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 & Wurmser [25]. Three years later Zwillinger [3] reported anti-arrhythmic properties of magnesium. Since then evidence has accumulated indicating that magnesium is a strong relaxant of most types of blood vessel, including coronary arteries [2, 6, 7, 26-28], and that magnesium can convert cardiac tachyarrhythmias [5, 8-10]. The present review was undertaken in order to focus on the recent progress in knowledge of the influence of magnesium on coronary vasomotor activity and cardiac tachyarrhythmias. Mechanisms behind these effects of magnesium are investigated, and the possible clinical implications of the coronary relaxant and anti-arrhythmic properties of magnesium are discussed. In many parts of the world the daily allowance of magnesium is below the recommended level [29-31]. In order to estimate the intake of magnesium the hardness of the water has to be taken into consideration, as being dependent not only on its content of calcium but also on magnesium. A soft water supply often implicates a low average intake of magnesium. Occasionally, the water might be soft due to a low concentration of calcium only, i.e. despite an intermediate or even high concentration of magnesium [6, 7]. It has been shown that subjects living in areas with soft water have a low content of magnesium in cardiac muscle [32, 33] and a high incidence of cardiovascular death [34-39]. The latter appears to be mainly attributable to sudden death ischaemic heart disease. This is in further support of the view of magnesium deficiency being an important pathogenetic factor for cardiovascular disease since magnesium deficiency is known to promote ventricular fibrillation (see below). In addition, regardless of the hardness of the water in the living area investigated, the myocardial content of magnesium has been reported to be low in sudden death ischaemic heart disease [37, 40-42], and in ischaemic heart disease without any proven myocardial infarction [43]. Hence, it may be suggested that magnesium can protect against sudden death ischaemic heart disease; 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 & Edvinsson [51] and Högestätt et al. [121]. The coronary arterial contractile response to a number of agonists is dependent on the extracellular concentration of magnesium, e.g. the magnitude of contractions produced by potassium (Fig. 2), noradrenaline, and 5-hydroxytryptamine is enhanced during magnesium-deficient conditions [26, 27, 44, 47]. The constrictor activity of the above agonists is attenuated by the presence of excess magnesium [26, 27, 44, 47] (Fig. 2). Contractile responses to 60 mmol potassium in isolated coronary arteries from pigs incubated in buffer solutions containing 0. 1.2 (standard buffer solution) or 4.4 mM magnesium. The vertical bars indicate the SEM (standard error of the mean). The asterisks indicate mean values significantly (Student's paired t-test) different from that noted in the presence of 1.2 mM magnesium (n = 7). Details of the methods are in [51] and [121]. The mechanisms behind relaxation and contraction in general of vascular smooth muscle cells have been investigated thoroughly [49, 50]. The activity of the contractile proteins, the actinmyosin filaments, is strictly dependent on the intracellular concentration of free calcium ions. The latter is in turn dependent on the transport of extracellular calcium across the cellular membrane (via potential- and/or receptor-operated calcium channels) and on the release of calcium from the sarcolemma and intracellular stores [49, 50]. Magnesium may influence the transport of calcium. The cumulative addition of calcium to calcium-depleted, potassium-depolarized arterial segments results in a concentration-dependent contraction. The magnitude of this contraction is dependent on the extracellular concentration of magnesium (Fig. 3), i.e. a dextral shift of the concentration-response curve is noted in the presence of excess magnesium [6, 44, 47, 51]. A similar calcium antagonizing effect of magnesium has previously been demonstrated using radiolabeled calcium, in vascular smooth muscle cells [45] and recently in cardiac myocytes using the patch clamp technique [52]. Hence, magnesium may counteract or compete with the transport of calcium across the cellular membrane. The exact site of this action of magnesium is at present not known in detail; 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 & Edvinsson [51]). Magnesium may, as indicated above, interfere with contractions induced by excess potassium ions. The contractile response to potassium is mainly the result of membrane depolarization and the subsequent passage of extracellular calcium across the cellular membrane via potential-operated calcium channels [53]. However, in the absence of extracellular calcium, potassium may still produce weak contractile responses [51, 53-55] (Fig. 3). This latter effect of potassium is due to the liberation of calcium from less readily depleted calcium stores within the cellular membrane or intracellularly; 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 & Altura [6], modulate calcium entry, binding, and translocation within vascular smooth muscle cells. The effects of magnesium on the transport of calcium into and within vascular smooth muscle cells are thus similar to those of traditional calcium entry blocking agents such as verapamil, nifedipine and diltiazem [50, 60]. Magnesium might, provocatively, be labelled a 'physiological' or endogenous calcium antagonist. There may be an additional mechanism behind the coronary vasomotor action of magnesium. According to recent findings from our laboratory, magnesium may induce marked effects directly on the membrane potential of coronary smooth muscle cells. The contractile response elicited by the exposure of an isolated arterial segment to a magnesium-free solution may be initiated by, or include, a direct depolarization of the smooth muscle cell membrane. The shift of the extracellular medium to a magnesium-free buffer solution leads not only to contraction, but also to strong depolarization, as observed in intramyocardial