Magnesium: Its proven and potential clinical significance.

ABSTRACT: Magnesium is the fourth most abundant cation in the body and is present in more than 300 enzymatic systems, where it is crucial for adenosine triphosphate (ATP) metabolism. Deficiency states result in increased insulin resistance, as well as increased smooth muscle and platelet reactivity. Magnesium deficiency has been shown to correlate with a number of chronic cardiovascular diseases, including hypertension, diabetes mellitus, and hyperlipidemia. Intravenous magnesium has been used therapeutically in critical situations such as status asthmaticus, torsades de pointes, and preeclampsia. Few controlled studies exist regarding the therapeutic uses of oral magnesium supplementation in chronic cardiovascular diseases. Randomized clinical trials are urgently needed to determine whether magnesium supplementation will alter the natural history of these disease states.

THE CLINICAL SIGNIFICANCE of magnesium as an important intracellular cation has been implied for decades. (1) Recently, magnesium deficiency has been implicated in the pathogenesis of a host of clinical disorders. (2) In an editorial, Resnick (3) stated, "A link between magnesium, diabetes mellitus, and hypertension seems established beyond a reasonable doubt."

Magnesium is the fourth most abundant cation in the body. It is involved in more than 300 enzymatic systems, such as adenosine triphosphate (ATP) metabolism, activation of creatine kinase, adenylate cyclase, and sodium-potassium-ATPase. Magnesium deficiency has been implicated in such diseases as diabetes, hypertension, cardiac arrhythmias, acute myocardial infarction, and atherosclerosis. This has come under increasing scrutiny in several recent publications. (3-5)

MAGNESIUM METABOLISM AND PHYSIOLOGY

The total body stores of magnesium are between 21 and 28 g in the average 70 kg adult. Normal serum magnesium usually has a range of 1.7 to 2.5 mg/dL. Most of the body's magnesium is in the skeletal bone mass, which accounts for more than 50% of the body's stores. The remainder is located in soft tissue, of which only 0.3% is located extracellularly. The common nutritional sources of magnesium are green leafy vegetables, legumes, nuts, and animal protein. (6)

Of the total magnesium consumed, approximately 30% to 50% is absorbed, mainly from the upper small intestine. The level of absorption of magnesium varies, depending on endogenous magnesium status. Magnesium is excreted via the kidneys. When magnesium stores are normal, excretion usually equates with absorption. There is a circadian excretory rhythm, with the maximal excretion occurring at night. Approximately one third of serum magnesium is bound to albumin and therefore is not filterable at the glomerulus. A total of 20% of serum magnesium is filtered by the kidneys, from which 50% to 60% is reabsorbed by the ascending loop of Henle, in contrast to other major electrolytes, which are reabsorbed principally at the proximal loop of Henle.

Extracellular magnesium in serum is 33% protein bound, 12% complexed to anions, and 55% in the free ionized form. At the cellular level, magnesium appears to influence the properties of various cell membranes; this process is thought to occur by means of calcium channels and ion transport mechanisms. Calcium flux is inhibited by magnesium from sarcolemmal membranes, through competition for binding sites on actin and via changes in the adenylate cyclase-cyclic AMP system. The next known physiologic role of magnesium involving cell membranes pertains specifically to its interrelationship with the sodium-potassium-ATPase pump. At the cellular level, magnesium also serves as a cofactor for many intracellular enzymes that generate energy via hydrolysis of ATP. It is also involved in DNA transcription and protein synthesis. Magnesium is responsible for the maintenance of transmembrane gradients of sodium and potassium. Patients with refractory hypokalemia will often not respond to potassium supplementation until ma gnesium deficiency is corrected. (68) As a result, magnesium deficiency should be considered whenever severe potassium deficiency is encountered.

From this short review, it is apparent that magnesium plays many roles in energy metabolism: as an enzyme cofactor, in electrolyte balance, and in the maintenance of the properties of various cell membranes. From this background, magnesium deficiency is being considered as an important mediator in various medical conditions.

DIAGNOSIS OF MAGNESIUM DEFICIENCY

The serum magnesium level correlates poorly with total body stores. (4) As a result, there have been several intracellular assays of magnesium from muscle biopsy, lymphocytes, and red blood cells. These assays include nuclear magnetic resonance (NMR) spectroscopy (9) and ion-specific electrode measures. (10) However, these tests are expensive and often require fresh specimens and are therefore not clinically applicable at present. For these reasons, despite its limitations, serum magnesium determination is deemed of value in assessing changes in magnesium status and is the entry level test for the evaluation of possible disorders of magnesium metabolism. When the serum magnesium level is low, intracellular magnesium is also low. (11,12) However, many patients may have normal serum magnesium levels but be intracellularly depleted. (6,13) Therefore, if the serum magnesium level is low, the patient is deficient; however, if it is normal, the patient may still be magnesium deficient.

