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Clin. Cardiol. 5, 556-568 (1992)

Review

Magnesium Disorders and Cardiovascular Diseases

JOHN R. PURVIS, M.D., ASSAD MOVAHED, M.D.*

Department of Family Medicine and *Department of Medicine/Section of Cardiology, East Carolina University, School of Medicine, Greenville, North Carolina, USA


Summary: The evidence linking magnesium disorders with the pathogenesis and treatment of various cardiovascular diseases will be reviewed.

Key words: magnesium deficiency, magnesium supplementation, cardiomyopathy, ischemic heart disease, hypertension, arrhythmias, digitalis toxicity


Introduction

Magnesium is critical to the proper functioning of many physiologic reactions, including those that are critical to the cardiovascular system.1 There is growing evidence that magnesium status is important in pathogenesis and treatment of cardiovascular disease.2-5 Magnesium activates adenosine triphosphatase (ATPase), which is essential for normal cell membrane function and is the energy source for Na-K pump.6 Intracellular magnesium deficiency may cause an increase in intracellular Na and Ca and a loss of K.6 Despite the importance of this cation, physicians frequently fail to consider magnesium status when managing a patient. In a recent study of hospitalized patients, 5.7% of the patients were hypermagnesemic and 42.2% were hypomagnesemic.7 Physicians initiated requests for magnesium measurements for 7.4% of these patients.7

Serum magnesium, like serum potassium, is often normal despite depletion of total body magnesium.8 Retention of an oral or intravenous magnesium load is a good estimate of the total body magnesium, but usually requires urine collection of 24 hours.9,10 Intracellular levels of magnesium are more accurate measures11 but there is often poor correlation of intracellular red blood cell and intracellular mononuclear cell magnesium,12,13 and these may correlate poorly with the magnesium content of muscle in different disease states.14,15 Of the two, intracellular mononuclear cell magnesium is a better indicator of the magnesium status of the heart. For example, in a recent study of coronary care unit patients, only 7.7% were hypomagnesemic, but 53% showed low levels of mononuclear cell magnesium.8

Yet, neither serum nor intracellular levels of magnesium may give as accurate a picture of physiologic activity as the level of free magnesium,16,17 which may best be determined by nuclear magnetic resonance (NMR) spectroscopy.9,16-18 Obviously, except for serum magnesium, it is impractical for clinicians to determine magnesium status. However, magnesium abnormalities may be important in pathogenesis and magnesium replacement may be necessary for treatment of ischemic heart disease, cardiomyopathy, congestive heart failure, and some arrhythmias.

Epidemiology

Epidemiologic evidence linking magnesium deficiency to ischemic heart disease and sudden death has been investigated for more than three decades. One area of interest is the possibility that people living in areas with magnesium-low water have more heart disease than those living in areas with magnesium-rich water. The hypothesis is that because modern western diets contain less magnesium than needed according to the recommended dietary allowance and magnesium balance studies,19 the marginal difference in magnesium intake occurs from the water supply.20 Therefore, people living in magnesium-low water areas have increased cardiovascular mortality because the total intake is insufficient.

This is referred to as the "water story" and is supported by numerous studies showing an inverse relationship between cardiovascular mortality and water hardness.21-27 Others have found good correlation between heart disease and the ratios of calcium to magnesium28 or sodium29 to magnesium in the water supply. In addition, areas switching to soft water from hard water have had increased mortality, while mortality decreased when the opposite change was made.30 Autopsies of patients in soft-water areas who died from noncardiac causes have shown lower levels of magnesium in cardiac tissue than those who had lived in hard-water areas.31 Finally, autopsies of men less than 45 years old who had lived in soft-water areas showed more coronary atheromata and evidence of myocardial infarction than similar men from hard-water areas.32

However, not all evidence supports this hypothesis. Many other elements are also found in hard water. Other researchers have found correlations between increased calcium,25,3 copper,34 potassium,35 lithium,25 and a host of other trace elements,25 and diminished heart disease. Other studies have shown no increased cardiac mortality with hard water.36-40 Reviews of the subject have been unable to demonstrate a conclusive association between magnesium content of water and ischemic heart disease.34,36,41 Some of the confusion may be due to the fact that "hard water" has varying amounts of calcium and magnesium.42,43

Nonetheless, it is important to remember that intake from food and water determines whether magnesium deficiency exists. Clinical studies looking at the importance of magnesium supplementation often do not consider environmental levels of magnesium. This may account for differences found between studies investigating the link between magnesium disorders and cardiovascular disease.

