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American Heart Journal
Volume 132 � Number 3 � September 1996
Copyright � 1996 Mosby-Year Book, Inc.

CURRICULUM IN CARDIOLOGY

Significance of magnesium in congestive heart failure

Summer Douban MD
Michael A. Brodsky MD
David D. Whang MD
Robert Whang MD

Irvine, Calif., Cincinnati, Ohio, and Honolulu, Hawaii

Department of Medicine, Division of Cardiology,
University of California, Irvine Medical Center;

Department of Medicine,
Christ Hospital, Cincinnati;

Department of Medicine, John A. Burns School of Medicine,
University of Hawaii Department of Veterans Affairs Medical and Regional Office Center, Honolulu.

Received for publication November 14, 1995; accepted December 20, 1995.
Reprint requests: Michael A. Brodsky, MD, Division of Cardiology, University of California, Irvine Medical Center, Bldg. 53, Rt. 81, Room 100, 101 The City Dr., Orange, CA 92668-3298.
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The most common serum electrolyte abnormalities in chronic congestive heart failure are hypomagnesemia, hypokalemia, and hyponatremia. [1] Among these, the two predominantly intracellular cations, magnesium and potassium, may contribute to the high mortality and sudden death associated with congestive heart failure. [2] Deficiencies in these two cations occur commonly in heart failure as a consequence of reduced intake or of increased losses. The former usually develops in response to consequences of the underlying disease, including decreased caloric intake and increased bowel edema. The losses are typically associated with heart failure therapy. [3] [4] This article reviews the current perspective of the important clinical implications of magnesium in patients with congestive heart failure.

MAGNESIUM BALANCE

It is estimated that the total body store of magnesium is approximately 21 to 28 gm, or 1700 to 2300 mEq. [5] Maintenance of magnesium balance requires a daily dietary intake of at least 24 to 30 mEq, the official United States recommended daily allowance. Higher daily intakes may be required for patients under physiologically stressful situations as diverse as pregnancy to heart failure. Excellent dietary sources of magnesium include ``heart-healthy'' legumes, green leafy vegetables, and animal proteins and nuts.
The principal areas of magnesium absorption and excretion are heavily influenced by cardiovascular function. One third of dietary magnesium is absorbed primarily in the proximal small bowel, an area prone to edema as a consequence of congestive heart failure. The kidneys maintain metabolic balance by excreting appropriate amounts of absorbed magnesium. Two thirds of plasma magnesium is filtered at the glomerular level because one third is bound to the protein albumin. Of the filtered magnesium, 20% to 30% is reabsorbed proximally; the major site for magnesium reabsorption is in the ascending limb of the loop of Henle. It follows that potent loop blocking diuretic agents commonly used in treating congestive heart failure contribute significantly to losses of urinary magnesium and potassium. In addition, altered renal hemodynamics (decreased glomerular filtration rate and a disproportionally greater decrease in renal plasma flow) result in increased filtration fraction as a consequence of heart failure. [6]

CLINICAL MAGNESIUM DEFICIENCY

On the basis of the eating habits and lifestyle in modern industrialized society it has been estimated that magnesium deficiency is very common. [7] Accurate measurement of that assessment is problematic. The predominately intracellular location of magnesium represents the major reason for difficulty in assessing the status of the total-body magnesium level. Various methods such as muscle biopsy; magnesium retention; nuclear magnetic resonance; and lymphocyte, leucocyte, and erythrocyte analysis have been used to assess the status of body magnesium stores. None of these methods is readily available to the clinician, however. Despite the limitations of the serum magnesium level, which represents <1% of total body magnesium, this determination is by far the most available and most expeditious method of evaluating for possible disorders of magnesium metabolism. [5] We concur with Elin [8] that ``the serum magnesium is the entry-level test for evaluation of possible disorders of magnesium metabolism.'' As a general rule for simple interpretation, if the serum magnesium level is low, a deficient state exists. If the serum magnesium level is high, the total-body stores are usually adequate. The most common result, a serum magnesium level within the normal range, however, gives little confidence regarding the total-body status.
In a general hospital population, approximately 7% to 10% of patients are hypomagnesemic, usually with a magnesium level of <1.5 mEq/L. [5] [9] Because of the absence of routine serum magnesium determination in most hospitals, it is estimated that approximately 90% of serum magnesium abnormalities (hypomagnesemia and hypermagnesemia) are not recognized by clinicians. [7] The prevalence of hypomagnesemia appears to be greatest in intensive care units, with estimates being as high as 65%. [9]
The many causes of clinical magnesium deficiency can be grouped into 10 major categories (Table I) . ``The 10 Ds'' cover a wide range of common abnormalities also categorized as problems with intake, absorption, or excretion or as other problems. [10]