BIOLOGIC MECHANISMS

A review of the literature reveals three biologic mechanisms that could potentially explain the physiologic effects of magnesium in hypertension, diabetes, and hyperlipidemia. First, magnesium deficiency causes a dysregulation of the Na-Mg exchanger, resulting in higher intracellular sodium and higher blood pressure. Second, a relatively low magnesium level creates an intracellular imbalance between calcium and magnesium, which results in increased vascular tone in the smooth muscle of the artery and therefore increased blood pressure. Third, magnesium deficiency causes insulin resistance, which in turn causes hyperinsulinemia, resulting in hypertension, diabetes, and hyperlipidemia.

Dysregulation of the Na-Mg Exchanger

A study of cyclosporine toxicity in spontaneously hypertensive rats found that rats placed on a low sodium diet did not get hypertension or nephrotoxicity, but during a high sodium diet, both these diseases occurred. These deleterious effects were blocked by magnesium supplementation, (14) revealing a causal relationship between magnesium and hypertension in spontaneously hypertensive rats. This result has implications for clinical trials because it may be that the hypotensive effect of a rigorously followed low-salt diet obviates the need for magnesium supplementation to improve blood pressure even in the face of magnesium deficiency. Some of the negative clinical trials for magnesium replacement did have patients on low salt diets. (15,16) This defect in the Na-Mg exchanger that results in higher intracellular sodium and lower intracellular magnesium was found in at least three other studies of patients with essential hypertension. (17-19)

Increased Vascular Tone

Again, both rat and human studies confirm that in the presence of decreased magnesium, there is increased intracellular calcium, resulting in increased vascular tone and hypertension. In a basic physiologic study that looked at isolated aortas from both normotensive and desoxycorticosterone acetate (DOCA)-salt hypertensive rats, it was found that "changes in extracellular magnesium concentration differentially alter endothelin-1-induced contraction in aortae from normotensive and hypertensive rats, possibly by interfering with calcium utilization during contraction." (20) In other animal studies, a salt load produced an increase in intracellular calcium with a concomitant decrease in magnesium. (21-23) This intracellular imbalance between magnesium and calcium has also been found in human studies. (24,25) There appears to be a clear connection between decreased magnesium, increased vascular tone, and essential hypertension.

Insulin Resistance

Insulin resistance has emerged as a major pathophysiologic mechanism for the creation of atherosclerosis in the body. Magnesium deficiency has clearly been shown to create insulin resistance. (24) This may well be a common link in increased cardiovascular risk, because hyperinsulinemia is related to hypertension, diabetes, and hyperlipidemia. (26)

This discussion shows strong evidence linking magnesium deficiency with altered physiologic states and chronic disease.

PREVALENCE OF HYPOMAGNESEMIA 

The prevalence of hypomagnesemia has been found to vary widely, depending on the patient's clinical condition. In a general population, 6.9% of patients were shown to be hypomagnesemic. (6) In hospital inpatients on a medical-surgical floor, there was a prevalence of 11%, (27) while in the intensive care unit it was found to be 20%. (28) In a postoperative intensive care unit setting, the prevalence was 60%. (28) A study of diabetic patients established a prevalence of 25%. (29) We did a 2-month period prevalence study of magnesium levels for 120 patients in an urban minority clinic and found that 24% of hypertensive patients and 25% of diabetic patients were hypomagnesemic. (30)

EPIDEMIOLOGY

Epidemiologic studies have shown an inverse relationship between magnesium in the drinking water and cardiovascular mortality. (31,32) This association between magnesium in drinking water and ischemic heart disease was reconfirmed in a major review of the literature done by epidemiologists at Johns Hopkins University. (33)

The largest epidemiologic study of magnesium status was the Atherosclerosis Risk in Communities (ARIC) study, published in 1995. (34) This was a 5-year, longitudinal study that examined 15,000 patients and compared dietary magnesium, serum magnesium, and race with the prevalence of hypertension, diabetes, and atherosclerosis. The study controlled for the potential confounding variables of age and body mass index. The results showed that African Americans had lower dietary magnesium intake along with lower serum magnesium levels, which significantly correlated with a higher prevalence of hypertension, diabetes, and atherosclerosis.