Ischemic Heart Disease

There is growing evidence that magnesium deficiency is important in the pathogenesis of ischemic heart disease.44-48 In addition to the indirect epidemiologic evidence already discussed, there is experimental evidence that supports the role of magnesium deficiency in ischemic heart disease.

Autopsies of patients who died from ischemic heart disease have shown lower cardiac magnesium levels than autopsies of those who died from other causes.49-51 In addition, patients with ischemic heart disease retain more magnesium than those without the disease, which points to a relative magnesium deficiency.52

Magnesium supplementation has been used to diminish the symptoms of ischemic heart disease for more than 50 years.53,54 Malkiel-Shapiro reported that 125 patients with angina improved with magnesium supplementation.54

Recently, Goto et al. showed increased magnesium retention in patients with variant angina.55 Calcium channelblocker therapy completely relieved symptoms in these patients, and magnesium retention decreased to the levels of control subjects.55 Other antianginal medications have been shown to affect magnesium levels as well. Unstable angina patients treated with nitrates and calcium channel blockers or nitrates alone have shown improved serum magnesium levels.56 Cohen et al showed that beta blockers also have a beneficial effect on serum magnesium in patients after myocardial infarction.57

There are physiologic reasons that magnesium may be important in the pathogenesis of ischemic heart disease. Magnesium deficiency has been associated with most of the major risk factors for atherosclerotic coronary artery disease, coronary artery spasm, and coronary artery disease, coronary artery spasm, and coronary artery thrombosis.

Atherosclerosis

There is considerable evidence linking magnesium deficiency to atherosclerosis and the major risk factors for coronary artery disease. Several studies on different species have shown that animals given magnesium supplementation have less atherosclerosis58-65 when given atherogenic diets than those not supplemented, even without a change in serum cholesterol.62 In fact, Resnick and associates66-68 have postulated that several coronary artery disease risk factors including hypertension, obesity, and insulin resistance have the common denominator of magnesium deficiency.69-70

Diabetes

The level of diabetic control has been shown to be inversely related to magnesium deficiency.71-73 In addition, diabetic retinopathy has been correlated to magnesium deficiency, irrespective of diabetic control in two different studies74-75

Both insulin-dependent and noninsulin-dependent diabetic patients have been shown to have increased urinary losses76 and reduced serum77,78 and intracellular levels of magnesium.77,79-81

However, not all diabetics have deficiencies of both serum and intracellular magnesium,73,82,83 and the levels differ depending on the type of diabetes and the gender of the patient. Nevertheless, oral magnesium supplementation has improved control in insulin-dependent84 and noninsulin-dependent diabetics.79

Magnesium deficiency could be important in diabetes for several reasons. Many of the enzymes involved in glycolysis are magnesium dependent.85 Increased insulin resistance86 has been found in patients with reduced free magnesium levels,70 and animal studies have shown increased glucagon stimulation,86 decreased insulin secretion87 and reduced insulin uptake88 with magnesium deficiency.89

Dyslipidemia

 The importance of magnesium deficiency in dyslipidemia has been suggested for some time.90-95 Experiments in rats have shown that magnesium deficiency produces hypertriglyceremia,96,97 hypercholesterolemia,96-99 increased low-density lipoproteins (LDL),97 and reduced high-density lipoprotein (HDL)95 through reduced triglyceride clearance,100 diminished activity of lecithin cholesterol acetyltransferase (LCAT)96 and lipoprotein lipase, and increased activity of HMG-COA reductase.101 The association between hypomagnesemia and hypertriglyceremia has been confirmed in studies of pigs.102

The association between lipid abnormalities and hypomagnesemia has not been as clear in human studies. Population studies have shown positive,103 inverse,91 or no104 correlation between serum magnesium and cholesterol levels.

