Millane T A, Camm A J. Magnesium and the Myocardium ... - LifeWave

British Heart J 1992;68:441-2441EditorialBRITISHHEARTJOUJRNALMagnesium and the myocardiumThe publication of the results of the Leicester IntravenousMagnesium Intervention Trial (LIMIT-2) producedheadlines in the national press. There was a 24% relativereduction in mortality and a 25% reduction in theincidence of heart failure, benefits conferred equally onthrombolysed and non-thrombolysed patients.' Magnesiumis clearly here to stay, but little is known of thisfascinating cation despite its presence at the centre of thechlorophyll molecule and as part of the active binding siteof ATPase. In humans magnesium is a physiologicalnecessity, but it is also active pharmacologically. This hasresulted in considerable confusion-particularly in the areaof cardiac arrhythmia.Cardiovascular consequences of magnesiumdepletionIn a classic description of magnesium deficiency, Whangand Welt described cerebral irritability with muscle tetanyand ataxia in dogs.2 Rapidly progressive hypomagnesaemiawas associated with severe hypokalaemia that was resistantto treatment with potassium supplementation. Histologicallythere was calcification of the myocardium withpathological arterial fibrinoid changes. A progressivecardiomyopathy was seen with a rise in intracellularcalcium and mitochondrial calcium deposition.3In humans there was a similar picture of calciumoverload associated with myocardial magnesium depletionin cardiac transplant recipients rendered (incidentally)magnesium deficient by cyclosporin.4 Cardiac arrhythmiawas not seen. In postmortem studies in ischaemic heartdisease, myocardial magnesium content was up to 20%lower and calcium content up to six times higher than innon-ischaemic controls, particularly when death was sudden.5Myocardial potassium content was concurrentlyreduced. Hypomagnesaemia is an independent risk factorfor patients with heart failure but it is not associated with anincreased incidence of arrhythmia on Holter monitoring.Lipid profiles are adversely affected with a reduction in theHDL/LDL ratio contributing to the adverse cardiovascularprofile of magnesium deficiency.Magnesium, potassium, and cardiac arrhythmiaMyocardial magnesium depletion is associated with importantintracellular potassium deficiency. Cardiac arrhythmiais well described in patients with hypomagnesaemia ormyocardial magnesium depletion, or both, but in allreports magnesium imbalance was associated with concurrenthypokalaemia. This association precludes the identificationof magnesium depletion as the single cause ofarrhythmia. The myth surrounding magnesium depletionand cardiac arrhythmia is seen to arise from the dubiousdeduction that because intravenous magnesium abolishesarrhythmia in hypomagnesaemic subjects, hypomagnesaemiais therefore the cause of the arrhythmia.However, magnesium modifies ventricular tachycardia andother arrhythmias, irrespective of serum magnesium concentration,in many patients who have no reason to bemagnesium deficient. Cardiac arrhythmia was not seen inthe animal studies of severe magnesium depletion.Magnesium as an antiarrhythmic agentIn 1935 Zwillinger used intravenous magnesium to treatventricular arrhythmia associated with digoxin toxicity.6Since then there have been numerous case reports of theefficacy of magnesium in both supraventricular and ventriculartachycardia, albeit with an unfortunate dearth ofrandomised, controlled trials. Since the CardiacArrhythmia Suppression Trial, the benefits of a safe, cheap,"natural" drug are more readily appreciated and the use ofmagnesium as an antiarrhythmic agent is once againbecoming popular.Five to ten mmol of magnesium sulphate administeredover a few minutes will abolish torsade de pointes (by aneffect on phase 4 calcium current), reduce digoxinassociatedarrhythmia (by modification of membranedigoxin kinetics), and terminate (or render pace-terminable)many sustained ventricular tachycardias. It is salutaryto note that in many studies, magnesium was effective inrestoring sinus rhythm when used as a "last resort" afterthe prior administration of a mixture of other agents.Patch-clamp studies showed that the magnesium ionmodifies at least three potassium channels, as well as actingon both L and T type calcium channels.7 The documentedelectrophysiological effects of magnesium are largelyconfined to slowing of conduction in the atrioventricularnode, but recent evidence from the denervated heart in vivosuggests that prolongation of the action potential doesoccurr (as predicted from in vitro studies). An increase intachycardia cycle length was seen in clinical practice.8These observations strongly suggest a mode of action formagnesium as an antiarrhythmic agent and should begin todispel the scepticism surrounding its use.Magnesium as a calcium antagonistMagnesium has been dubbed "nature's calcium antagonist",an effect most clearly seen in the antagonistic roles ofmagnesium and calcium in the determination of arterialtone. The action of endothelium relaxing factor (EDRF) ismagnesium dependent and is antagonised by calcium.Spasm in angiographically normal coronary arteries waslessened or abolished by an intravenous bolus ofmagnesium, and there was some suggestion that hypomagnesaemiacan provoke spasm.'The haemodynamic effects of magnesium in vivo are