Finally, a 10-year study of 400 high-risk subjects predisposed to coronary artery disease were divided into two groups--one that received a magnesium-rich diet and another group that received a "usual" diet. Increased dietary magnesium was shown to correlate with fewer cases of sudden death, less total mortality, and a lower incidence of hypokalemia, hypomagnesemia, and other coronary risk factors. The group that had lower dietary magnesium also had a lower mean serum magnesium level. (35)

CLINICAL SIGNS AND SYMPTOMS

Magnesium deficiency is almost always asymptomatic. There are no pathognomonic signs and symptoms of the magnesium deficient state. The situation must be severe if clinical manifestations are to occur. This would also always be accompanied by a low serum magnesium level. Symptoms, when they do occur, generally fall into the categories of cardiac effects, metabolic effects, and neurologic effects (Table 1).

Clinical Correlations

Magnesium has been associated with a number of chronic diseases, such as hypertension, diabetes mellitus, and hyperlipidemia. Studies showing the effect of magnesium supplementation on these clinical states are summarized in Table 2. We found 15 studies in which magnesium supplementation was used to measure the effect on hypertension. Ten of these studies (67%) showed a statistically significant decrease of blood pressure with the use of magnesium. In patients

with diabetes, 3 studies looked at the effect of magnesium replacement on hemoglobin [A.sub.IC]. None of these investigations showed a statistically significant effect. Two studies examined the effect of magnesium supplementation on hyperlipidemia. Both of these showed decreased triglycerides, and one of them showed a decreased low-density lipoprotein/high-density lipoprotein ratio.

Diabetes Mellitus

The clinical correlation between decreased plasma magnesium and the diabetic condition was first proposed by Londono and Rosenbloom (30) in 1971. This was shown in diabetic children after a glucagon injection induced a significant decline in plasma magnesium levels.

The inverse relationship between glycemic control and plasma magnesium levels has been attributed to increased magnesium urinary losses. McNair et al (37) observed that in the presence of hypomagnesemia, magnesium plasma levels were inversely correlated with fasting blood glucose values and urinary magnesium. The conclusion was that net tubular reabsorption of magnesium was decreased in severe hyperglycemia. The relationship between metabolic control and impaired magnesium balance was confirmed by Fugii et al, (38) who analyzed magnesium levels in plasma, erythrocytes, and urine of diabetic patients.

The role of magnesium in the pathogenesis of macroangiopathy and microangiopathy have been the subject of several investigators. Seelig and Heggtveit, (39) as well as Mather, (29) suggested that atherosclerotic disease may be prevented by normal magnesium homeostasis by counteracting the adverse effects of excessive intracellular calcium, thereby retaining intracellular potassium and contributing both to the stabilizing of plasma membrane and maintaining the integrity of subcellular structures.

Hypertension

Considerable evidence suggests a linkage between magnesium deficiency and hypertension. One study showed reduced intracellular free magnesium concentration in hypertensive laboratory animals as well as in human subjects. The researchers described an inverse relationship between intracellular magnesium concentration and blood pressure. (19)

Magnesium has been implicated in a regulatory role in a variety of cellular ion channels and pumps that modulate peripheral vascular tone; these include sodium-potassium-ATPase and calcium-activated potassium channels, as well as calcium calmodulin binding. In each of these instances, low intracellular magnesium levels would potentiate calcium-dependent vasoconstriction.

THERAPEUTIC USES

Cardiac Arrhythmias

Magnesium deficiency in the pathogenesis of cardiac arrhythmias has recently been accepted. This is exemplified in the latest Advanced Cardiac Life Support protocol for the treatment of torsades de pointes. In experimental models, magnesium deficiency results in a number of electrocardiographic alterations, as well as changes in automaticity and conduction. Among the electrocardiographic changes are prolonged PR interval and QT interval, premature atrial complexes, atrial tachycardia, and fibrillation. Ventricular premature complexes and tachycardia have also been noted, in addition to ventricular fibrillation and torsades de pointes.

Magnesium is a crucial cofactor in the sodium-potassium-ATPase enzyme system, which contributes to the sodium and potassium flux across cell membranes. This flux in turn determines the potential needed for depolarization of cardiac muscle. Of note, digitalis blocks the sodium-potassium-ATPase enzyme system; it has been shown in the dog model that hypomagnesemia facilitated digitalis-toxic arrhythmias and that most of these arrhythmias were terminated with intravenous magnesium sulfate. (40)

Iseri et al (41) showed that ventricular arrhythmias recalcitrant to antiarrhythmics (lidocaine or beryllium) or to potassium supplementation responded to magnesium used as a therapeutic agent. This response occurred even in the presence of normal serum magnesium levels.