Supplementation has had variable results. Healthy volunteers have shown no improvement in lipid panels with magnesium oxide supplementation.105 Studies in patients with lipid disorders have shown both no effect106 and a statistically significant improvement107 in cholesterol and triglycerides. The latter study showed reductions in total cholesterol from 297 mg/dl to 257 mg/dl and improvements in HDL levels from 35 mg/dl to 47 mg/dl with magnesium supplementation.

The earlier suggestion that patients with ischemic heart disease had improvement in cholesterol levels with parenteral magnesium supplementation108 has been confirmed in a short-term follow-up of a relatively small group of patients with oral magnesium supplementation93 Other studies also have shown a beneficial decrease in beta-lipoprotein levels,93,108,109 which would reduce risk of coronary artery disease. 110

Hypertension

Magnesium deficiency has been linked to the pathogenesis of another coronary artery disease risk factor, hypertension.111,112 Magnesium is important in activating the Na-K-ATPase pump, which in turn expedites the movement of potassium into the cell and sodium out of the cell. 1 112,113 Magnesium is important in decreasing the entry of calcium into the cell as Well.112,113 Therefore, magnesium deficiency can lead to increased intracellular sodium and calcium,114 increased peripheral resistance, and vasospasm,115,116 which have been observed experimentally in animals.117 A decrease in retinal spasm with magnesium supplementation has also been noted in a group of eight hypertensive patients with elevated renin levels although the systemic arterial pressure did not change. 118

A number of studies report the relationship between hypertension and intake of a variety of cations. 119-127 The importance of magnesium in the pathogenesis of hypertension is not clear. For instance, the Honolulu heart study 126 found that total magnesium intake was strongly and inversely related to systolic and diastolic arterial pressure, but other studies have found varying relations.119-125,127 One Belgian study showed an inverse relationship between systemic arterial blood pressure and 24-h magnesium excretion, 120 and another did not. 119

Likewise, evaluations of magnesium status in untreated hypertensives have found increased, 128 decreased, 129,130 or the samel3l-132 levels as in normotensive patients. Furthermore, studies have shown no overall improvement in the systemic arterial pressure of otherwise untreated hypertensivel33-135 patients with magnesium supplementation. A comprehensive review of the epidemiologic and clinical evidence linking magnesium deficiency and hypertension concluded that the evidence was insufficient to prove a link between magnesium status and hypertension. 136

However, there is evidence to suggest that magnesium status may be important in some hypertensive patients. Studies of junior high school students found that patients with a family history of hypertension did have an inverse relationship between systemic arterial pressure and intracellular magnesium levels, which was not found when there was no family history. 137,138 One study which showed no difference between serum magnesium values of normotensive and hypertensive patients did show that hypertensive patients excreted less urinary magnesium due to depleted magnesium stores. 132 A very recent study found that magnesium supplementation had no benefit in unselected mild hypertensive subjects or in subjects with a high-normal arterial pressure,134 although, in subjects with a low urinary excretion of magnesium, a hypotensive effect was seen. 134 Others have shown that hypertension response to magnesium is dependent on intracellular sodium concentration. 139 It has been shown that high-renin hypertensive patients have lower serum magnesium levels and respond better to magnesium supplementation, and low-renin hypertensives have higher serum magnesium levelsl40 and may have a pressor response with supplementation. 141 An inverse correlation between plasma aldosterone and serum magnesium has also been found,142 suggesting that low magnesium levels are associated with elevations of the entire renin angiotensin-aldosterone system. 141

Magnesium supplementation has been shown to benefit some patients receiving other antihypertensives. Patients on traditional non-potassium-sparing diuretics tend to have a potentially dangerous magnesium deficiency, 143-147 and have had particular benefit from the addition of oral magnesium supplementation. Studies have shown that magnesium supplementation in these patients will lower systolic arterial pressure by approximately 10 mmHg,148-150 although another study could find no benefit. 151 It is of interest that Resnick et al found that, as hypertension was controlled, the levels of intracellular free magnesium rose, regardless of which antihypertensives was used. 16

Other Coronary Artery Disease Risk Factors

 Less is known about the relationship of other coronary artery disease risk factors and magnesium deficiency. It is interesting that Type A patients may have magnesium deficiency. 152 Experimental evidence suggests that Type A patients may produce more catecholamines when exposed to stress. This would result in increased free fatty acids and diminished intracellular and plasma magnesium stores. 153

One investigator has linked decreased free intracellular magnesium to obese patients,69 even though total intracellular magnesium is normal in obese patients.154 In addition, it is known that patients have hypomagnesemia after jejuno-ilial bypass surgery, 154,155 but not with newer methods of gastric bypass surgery. Obese patients on diets supplemented by protein, 156 diets high in saturated fat, or high in polyunsaturated fats,157 have shown diminished levels of intracellular magnesium.