Associated electrolyte abnormalities

There is an association between hypomagnesemia and other electrolyte disorders including hypokalemia, hyponatremia, hypophosphatemia, and hypocalcemia. [11] Of patients who were found to be hypomagnesemic, 42% were hypokalemic; 29% were hyponatremic; 23% were hypophosphatemic; and 22% were also hypocalcemic. Especially relevant is the high frequency of hypomagnesemia in hypokalemic patients.
Experimental observations indicate that magnesium depletion is associated with diminished muscle-cell potassium kaliuresis and phosphaturia. [12] Potassium depletion is accelerated by concurrent magnesium depletion. [13] Potassium repletion is impeded when coexisting magnesium depletion is not corrected. [14] Magnesium depletion is associated with increased cell-membrane permeability to potassium. [15] With magnesium depletion, potassium and sodium-chloride cotransport is decreased. [16] Magnesium causes unblocking of potassium channels, resulting in decreased inward rectification. [17] [18] Magnesium depletion also causes diminished cell-membrane adenosine triphosphatase (ATPase) activity with diminished potassium transport and cellular sodium accumulation and diminished calcium-channel blockade. [19] [20] [21]
The net result of these alterations in cellular ion transport found in experimental magnesium deficiency support clinical observations of an inability to correct persisting hypokalemia. In a series of 69 cases of refractory potassium repletion, 60% of the

cases involved patients with congestive heart failure. [22] Administration of loop blocking diuretic agents resulting in urinary magnesium and potassium losses was considered the most likely cause of these cases of refractory potassium repletion.
In an investigation of congestive heart failure and hypokalemia in 79 patients receiving long-term diuretic therapy, skeletal-muscle biopsy samples taken before and after correction of the hypokalemia showed that most of the patients had a low muscle magnesium concentration and that in those patients correction of the hypokalemia did not increase the skeletal-muscle potassium, whereas in patients with normal skeletal-muscle magnesium concentrations, correction of the hypokalemia resulted in a significant increase in muscle potassium concentration. [23] This finding suggests that in patients who have heart failure and in whom hypokalemia develops, both magnesium and potassium should be supplemented.

MAGNESIUM MEASUREMENTS IN CONGESTIVE HEART FAILURE

In patients with heart failure, electrolyte balance is particularly important, and studies have reported the incidence of hypomagnesemia in these patients to be variable. The largest study (297 patients) documented hypomagnesemia in 37%, whereas in another, smaller study (46 patients) only 7% had a low magnesium level. [24] [25] Whang et al. [26] reported that 19% of patients receiving digitalis therapy had a serum magnesium level <1.25 mEq/L. The variable frequency of hypomagnesemia in these reports may be attributable to differences in the severity of heart failure, the degree of congestion, the dosages of loop diuretic agents, and the degree of neurohormonal activation.
The causes of hypomagnesemia in heart failure are multifactorial. Clinically, the most common offender is the use of diuretic agents. Loop blocking diuretic agents act on the ascending limb of the loop of Henle to cause loss of magnesium and of sodium,

chloride, and water. Thiazides cause a lesser degree of magnesium loss because they act more distally on the nephron, where usually only small amounts of magnesium are reabsorbed. The continuous use of diuretic agents for years has been shown to deplete tissue magnesium levels, and this depletion may exist despite normal serum magnesium levels. [3] [27] Several reports have noted that 50% of patients with heart failure had tissue magnesium depletion according to skeletal-muscle biopsies. [3] [27] [28] Neurohormonal activation of the renal angiotensin-aldosterone system may also contribute to magnesium depletion, [29] [30] perhaps because of decreased magnesium reabsorption in the proximal renal tubule from the expanded extracellular volume produced by aldosterone's effects on fluid retention. [29] [30]