In several of the cases mentioned, the arrhythmia appeared to be that of torsades de pointes, and studies have indeed shown therapeutic confirmation in the abolition of this arrhythmia by bolus infusion of magnesium.

Acute Myocardial Infarction and Ischemic Heart Disease

Magnesium's effect as it pertains to acute myocardial infarction has been difficult to interpret, especially with respect to mortality rate differences. (42) This has occurred because of nebulous reporting of concomitant use of therapy with [beta]-blockers, aspirin, or antiarrhythmics and different lengths of observations.

Schecter et al (43) concluded that the cardioprotective effect of magnesium was more of a general myocardial protective effect than one solely due to reduction of arrhythmias. They postulated that among the possible mechanisms included were coronary vasodilatation, reduction of the catecholamine effect in myocardial tissue, and calcium-magnesium interactions at the cellular level preventing ischemic deposition of calcium in cardiac mitochondria.

The LIMIT-2 study of 1992 was the first large-scale randomized placebo-controlled trial to show a decrease in total mortality of the magnesium-treated group; this effect reached statistical significance. (44) The second large-scale trial to study survival after myocardial infarction in patients given magnesium infusion was the ISIS-4 trial. (45) The ISIS-4 study showed no survival benefit from the addition of intravenous magnesium. In a recent review of these contradictory results, Hennekens et al (46) stated, "Nonetheless, the data suggesting that early magnesium therapy reduces reperfusion-related injury have led to the hypothesis that the longer time between the start of myocardial reperfusion and the achievement of therapeutic serum magnesium concentrations may account for the null finding in ISIS-4."

Preeclampsia

The use of parenteral magnesium as a therapeutic modality in the treatment of preeclampsia is time honored. The proposed mechanism of action relates to magnesium acting as a calcium antagonist either at the membrane level or intracellularly. Although magnesium-induced reduction in vascular tone is partially explained by altered calcium flux, (2) it may also produce this effect by altering the prostaglandi n system. Watson et al (47) showed that magnesium facilitated release of potent vasodilatory prostaglandin in a dose-dependent manner. They suggested that increased prostaglandin is the explanation for magnesium's therapeutic effect in preeclampsia.

Asthma

The utility of magnesium as a therapeutic modality in the treatment of asthma has been alluded to for decades. (13) Two studies have shown that magnesium infusions increased the forced expiratory volume in 1 second ([FEV.sub.1]), (13) though the mechanism of action on the respiratory tree remains to be elucidated. One proposed mechanism is smooth muscle relaxation at the bronchial level. This is similar to the effect exerted by magnesium on vascular smooth muscle by means of its influence on calcium channels. (2)

CONCLUSION

Magnesium is critical to normal human homeostasis. Pharmacologic doses of magnesium given intravenously have been used to successfully treat such critical conditions as torsades de pointes, preeclampsia, and status asthmaticus. The usefulness of magnesium in acute myocardial infarction has yet to be fully elucidated. Deficiency states have been shown to correlate with the chronic cardiovascular diseases of hypertension, diabetes, and hyperlipidemia. Numerous studies have called for randomized controlled trials to determine whether magnesium replacement will alter the natural history of these diseases. Previous trials of magnesium supplementation have not answered the question of whether magnesium replacement would improve the health status of patients afflicted with chronic cardiovascular diseases.

Research on magnesium continues to grow as exemplified by a recent paper on the inverse relationship between prenatal magnesium sulfate exposure and cerebral palsy or mental retardation among very low birth weight children. (48)

Randomized controlled trials need to be done to see whether magnesium supplementation will ameliorate the debilitating effects of hypertension, diabetes, and hyperlipidemia, especially in minority populations. (34,49) The clinical implications of replacement therapy, if successful, would have a profound effect on improving the health of the population.

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TABLE 1

Clinical Manifestations of Severe Magnesium Deficiency

Cardiac Effects               Metabolic Effects

Atrial fibrillation           Hypokalemia
Atrial flutter                Hypocalcemia
Supraventricular tachycardia  Increased intracellular calcium
Ventricular tachycardia       Hyponatremia
Torsades de pointes           Increased intracellular sodium
Coronary artery spasm         Hypophosphatemia
Hypertension                  Metabolic alkalosis
Electrocardiogram changes     Hyperglycemia
  Prolonged PR interval       Hypercholesterolemia
  Widened QRS complex
  Prolonged QT interval
Atherosclerosis.