Coronary Artery Spasm

There is considerable evidence that magnesium deficiency can induce coronary artery spasm. It seems that magnesium can control the movement of calcium into and out of smooth muscle cells. 115,116 In fact, magnesium may be considered a naturally occurring calcium channel blocker. 158 In vitro experiments on coronary arteries of dogs have shown that the arteries are more likely to go into spasm if they are incubated in solutions with low concentrations of magnesium. 159 Low-magnesium solutions significantly increased the potential for contractile responses of both small and large coronary arteries to norepinephrine, acetylcholine, serotonin, angiotensin, and potassium.159 Experiments on intact dogs l60 and isolated coronary arteries of pigs show the same tendency.89 Furthermore, vulnerability of human coronary arteries to spasm increases with magnesium deficiency.161 Variant angina has been treated successfully by intravenous magnesium sulfate, 162 which also points to the importance of magnesium deficiency in coronary spasm.

Thrombosis

The efficacy of parenteral magnesium in reducing coronary thrombosis has been suspected since 1954. In an uncontrolled study, Parsons and associates found that patients admitted with angina or myocardial infarction had a reduced death rate, from approximately 30 to 1%, with treatment by 2cc of 50% magnesium sulfate intramuscularly every 5 days for a total of 60 days. 108 The improvement in mortality was thought to be due partly to favorable effects on reducing the inhibition of plasmin.108

Recent animal experiments have shown that magnesium halogenates inhibit adenosine diphosphate (ADP)-induced platelet aggregation. 163 In 1986, a study demonstrated that bleeding time increased with magnesium infusion in postmyocardial infarction patients.164 Magnesium infusions have been shown to reduce clotting in preeclamptic patients by reducing certain clotting factors.165 Paolisso and colleagues have been able to reduce the increased platelet aggregation of diabetic patients by oral supplementation of magnesium. 166 This evidence suggests that magnesium supplementation can reduce thrombosis in some patients.

Myocardial Infarction

Magnesium deficiency appears to be extremely important in the peri-infarction period.167 In addition to previous uncontrolled studies,54,108 several more recent controlled studies have evaluated the effect of magnesium infusion in the peri-infarction period. 168-175 When findings from all studies were analyzed, only 3.8% of the patients in the treated group died, compared with 8.0% of the control group.174 The primary benefit of magnesium therapy has been the reduction of malignant arrhythmias.171-176

Magnesium infusion in patients with suspected myocardial infarction could reduce myocardial oxygen demand45 and limit the infarct size. 171 The preinfarction magnesium status is unclear, because serum and intracellular magnesium levels have been found to be decreased, 177-180 no different from,181-185 or increased, compared to patients without myocardial function.186-187 However, a study of magnesium retention after myocardial infarction showed magnesium deficits,164 and patients have been found to be hypomagnesemic up to 6 months after a myocardial infarction.56 The differences in these findings may be due in part to the cation shifts which occur after myocardial infarctionl88-190 and which correspond with the size of the infarct.187 These changes resolve over time,177,188,191 resulting in different magnesium values at different times after infarction. 191

A correlation between hypomagnesemia and postinfarction ventricular arrhythmias has been shown in most,178,181,183 but not all, studies.184 Supraventricular tachycardia and atrial fibrillation have been found more frequently in hypomagnesemic patients, and atrioventricular blocks and supraventricular bradycardias have been found more frequently in hypermagnesemic patients.178

Cardiomyopathy

Magnesium deficiency has been suggested as the cause of cardiomyopathy.4,192 Pathologic associations as well as epidemiologic, histological, and animal studies, have implicated magnesium deficiency in a variety of cardiomyopathies.