In patients with congestive heart failure, myocardial dysfunction is associated with increased catecholamine concentrations in plasma and urine. Adrenergic overstimulation causes efflux of intracellular magnesium resulting in renal wasting and stimulates beta-adrenergic receptors and an increase in cyclic adenosine monophosphate, which in turn activates the magnesium-dependent adenosine triphosphate pump. This process requires an increased magnesium supply to maintain intracellular energy-bound metabolic processes. [31] Smetana et al. [32] investigated the effects of angiotensin-converting-enzyme (ACE) inhibitor therapy on 66 patients with congestive heart failure resulting from dilated cardiomyopathy and coronary artery disease. They found that these drugs often ameliorate the electrolyte abnormalities seen in congestive heart failure, likely because of their ability in blocking the renin angiotensin aldosterone system.
The serum magnesium concentration has been considered an important prognostic indicator in patients with congestive heart failure. [33] [34] Gottlieb et al. [33] studied 199 patients with heart failure and found that the highest survival rate, 71%, was found in patients with normal serum magnesium levels. The 1-year survival rate was significantly lower in patients with hypomagnesemia (45%) or hypermagnesemia (37%). Patients with hypermagnesemia (serum magnesium >2.1 mEq/L) may have had the worst outcome; they were more likely to be seriously ill patients with greater neurohormonal activation and worse renal function. The patients with hypomagnesemia (serum magnesium <1.6 mEq/L) were found to have the highest frequency of ventricular arrhythmia and ventricular tachycardia. The PROMISE Study, which also assessed serum magnesium as a prognostic indicator, included 1088 patients with heart failure and found that the serum magnesium level was not an independent risk factor for sudden death or increased mortality. [34] These two studies appear to reach opposite conclusions, [33] [34] perhaps because their method of determining the total-body magnesium state (i.e., serum magnesium levels) are unreliable. Lim and Jacob [3] ; Dyckner et al. [27] ; and Ryzen et al. [35] showed that the incidence of intracellular magnesium deficiency is much higher than the serum magnesium level suggests. Ralston et al. [36] later found no correlations between serum and tissue (myocardial, skeletal muscle, mononuclear cell) magnesium concentrations in patients with heart failure. These reports should caution the clinician from an overreliance on the serum magnesium level.

