, magnesium can, as stated by Altura reduction of the extracellular concentration of magnesium leads to a strong contraction of isolated coronary arteries from animals: the greater the degree of reduction of extracellular magnesium the greater the magnitude of the contractile responses. Similar findings have been demonstrated in dogs kept on a magnesium-deficient diet 73, and it is in this review illustrated in a ring segment of a human coronary artery taken postmortally (Fig. 1D). The ligation of the coronary artery in animals results in a marked loss of magnesium from the myocardium 78. The size of the myocardial infarction thus established is increased in conjunction with magnesium deficiency 79, 80. The above noted reduction in myocardial magnesium, which is uniformly distributed in the heart 81, has been confirmed in man as analysed in myocardial specimens from subjects dying from myocardial infarction 6, 70, 81, 82. Acute myocardial infarction leads to a reduction in the serum level of magnesium; this was already noted a few hours after the onset of the myocardial infarction, and followed by a normalization within 10–15 d 74, 75, 83-86. The most likely explanation for this pattern of reaction is a binding of magnesium to catecholamineliberated free fatty acids 26, 84, 87. An additional mechanism may be an increase in the urinary excretion of magnesium induced by the release of catecholamines 26. The latter suggestion has, however, been contradicted by others, e.g. a reduced urinary excretion of magnesium has been noted in subjects with myocardial infarction 85. There are several case reports on cardiac tachyarrhythmias in association with magnesium deficiency: mainly ventricular 1, 5, 8-10, 88, 89, but also supraventricular arrhythmias have been observed 90. Cardiac arrhythmias due to magnesium deficiency may be seen not only in subjects with cardiac disorders such as congestive heart failure and myocardial infarction, but additionally in subjects with inflammatory bowel or renal diseases, or during treatment with cardiac glycosides and/or diuretics (see below). In conjunction with myocardial infarction, the incidence of ventricular arrhythmias, i.e. extra-systoles, tachycardias and fibrillations, has been found to be inversely correlated with the serum level of magnesium 83, 85. It has been shown that the incidence of arrhythmia following the ligation of a coronary artery in dog is increased during magnesium-deficient conditions 69. The mechanism behind the arrhythmogenic properties of the magnesium deficient condition is not fully clarified: a lesional effect on the cellular membrane 91-93, an increase of the intracellular levels of calcium 26, 45, 51, 59, 93, 94, and/or a decrease of the intracellular levels of potassium (see below) may be responsible. Hypothetically, a direct effect on the myocyte membrane potential may be invoked, i.e. similar to that presently observed in coronary vascular smooth muscle cells (Fig. 4A). The association between potassium deficiency and cardiac arrhythmias is well known clinically and explained in detail 95. There is a strong correlation between the intracellular levels of magnesium and potassium in the myocardium (Fig. 5) and in skeletal muscle 96, 97. It has been demonstrated that intracellular potassium depletion may be the consequence of magnesium deficiency. Rats kept on a low-magnesium diet gradually develop depletion not only of magnesium but also of potassium 46, 93, 98, 99. The administration of magnesium to subjects or animals with a combined magnesium and potassium depletion will replete both deficiencies, while the administration of potassium alone will replete none 92, 93. Dyckner the symptoms are not specific and the serum level of magnesium does not adequately reflect the corresponding tissue level 96, 97. It is important to know the latter since magnesium is primarily an intracellular ion. The finding of a low level of magnesium in serum should, however, result in the suggestion that magnesium deficiency exists, while a normal level will not refute this possibility 96, 97. It should be kept in mind that magnesium deficiency is not a rare condition; a variety of renal and intestinal disorders, hyperaldosteronism, and diabetes mellitus, may all result in magnesium depletion 118. Furthermore, loop and thiazide diuretics, frequently administered to subjects with cardiovascular diseases, are known to induce raised levels of urine magnesium 97, 119, 120. Consequently, magnesium administration should be used in a liberal manner in subjects with myocardial infarction and/or cardiac arrhythmias. This is justified not least because the risk of adverse effects of such a treatment is small, provided that subjects with renal failure, heart block and severe respiratory disease are excluded 5. The authors wish to thank Associate Professor Stig Persson, Department of Cardiology, University Hospital of Lund, Sweden, for his valuable advice and criticism during the preparation of the manuscript. The study was supported by grants from the Swedish Association against Heart and Chest Disorders, and the Swedish Medical Research Council (No. 5958).