For instance, patients with hypoparathyroidism can manifest a cardiomyopathy which responds to calcium and magnesium replacement. 193 Alcoholic patients are known to have both cardiomyopathy and magnesium deficiency.4 People living in low-magnesium equatorial areas, and who have magnesium-deficient diets, develop spontaneous endomyocardial fibrosis of undetermined etiology.194,195 Postmortem heart examinations have shown low concentrations of magnesium and high concentrations of thorium and cerium which are thought to be cardiotoxic.194,195

Several different experimental animal models have shown that magnesium deficiency is cardiotoxic, resulting in gross pathologic changes and histologic changes from injury.196-198 Postmortem evaluation has shown that with a variety of insults, magnesium and potassium leave cardiac tissue and calcium and sodium accumulate in cardiac tissue. Any of these changes could cause necrosis.196,199-201 However, magnesium is the first ion to shift in the myocardial necrosis of parathyroidectomized rats. 199 The necrosis in parathyroidectomized rats was partially prevented by parenteral, but not oral, magnesium supplementation.199 Other animal studies have suggested that preventing magnesium loss can protect the heart against cardiotoxic agents. In vitro experiments show that dopamine-induced postischemic injury is attenuated by magnesium-rich perfusate solutions.202 Spironolactone, which spares both potassium and magnesium, prevents calcium accumulation in spontaneously cardiomyopathic hamsters,203 although potassium may be more protective.204 The cardiomyopathy in hamsters given magnesium-deficient diets is reduced with nifedipine,205 pointing to the importance of magnesium and calcium disturbances in cardiomyopathy in these animals. An infusion of potassium, magnesium aspartate prevents and reverses isoproterenol-induced cardiomyopathy in dogs, again suggesting a protective effect of magnesium.206 The relevance of magnesium deficiency to cardiomyopathy in humans is yet to be determined.

Congestive Heart Failure

Patients with congestive heart failure (CHF) frequently have magnesium deficiency207 due to increased urinary excretion.208 There is decreased tubular absorption of magnesium due to increased extracellular volume and the effects of the secondary hyperaldosteronism found in CHF.209 Diuretics that do not spare potassium210-213 and digitalis can worsen the problem of diminished tubular resorption.209,214

Other neurohumoral transmitters may also be at work. The renin-angiotensin 11 system may stimulate an already elevated aldosterone.209,215 Norepinephrine may reduce magnesium through increased fatty acids.216 Angiotensin converting enzyme (ACE) inhibitors, which conserve magnesium,217 have resulted in diminished mortality in patients with CHF.

Magnesium deficiency worsens hyperaldosteronism, which may lead to fluid retention.209,218 Magnesium loss also compounds hypokalemia, which could theoretically produce ventricular arrhythmias and hemodynamic deterioration in CHF.214 Magnesium depletion may worsen cardiac function by diminishing contractility, increasing vasoconstriction,207,218 or by depleting energy stores.207

Patients with CHF and magnesium abnormalities whereas hypomagnesemic patients 45 and 42%, and hypermagnesemic patients 37 and 30%, respectively.219 The hypomagnesemic patients probably died as a result of ventricular arrhythmias. The increased mortality of patients with hypermagnesemia was thought to be a reflection of poorer renal perfusion associated with more serious CHF, since these patients had fewer arrhythmias than patients with low or normal levels of serum magnesium.219

The potential value of correcting electrolyte imbalance in CHF-associated ventricular arrhythmias is evident because it is difficult to predict which arrhythmias may result in sudden death.215,220 Conventional antiarrhythmic drugs also are notoriously ineffective in reducing sudden death in these patients and patients with cardiomyopathy.215 In a study of 10 patients with ischemic dilated cardiomyopathy without CHF who received magnesium infusions, the number of premature ventricular contractions and couplets decreased 95% and runs of ventricular tachycardia stopped.221 It is interesting that all patients had normal levels of magnesium before and after infusions.