CARDIOVASCULAR EFFECTS OF MAGNESIUM DEFICIENCY

Current evidence suggests that magnesium deficiency has an effect on cardiovascular structure, including the development of such common diseases as coronary artery disease and cardiomyopathy (Table II) . Magnesium has been shown indirectly to affect the development of atherosclerosis in experimental studies. When rabbits fed a high-cholesterol diet were given magnesium supplementation, aortic atherosclerotic lesions were reduced in a dose-dependent fashion. [37] Studies have also shown that magnesium deficiency may play an important role in modifying risk factors of atherosclerosis such as diabetes, hyperlipidemia, and hypertension. Altura [38] and others [39] have documented an association between magnesium deficency and several dyslipidemias. In animal models, magnesium deficency has been shown to be involved in several steps of the atherosclerotic process, including the metabolism of elastin, collagen, and lipid and in platelet aggregation. [39]
Patients with diabetes have been shown to have reduced tissue (including myocardial) and serum magnesium concentrations, and this deficiency correlates with difficulty in controlling blood glucose. [40] This condition may be explained by the importance of magnesium as a cofactor in several of the enzymatic reactions of glycolysis. Magnesium deficiency has also been associated with hypercholesterolemia, hypertriglyceridemia, increased levels of low-density lipoproteins, and decreased levels of high-density lipoproteins in animal studies. [41] [42] In addition, magnesium has an important physiologic role for hypertension in regulating vascular tone and decreasing systemic vascular resistance. By serving as a cofactor in the sodium-potassium ATPase pump, magnesium deficiency can lead to increased intracellular sodium and calcium concentrations, both of which can lead to increased peripheral resistance and vasospasm. [19] [43] Numerous studies have shown that magnesium can regulate calcium flux across the vascular smooth-muscle cell membranes and its release from intracellular storage sites. [44] Because cytosolic free-calcium concentration is an important second messenger in the facilitation of contraction and relaxation, magnesium may be the physiologic regulator of the vascular smooth-muscle cells by competing with calcium and modulating the level of cytosolic intracellular free calcium in vascular smooth-muscle cells. In a clinical study, Whang et al. [45] found that patients with hypertension who also had hypomagnesemia required more blood pressure lowering medication than did patients with hypertension but normal serum magnesium levels. In other studies magnesium deficiency was associated with coronary artery vasospasm, which in turn responds well to magnesium therapy. [46] [47] [48]
Although ischemic heart disease is the most common cause of cardiac muscle dysfunction, magnesium deficiency has also been associated with cardiomyopathy from other causes such as alcohol, pregnancy, malnutrition, and even idiopathic. [49] [50] [51] It has also been reported that magnesium-deficient diets may lead to cardiomyopathy as a result of endomyocardial fibrosis. [52] [53]
Magnesium deficiency contributes significantly to cardiovascular electrophysiologic abnormalities. Electrocardiographically, magnesium deficiency causes an increase in heart rate, mildly prolongs the PR and QRS intervals, significantly prolongs the QT interval, flattens ST-T segments, and potentiates U waves. [54] Many reports have supported a relation between hypomagnesemia and various types of supraventricular tachyarrhythmias including multifocal atrial tachycardia and atrial fibrillation. [55] [56] [57] Several clinical studies have also demonstrated an increased incidence of ventricular ectopy, ventricular tachycardia, torsade des pointes, and ventricular fibrillation with hypomagnesemia. [58] [59] [60] [61] [62] [63] [64] [65] [66] [67] Surawicz [68] and later Millane et al. [69] criticized many of these reports as lacking in specific documentation of an isolated magnesium effect as opposed to a combination of hypomagnesemia and other factors, notably hypokalemia or digitalis preparations. Rebuttal of their arguments is difficult because many of these patients have complex medical conditions, and accurate measurement of magnesium and potassium requires uncommon tests such as myocardial biopsy. Whether hypomagnesemia is arrhythmogenic will be answered in the long term, as the already large body of evidence suggesting the importance of magnesium grows.
Strong evidence had accumulated to implicate magnesium deficiency as an important cause of digitalis-toxic associated arrhythmias. [70] [71] [72] [73] [74] In dog models hypomagnesemia was found to facilitate the induction of digitalis-toxic arrhythmias, most of which were terminated with intravenous magnesium. Even the heart rhythm of dogs with digitalis-toxic ventricular arrhythmias and normal serum magnesium levels converted to sinus rhythm with intravenous magnesium therapy; furthermore, pretreatment of these dogs with magnesium resulted in an increased dose of digoxin necessary to induce the arrhythmias. Magnesium deficiency potentiates digitalis toxicity by two important mechanisms: it works synergistically with digoxin to suppress sodium-potassium ATPase activity, and it exacerbates the problem of refractory potassium repletion in concurrent magnesium and potassium deficiency. [71] [72] [73] [74] Similarly, studies by Dyckner and Wester examined the effects of magnesium and potassium repletion on the incidence of extrasystoles in patients receiving diuretic agents and suggested that magnesium deficiency on a cellular level may lead to an inability of the cell to accumulate potassium against a concentration grade, resulting in a less-negative resting membrane potential, which would make the cell more easily depolarized. [27] Again, this condition is thought to occur because of magnesium's essential role in the sodium-potassium pump. [75]

CARDIOVASCULAR EFFECTS OF MAGNESIUM THERAPY

Magnesium therapy has been associated with significant hemodynamic and electrophysiologic effects (Table III) . Hemodynamically, magnesium therapy has been shown to reduce systemic vascular resistance and mean arterial pressure in animals and

humans, improve cardiac indexes, increase coronary artery blood flow, and reduce coronary vascular resistance. [48] [76] [77] [78] Each of these actions is particularly beneficial in cases of left ventricular dysfunction. Electrophysiogically, magnesium therapy is associated with a decrease in heart rate, prolongation of the PR and AH intervals, and a shortening of the duration of the QT interval. Rasmussen and Thomsen [79] gave intravenous magnesium therapy to 13 patients in the electrophysiology laboratory and demonstrated that magnesium increased the PR interval and QRS duration with an increase in the effective and functional atrial refractory period and in the atrioventricular nodal functional refractory period. These observations are clinically significant because they may explain how magnesium works as an antiarrhythmic agent. Multiple types of supraventricular tachyarrhythmias have been noted to respond to magnesium administration, including supraventricular tachycardia, multifocal atrial tachycardia, atrial fibrillation, and a variety of arrhythmias in patients after cardiac operations. [55] [56] [80] [81] [82] [83] [84] [85] Numerous studies have also shown magnesium to be effective in treating ventricular arrhythmias, including ventricular tachycardia and ventricular fibrillation. [59] [60] [61] [62] [63] [64] [65] [86] [87] [88] [89] [90] [91] [92] [93] [94] [95] [96] Often these acute ventricular tachyarrhythmias were resistant to therapy with potassium, lidocaine, procainamide, and bretylium yet responded dramatically to magnesium administration. In the amelioration of ventricular arrhythmias, several studies support the concept that an increase in serum magnesium levels to approximately two times normal results in its therapeutic action. [97] [98] These data suggest that impaired myocardial cells or cellular membranes may require significantly higher extracellular magnesium levels to function normally.