arteries from guinea pig (Fig. 4A). The resting potential across the arterial smooth muscle cell membrane was approximately — 50 mV, being depolarized to — 2 5 mV by shifting from the normal buffer medium (1.2 mM magnesium) to a magnesium-free solution (Fig. 4A). The addition of 10 mM magnesium, on the other hand, produced a marked hyperpolarization (Fig. 4B). Hence, a change in membrane potential appears to be involved in the mechanism behind the vasomotor actions of magnesium. Changes in the resting membrane potential of a smooth muscle cell from the guinea pig coronary artery. Effect of exposure to a magnesium-free (A) or a high-magnesium (B) buffer solution. For the methods see [122]. Relaxation of vessels may in addition be induced by enzymatic reactions, i.e. increased activity of adenylate or guanylate cyclases, or by the release of an endothelium-derived relaxing factor (EDRF). The vasorelaxations produced by nitroglycerin and acetylcholine, for instance, involve the activation of guanylate cyclase and the release of EDRF, respectively [61-63]. It has been speculated, but not shown, that these dilator mechanisms might be initiated by magnesium. The release of EDRF per se requires the presence of magnesium [64], while the dilator action of magnesium appears not to be affected by the removal of the endothelium [51]. Changes in magnesium status may influence the electrical activity of the myocardium. The rate of the SA-node is increased, the duration of the action potential of the atria is decreased, the duration of the QRS complex is increased, the T-wave is peaked, the P-R interval is prolonged, and the ST segment is depressed in conjunction with magnesium deficiency [4, 65, 66]. The above listed electrocardiographic changes are reversed by the administration of magnesium [23]. Excess magnesium, on the other hand, may result in a decrease in the rate of the SA-node, increase in PR- and QT-intervals, and decrease in P-wave voltage, in parallel with an increase in the absolute refractory time period [67-69], During severe magnesium intoxication heart block and eventually asystole are seen to occur [68]. Magnesium deficiency may lead to coronary arteriosclerosis [70, 71], and the levels of magnesium in serum have in fact been reported to be inversely correlated with the severity of coronary artery disease [72]. It has been proposed that magnesium deficiency may promote angina pectoris [73]. The level of magnesium in serum has been reported to be reduced in conjunction with myocardial ischaemia [74-76]. Furthermore, Altura [77] has suggested that hypomagnesaemia is an important pathogenetic factor in coronary artery spasm; 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 & Wester [12] have demonstrated that the frequency of ventricular extrasystolic beats is reduced following the infusion of magnesium in subjects on diuretic treatment with a suspected magnesium-potassium depletion. The reason behind the explanation of this interaction between magnesium and potassium is not fully known. However, an influence of magnesium on the aldosterone secretion [100, 101], the activity of cellular Na-K-ATPase [102-105], and on the integrity of the cellular membrane [91-93], may be involved. Hence, cardiac arrhythmias due to potassium depletion may sometimes be the result of a magnesium deficiency. The correlation between levels of magnesium (mmol 100 g−1 FFDS) and potassium (mmol 100 g−1 FFDS) in cardiac muscle taken from 23 spontaneously hypertensive rats. The correlation is assessed by linear regression analysis. FFDS = fat free dry solid weight, r = coefficient of correlation (linear regression analysis). For the methods see [96]. The association between magnesium deficiency and cardiac toxicity of digitalis is well known. Reduced levels of magnesium in serum frequently occur in conjunction with digitalis intoxication, and digitalis-induced tachyarrhythmias may be converted by the administration of magnesium [9, 106-109]. Experiments in animal models have revealed that the threshold concentration of digitalis for the induction of toxic arrhythmias is directly correlated with the serum level of magnesium [110]. Furthermore, the administration of digitalis may result in a loss of magnesium from the myocardium [111]. In addition, the myocardial uptake of digitalis is increased during magnesium-deficient conditions [112]. The mechanism behind these interactions between magnesium and digitalis is not fully elucidated. However, additive depressor effects on the activity of myocardial Na-K-ATPase, and thereby on intracellular potassium levels, might tentatively be involved. In view of data suggestive of an involvement of magnesium deficiency in the pathogenesis of coronary artery disease, the notion that magnesium is a strong relaxant of coronary arteries, and the frequent findings of reduced serum levels of magnesium in conjunction with myocardial infarction, it is pertinent to suggest that magnesium administration might be of value in acute myocardial infarction. Arrhythmias induced in animal models by ligation of a coronary artery are reversed by the administration of magnesium [69]. Furthermore, the intravenous infusion of magnesium reduces the incidence of serious arrhythmias [11, 14-16] and death [11, 16] related to acute myocardial infarction. The doses of anti-arrhythmic drugs given to subjects with myocardial infarction can be reduced during the administration of magnesium [13]. The anti-arrhythmic properties of magnesium are valid also in clinical situations without acute myocardial infarction [1, 5, 8, 9, 12, 88, 90, 113] or magnesium deficiency [5, 9, 109, 114]. Magnesium should, in our view, be considered as an adjuvant in the treatment of cardiac tachyarrhythmias, especially in conjunction with hypokalemia and/or digitalis intoxication, following coronary bypass surgery [115], or in 'torsades de pointes' type of ventricular tachycardia [9, 116, 117]. Magnesium deficiency must be treated promptly in subjects with myocardial infarction and/or cardiac arrhythmias. Magnesium deficiency is, however, not easily demonstrated; 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).