Not all evidence supports the importance of magnesium in CHF. Ralston et al, have shown that in ambulatory patients with dilated cardiomyopathy and CHF, the prevalence of hypomagnesemia is relatively low (9%) and serum, circulating mononuclear cell, skeletal muscle, and myocardial magnesium concentrations correlate poorly with each other.15 Another study indicated that CHF per se and treatment with digoxin were not the causes of magnesium depletion.222 Pronounced diuresis by diuretics and increased renal excretion of magnesium was the cause of magnesium deficiency in 55% of their patients.222

Arrhythmias

The value of magnesium supplementation in arrhythmias associated with CHF and myocardial infarction has been discussed. The importance of magnesium in ventricular-, supraventricular and digitalis-related arrhythmias has been the subject of considerable interest.223-232

Magnesium deficiency which is often accompanied by hypokalemia produces prolongation of QT interval,233-234 ST-segment depression,235 and low-amplitude T waves. 1

Increased magnesium levels lead to bradycardia,236 increased conduction time, and diminished automatism.231 Magnesium probably influences transport of potassium,235-237 sodium,238 and calcium across the cell.237 Magnesium may abolish ventricular arrhythmia during acute myocardial ischemia due to prevention of conduction slowing by an anti-ischemic action.239

Although hypomagnesemia is associated with hyponatremia, hypocalcemia, and hypophosphatemia,3 the association with hypokalemia is the best known association.240-241 Both potassium and magnesium tend to be depleted with thiazide diuretics240-243 and spared with potassium-sparing diuretics.244 This is particularly true for the elderly245 and for patients on high doses of diuretics, 243 and may be true for others already at risk for electrolyte abnormalities, including alcoholics,1,11 diabetics,11 those with congestive heart failure, 11 or those with a recent myocardial infarction. 11 It has been shown that although serum potassium rises with replacement therapy, the level of potassium in muscle will not increase unless magnesium is replaced as well.230,241,246 The benefit of replacing potassium and magnesium in patients with deficits in both seems to be larger than for either alone, particularly in patients treated with non-potassium-sparing diuretics.243,247 Patients on non-potassium-sparing diuretics have more frequent ventricular arrhythmias.243,247 Even more ominous is the finding in a recent prospective study that 66% of patients in cardiac arrest had magnesium abnormalities and none of these patients were successfully resuscitated.241

Ventricular Arrhythmias

Some studies have shown that intravenous replacement of magnesium is essential in reducing ventricular extrasystoles in patients with combined magnesium and potassium deficits246 or those with magnesium deficits alone.249,250 Even patients who have normal levels of magnesium may benefit from magnesium infusions after other antiarrhythmics have failed,224,251,252 particularly if the patient is also on quinidine or digoxin.251,252 Doses of 2-3 g MgSO4 over 1 min,224,251,212 followed by 10 g of MgSO4 over five hours, are usually given in life-threatening situations. The antiarrhythmic effects are perhaps in part due to supraphysiologic doses of magnesium resulting in increased blood levels 252,253 rather than due to simple replacement.253 Fortunately, intravenous magnesium is well tolerated except in those with renal failure226,235 or preexisting bundle-branch blocks.227 However, the loading dose should not be given faster than over one min, since cardiac arrest may occur.254,255

Recent investigation has cast doubt on the value of magnesium in some ventricular arrhythmias. Ralston et al. reported no statistical association between ventricular arrhythmias and magnesium levels of serum, mononuclear cells, skeletal muscle, or cardiac muscle of ambulatory patients with CHF.256 In addition, a recent study found magnesium infusion to be of limited effect in suppressing inducible, sustained, monomorphic ventricular tachycardias in a group of 11 patients.257

Torsade de Pointes

In patients with torsades de pointes (polymorphous ventricular tachycardia associated with marked QT prolongation), when treated with magnesium sulfate, arrhythmia episodes would be abolished.258-261 A variety of dosages have been used, from continuous infusions of 50 mg/min258 to a bolus of 1 g to 2 g within 1 to 2 min.259-261

Tzivoni and associates259 reported 12 patients with torsade de pointes and marked QT prolongation who responded to intravenous magnesium sulfate. In eight of their patients magnesium was the only therapy given, while in four others, initial therapy failed and therefore magnesium sulfate was given. Tzivoni et al.259 recommend that intravenous magnesium should be used as the first line of therapy in patients with torsade de pointes and marked QT prolongation.