Three recent publications documented a significant antiarrhythmic benefit of solitary magnesium therapy in patients with heart failure. [94] [95] [96] Bashir et al. [94] noted a reduction in all types of ventricular arrhythmias and in plasma epinephinine levels as a result of oral magnesium therapy. Gottlieb et al. [95] and later Sueta et al. [96] used intravenous magnesium in reducing ventricular arrhythmia in the setting of heart failure.

HYPERMAGNESEMIA

Although we support the recognition and aggressive correction of magnesium deficiency in patients with cardiovascular disease, hypermagnesemia must also be avoided. Hypermagnesemia has been associated with acute and chronic morbidity and mortality. [33] [99] [100] [101] Most of the complications from hypermagnesemia are transient. The most common setting for hypermagnesemia is excess ingestion related to problems with therapy or renal failure, the latter very important because magnesium is eliminated primarily through the kidneys.
The typical manifestations of hypermagnesemia are cardiovascular and neurologic. At slightly increased concentrations, hypotension and mental status changes may occur. As levels increase, neuromuscular reflexes including respirations are reduced, and electrophysiologic abnormalities develop and may lead to cardiac arrest. The latter has been reported as high-grade heart block and asystole. Patients with heart failure are particularly prone to complications from hypermagnesemia because of their reduced renal function and sensitive cardiovascular and neurologic state.

CONCLUSIONS

To date, the correlation between magnesium status and prognosis in heart failure has been confusing in part because of the lack of reliable data. A well-designed study with advanced techniques might answer whether the total body magnesium concentration by itself is important. We believe, however, that these future studies will show that magnesium is of major significance in heart failure for many reasons. Magnesium is an important variable in the risk factors for the development of heart failure. These risk factors include primary associations with cardiomyopathy, secondary associations relating to atherosclerosis and acute myocardial infarction, and tertiary factors regarding risk factors for atherosclerosis. Magnesium deficiency also has an important relation to complications of heart failure, particularly tachyarrhythmias. The magnesium status may be important in the balance between the risks of tachyarrhythmia and high-grade heart block and asystole, also observed in patients with advanced heart failure. [102] Magnesium balance does affect therapy for heart failure including the action of digoxin, and therapy for heart failure has an important effect on magnesium balance. Patients with heart failure who are treated with ACE inhibitors had significantly higher intracellular potassium and magnesium concentrations, perhaps contributing to their therapeutic effects in heart failure patients. [103] Maintaining adequate concentrations of magnesium and potassium and of other electrolytes is extremely important in cases of heart failure. Whether a complication is related to a low level of a particular electrolyte is less important than maintenance of balance among all electrolytes. Coordinating a stable magnesium status is especially difficult in cases of heart failure because reduced absorption and complicated excretion must be balanced with potential overdose when there is reduced renal function. These issues underscore the need for a better understanding of magnesium status in cases of heart failure.

SUMMARY

Electrolyte balance has been regarded as a factor important to cardiovascular stability, particularly in congestive heart failure. Among the common electrolytes, the significance of magnesium has been debated because of difficulty in accurate measurement and other associated factors, including other electrolyte abnormalities. The serum magnesium level represents <1% of total body stores and does not reflect total-body magnesium concentration, a clinical situation very similar to that of serum potassium. Magnesium is important as a cofactor in several enzymatic reactions contributing to stable cardiovascular hemodynamics and electrophysiologic functioning. Its deficiency is common and can be associated with risk factors and complications of heart failure. Typical therapy for heart failure (digoxin, diuretic agents, and ACE inhibitors) are influenced by or associated with significant alteration in magnesium balance. Magnesium therapy, both for deficiency replacement and in higher pharmacologic doses, has been beneficial in improving hemodynamics and in treating arrhythmias. Magnesium toxicity rarely occurs except in patients with renal dysfunction. In conclusion, the intricate role of magnesium on a biochemical and cellular level in cardiac cells is crucial in maintaining stable cardiovascular hemodynamics and electrophysiologic function. In patients with congestive heart failure, the presence of adequate total-body magnesium stores serve as an important prognostic indicator because of an amelioration of arrhythmias, digitalis toxicity, and hemodynamic abnormalities.

We thank Sue D'Amato, Moana Scola, and James Myers for their assistance.

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