442largely mediated by a fall in systemic vascular resistancesecondary to arteriolar vasodilatation. An intravenousbolus sufficient to double serum concentrations is clearedfrom the blood within 20 minutes, largely by renal excretion.Optimistic trials exploiting these effects to treatsystemic hypertension with oral magnesium have met withlittle success-rapid clearance by the kidney preventsserum concentrations rising above normal.'"The use of intravenous magnesium in the acute treatmentof uncontrolled pregnancy related hypertension (preeclampsia)is established in Australia and the UnitedStates, but for some reason has not proved popular inEurope. The intense vasoconstriction associated with thiscondition is particularly sensitive to the dilatatory effects ofmagnesium, which also acts in neurological tissue as amembrane stabiliser to reduce muscular and cerebralirritability. Indeed, the first use of magnesium in humansrelated to an attempt to induce "anaesthesia" in twointrepid researchers, who discovered that the illusion ofanaesthesia was in fact a state of profound muscle relaxationbounding on-paralysis!"Magnesium as an anti-ischaemic agentMeta-analysis of several trials has suggested a beneficial rolefor intravenous magnesium infused in the 24 hours afteracute myocardial infarction. 2 The most recent ofthe International Studies of Infarct Survival (ISIS 4),investigating the effects of oral nitrates and angiotensinconverting enzyme inhibitors includes a similar period ofintravenous magnesium administration in a 2 x 2 x 2 factorialdesign, and will complement the results of theLIMIT-2 study.The mechanisms of action of magnesium in thiscircumstance are unknown. A significant reduction in theincidence of cardiogenic shock was noted in one study,which, taken with the LIMIT-2 data, suggests that magnesiummay preserve left ventricular function by reducingischaemic damage. Evidence from animal models suggeststhat this may be due to reduction in calcium-mediatedischaemic damage. During ischaemia, intracellular freemagnesium concentrations rise rapidly as the formation ofATP from ADP (incorporating magnesium) is limited byhypoxia and acidosis with subsequent loss of magnesiumfrom the cell magnified by cAMP mediated 13 receptorstimulation.'3 During reperfusion, magnesium is re-incorporatedinto ATP to produce a net fall in intracellular freemagnesium with reciprocal calcium overload.In addition to any possible antiarrhythmic action, magnesiumraises fibrillation thresholds; it also has antiplateletMillane, Cainiiieffects mediated via prostacyclin, prolonging bleedingtime. '" The beneficial effects of magnesium on arterial tonemay also be important in what will prove to be a verycomplex relation.Magnesium deficiency is probably an important riskfactor in cardiovascular disease that has adverse effects onarterial tone and myocardial calcium balance. The arrhythmogeniceffects of hypomagnesaemia are not seen in theabsence of concomitant potassium imbalance. Therapeutically,magnesium has many of the characteristics ofthe ideal drug-it is simple, cheap, has a wide therapeuticrange, a short half-life and a limited capacity for adverseinteraction with other agents. As an adjuvant antiarrhythmicagent for the acute control of ventriculartachycardia, magnesium might be considered as a first lineagent. Its potential anti-ischaemic actions are becomingestablished in myocardial infarction, but it might alsoprove useful in unstable angina and in the peri and postangioplasty periods.Department of Cardiological Sciences,St George's Hospital Medical School,LondonT A MILLANEA J CAMM1 Woods K, Fletcher S, Roffe C, Haider Y. Intravenous magnesium sulphate insuspected myocardial infarction: results of the second Leicester IntravenousMagnesium Intervention Trial (LIMIT-2). Lancet 1992;339:1553-8.2 Whang R, Welt L. Observations in experimental magnesium depletion.J Clin Invest 1963;42:305-13.3 Heggtveit H. The cardiomyopathy of magnesium-deficiency. In: Bajusz E,ed. Electrolytes and cardiovascular diseases. Basel/New York: S Karger,1965:204-20.4 Millane T, Jennison S, Patel M, Moss R, Holt D, McKenna W. Progressivemyocardial calcification associated with prolonged hypomagnesemia aftercardiac transplantation [abstri. J Am Coll Cardiol 1992;19:396.5 Johnson CJ, Peterson DR, Smith EK. Myocardial tissue concentrations ofmagnesium and potassium in men dying suddenly from ischaemic heartdisease. Am J Clin Nutr 1979;32:967-70.6 Zwillinger L. Uber die Magnesiumwirkung auf das Herz. Klin Wochnenschr1 935;14: 1429-33.7 Agus Z, Morad M. Modulations of cardiac ion channels by magnesium.Annu Rev Physiol 1991;53:299-307.8 DiCarlo LA, Morady F, de Buitleir M, Krol RB, Schurig L, Annesley TM.Effects of magnesium sulfate on cardiac conduction and refractoriness inhumans. J Am Coll Cardiol 1986;7:1356-62.9 Miyagi H, Yasue H, Okumura K, Ogawa H, Goto K, Oshima S. Effect ofmagnesium on an anginal attack induced by hyperventilation in patientswith variant angina. Circulation 1989;79:597-602.10 Cappuccio FP, Markandu ND, Beynon GW, Shore AC, Sampson B,MacGregor GA. Lack of effect of oral magnesium on high blood pressure: adouble blind study. Br Med J 1985;291:235-8.11 Neuwirth I, Wallace G. On the use of magnesium as an aid to anaesthesia.J Pharmacol Exp Ther 1929;35:171-87.12 Teo K, Yusuf S, Collins R, Held P, Peto R. Effects of intravenous magnesiumin suspected myocardial infarction: overview of randomised trials. B MedJ 1991;303:1499-504.13 Romani A, Scarpa A. Hormonal control ofMg transport in the heart. Nature1990;346:841-4.14 Lauler DP, Seelig M, Hollifield JW, et al. A symposium: Magnesiumdeficiency-pathogenesis, prevalence, and strategies for repletion. An? JCardiol 1989;63:1-46.