Supraventricular Arrhythmias

Magnesium also has been shown to be of benefit in supraventricular tachyarrhythmias.223,224,249,262 Magnesium infusion has been shown in some patients to convert atrial tachycardia,249,262-264 multifocal atrial tachycardia,224,263 and reentrant junctional tachycardia264 to sinus rhythm. Most of these patients had low serum magnesium224,249,262 or were on digoxin, furosemide, or aminoglycosides, which may have depleted magnesium stores.224,263 However, magnesium infusion has been shown to be effective in supraventricular tachycardia264 and reentrant junctional tachycardia,265 even with normal serum magnesium, when the atrioventricular node is a part of the reentrant circuit264 Magnesium sulfate was usually given by 2 g infusion over a period of one min224,263 or less.264,265

Digoxin Related Arrhythmias

Magnesium status is probably important in digoxin-related arrhythmias. In one study, hypomagnesemic patients in atrial fibrillation required twice the amount of intravenous magnesium to control atrial fibrillation than those who were not.266 Unfortunately, patients on digoxin therapy may tend to be hypomagnesemic.209 One study of hospitalized patients who received digitalis found 19% to be hypomagnesemic.267

Hypomagnesemia has been shown to lower the ventricular premature contraction threshold and the ventricular fibrillation threshold in dogs receiving digitalis.268 Some investigators have found hypomagnesemia in patients with atrial fibrillation.269,270 Singh et al. found hypomagnesemia in 5 of 9 children with a variety of digoxin-toxic dysrhythmias, and in 3 of 10 children on digoxin but without toxicity.271 Decreased lymphocyte magnesium and potassium were found in a series of seven patients on digoxin with idionodal tachycardia who were successfully treated with magnesium repletion alone.272

Supplementation has been used successfully in patients with decreased 269-271 or normal 272 serum magnesium. The mechanism of magnesium's effect on digitalis-induced arrhythmias remains unclear.273-276 Magnesium may work by blocking potassium274 or calcium275 fluxes across the cell or even through the central nervous system.276 However, magnesium supplementation has some risk in patients with renal insufficiency. A prospective study 277 in patients with cardiac digitalis toxicity and in digitized patients without toxicity showed that hypomagnesemia was present in 21% of patients with and 10% of those without digitalis toxicity. The presence of hypermagnesemia was significantly greater in patients with toxicity (18%) than in those without toxicity (5%) and appeared to be related to a significantly greater prevalence of abnormal renal function in the former group.277

Magnesium infusion does seem to have a role in the treatment of ventricular arrhythmias associated with digitalis overdose,278 including in patients with hyperkalemia279 or with life-threatening ventricular arrhythmias refractory to lidocaine and diphenylhydantoin278,279 Usually, 2-3 g of MgSO4 are given intravenously over one min, followed if needed by a continuous infusion sufficient to reach a serum level of 4-5 mEq/l. Serum magnesium levels should be monitored every two h and the infusion should stop immediately at the onset of respiratory depression or if deep tendon reflexes are diminished.279

Conclusion

Magnesium deficiency may play a critical role in the pathogenesis of ischemic heart disease, cardiomyopathy, and certain arrhythmias. How a clinician should use this information in treating his or her patients is still not clear. It is important to be aware that patients may have magnesium deficiency, even with serum magnesium levels within the normal range. 11 Because many of these patients are taking diuretics for associated hypertension or congestive heart failure, it may be prudent to use potassium-sparing diuretics, which also spare magnesium.241

In the hospital setting, it is particularly important to check serum magnesium in patients with cardiovascular disease.7 In patients with documented hypomagnesemia, the magnesium may be given orally, intramuscularly, or intravenously depending on the urgency of the situation.280,281

In patients with severe deficits or life-threatening situations, intravenous magnesium supplementation is preferred.280,281 Fortunately, magnesium infusion is well tolerated, even in patients with ischemic heart disease.282

Magnesium infusion is indicated in patients with torsade de pointes associated with marked QT prolongation.259 Patients with life-threatening digitalis-related ventricular arrhythmias refractory to other therapy should be considered for intravenous magnesium administration.228 Caution should be exercised in the administration of magnesium sulfate to azotemic patients who may already be hypermagnesemic.277

Acknowledgments

The authors would like to acknowledge Jerri Harris, Alicia Harris, and Sharon Lindsay for preparation of the manuscript.