Cardiac Effects               Neurologic Effects

Atrial fibrillation           Grand mal seizures
Atrial flutter                Focal seizures
Supraventricular tachycardia  Paresthesias
Ventricular tachycardia       Dizziness
Torsades de pointes           Vertigo
Coronary artery spasm         Ataxia
Hypertension                  Nystagmus
Electrocardiogram changes     Tremor
  Prolonged PR interval       Myopathy
  Widened QRS complex         Dysphagia
  Prolonged QT interval       Esophageal spasm
Atherosclerosis.              Delirium, personality changes,
                              depression, coma
TABLE 2

Studies of Magnesium Replacement in Hypertension, Diabetes, or
Hyperlipidemia

Reference/                Target                  Study
Date                      Population      Number  Design        Duration

Nowson and Morgan (15)    Hypertension      25    RCT           8 weeks
 1989
Sanjuliani et al (18)     Hypertension      15    RCT           6 weeks
 1996
Kawano et al (50)         Hypertension      60    RCO           16 weeks
 1998
Yamamoto et al (51)       High normal BP   698    RCT           6 months
 1995
Eibl et al (52)           Type 2 DM         40    RCT           3 months
 1995
Corcia et al (53)         Type 2 DM         43    RCT           1 month
 1994

Purvis et al (54)         Type 2 DM         28    RCO           12 weeks
 1994


Wirell et al (55)         Hypertension      39    RCT           8 weeks
 1994
Wittman et al (56)        Hypertension      91    RCT           6 months
 1994

Kysters et al (57)        Hyperlipidemia    69    RCT           4 weeks
 1993
Widman et al (58)         Hypertension      17    RCO           18 weeks
 1993
Ferrara et al (59)        Hypertension      14    RCT           6 months
 1992
Haga, (60)                Hypertension      25    Case control  2 weeks
 1992
Lind et al (61)           Hypertension      71    RCT           6 months
 1991
Motoyama et al (62)       Hypertension      21    Case control  4 weeks
 1989
Rasmussen et al (63)      Hyperlipidemia    47    RCT           3 months
 1989
Hattori et al (64)        Hypertension      41    Case control  4 weeks
 1988
Sato et al (65)           Hypertension      20    RCO           8 weeks
 1988
Cappucio et al (66)       Hypertension      17    RCT           4 weeks
 1985
Dyckner and Western (67)  Hypertension      20    Case control  6 months
 1983

Reference/
Date                      Result

Nowson and Morgan (15)    No effect
 1989
Sanjuliani et al (18)     Positive effect
 1996                     (-7.6 SBP; -3.8 DBP)
Kawano et al (50)         Positive effect
 1998                     (-3.7 SBP; - 1.7 DBP)
Yamamoto et al (51)       No effect
 1995
Eibl et al (52)           No effect on [HbA.sub.10]
 1995
Corcia et al (53)         No effect on [HbA.sub.10]
 1994                     Increased HDL;
                          decreased LDL
Purvis et al (54)         Decreased SBP (-7.4)
 1994                     No effect on DBP
                          No effect on serum
                          glucose or lipids
Wirell et al (55)         Positive effect
 1994                     (-7.0 SBP)
Wittman et al (56)        No effect on SBP
 1994                     Positive effect on DBP
                          (-3.4)
Kysters et al (57)        No effect on HDL or LDL
 1993                     Decreased triglycerides
Widman et al (58)         Positive effect (-8.0
 1993                     SBP; -8.0 DBP)
Ferrara et al (59)        No effect (43% dropout
 1992                     rate)
Haga, (60)                Positive effect
 1992                     (MBP -4.8)
Lind et al (61)           No effect
 1991
Motoyama et al (62)       Positive effect
 1989                     (MBP -7.0)
Rasmussen et al (63)      Decreased triglycerides
 1989                     Decreased LDL/HDL ratio
Hattori et al (64)        Positive effect
 1988                     (MBP -5.4)
Sato et al (65)           Positve effect
 1988                     (MBP -4.5)
Cappucio et al (66)       No effect
 1985
Dyckner and Western (67)  Positive effect (-12.0
 1983                     SBP; - 8.0 DBP)

RCT = Randomized controlled trial,

SBP = systolic blood pressure,

DBP = diastolic blood pressure,

RCO = randomized crossover trial,

DM = diabetes mellitus,

HDL = high-density lipoprotein,

LDL = low-density lipoprotein,

MBP = mean blood pressure.