References

1. Seelig M: Cardiovascular consequences of magnesium deficiency and loss: Pathogenesis, prevalence and manifestations-magnesium and chloride loss in refractory potassium repletion. Am J Cardiol 63, 4G-21G (1989)

2. Sjogren A, Edvinsson L, Fallgren B: Magnesium deficiency in coronary artery disease and cardiac arrhythmias. J Int Med 226, 213-222(1989)

3. Altura BM, Altura BT: New perspectives on the role of magnesium in the pathophysiology of the cardiovascular system. Magnesium 4, 226-244 (1985)

 4. Seelig MS: Magnesium Deficiency in the Pathogenesis of Disease: Early Roots of Cardiovascular Skeletal, and Renal Abnormalities. Plenum Medical Book Company, New York (1980),1-24,141-266

5. McCarron DA: Calcium, magnesium, and phosphorus balance in human and experimental hypertension. Hypertension 4, (suppl 111);III-27-III-33 (1982)

6. Rardon DP, Fisch C: Electrolytes and the Heart. In The Heart, 7th edition (Ed. Hurst JW). McGraw-Hill Book Co., New York (1990),1567

7. Whang R, Ryder KW: Frequency of hypomagnesemia and hypermagnesemia: Requested vs. routine. J Am Med Assoc 263, 3063-3064(1990)

8. Ryzen E, Elkayam U, Rude RK: Low blood mononuclear cell magnesium in intensive cardiac care unit patients. Am Heart J 111,475-480(1986)

9. Elin RJ: Assessment of magnesium status. Clin Chem 33, 1965-1970(1987)

10. Ryzen E, Elbaum N, Singer FR, Rude RK: Parenteral magnesium tolerance testing in the evaluation of magnesium deficiency. Magnesium 4, 137-147 (1985)

11. Reinhart RA: Magnesium metabolism. Arch Intern Med 148, 2415-2420(1988)

12. Ryan MF, Ryan MP: Lymphocyte electrolyte alterations during magnesium deficiency in the rat. Irish J Med Sci 148, 108-109 (1979)

 13. Elin RJ: Status of the determination of magnesium in mononuclear blood cells in humans. Magnesium 7, 300-305 (1988)

14. Lim P, Jacob E: Magnesium deficiency in patients on term diuretic therapy for heart failure. Br Med J 3, 620-622 (1972)

15. Ralston MA, Murnane MR, Kelley RE, Altschuld RA, Unverferth DV, Leier CV: Magnesium content of serum, circulating mononuclear cells, skeletal muscle, and myocardium in congestive heart failure. Circulation 80, 573-580 (1989)

16. Resnick LM, Gupta RK, Laragh JH: Intracellular free magnesium in erythrocytes of essential hypertension: Relation to blood pressure and serum divalent cations. Proc Natl Acad Sci 81,6511-6515(1984)

17. White RE, Hurtle HC: Magnesium ions in cardiac function: Regulator of ion channels and second messengers. Biochem Pharmacol 38, 859-867 (1989)

18. Elin RJ: Magnesium metabolism in health and disease. In Disease-a-Month. (Ed. Bone RC). Year Book Medical Publishers, Inc. (1988)

19. Lichton IJ: Dietary intake levels of requirements of Mg and Ca for different segments of the U.S. population. Magnesium 8, 117-123(1989)

20. Marier JR: Magnesium content of the food supply in the modern-day world. Magnesium 5,1-8 (1986)

21. Bierenbaum ML, Fleischman Al, Dunn JP, Hayton T, Pattison DC, Watson PB: Serum parameters in hard and soft water communities. Am J Public Health 63, 169-173 (1973)

22. Crawford MD, Gardner MJ, Morris IN: Changes in water hardness and local death-rates. Lancet 2, 327-329 (1971)

 

Address for reprints:

Assad Movahed, M.D.
East Carolina University
School of Medicine
Section of Cardiology
Greenville, NC 27858-4354, USA


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