Significance of hypomagnesemia in cardiovascular disease

INTRODUCTION — Mild hypomagnesemia is a common electrolyte abnormality [1], particularly in older adults who may have increased urinary magnesium losses due to diuretic therapy or interstitial kidney disease. Whether this abnormality should be treated or prevented with prophylactic magnesium administration is unclear. The major concern is whether mild magnesium depletion predisposes to cardiac arrhythmias [2,3]. There are conflicting data as to whether this occurs in otherwise healthy subjects. A report on over 3000 patients from the Framingham Heart Study suggests that how arrhythmia is defined is an important determinant [4]. No association with hypomagnesemia was noted for more than 10 ventricular premature complexes (VPCs) per hour or for repetitive VPCs. There was, however, an increased risk of complex or frequent (≥30/hour) VPCs with reductions in the plasma magnesium concentration of 0.16 mEq/L (0.2 mg/dL or 0.08 mmol/L) or more. The formulas to convert between these units can be found elsewhere. (See "Regulation of magnesium balance".)

Thus, attempts have been made to identify those patients who might be at risk. The data suggest that this might occur when hypomagnesemia occurs in the setting of an acute ischemic event, congestive heart failure, torsades de pointes, after cardiopulmonary bypass, or in the acutely ill patient in the intensive care unit.

The mechanisms underlying the possible association between hypomagnesemia and arrhythmias are at present unknown. Arrhythmias could be due to concurrent hypokalemia, hypomagnesemia itself, or both [2,3]. Magnesium regulates several cardiac ion channels, including the calcium channel and outward potassium currents through the delayed rectifier [5]. Lowering the cytosolic magnesium concentration in magnesium depletion will markedly increase these outward currents, shortening the action potential and increasing susceptibility to arrhythmias.

ACUTE ISCHEMIC HEART DISEASE — Patients with acute myocardial infarction who have mild hypomagnesemia appear to have a two- to threefold increase in the frequency of ventricular arrhythmias in the first 24 hours when compared with those with normal plasma magnesium levels [6,7]. Uncontrolled studies suggest that the administration of intravenous magnesium at this time can reduce the frequency of potentially fatal ventricular arrhythmias [8,9].

A relationship has also been found between the plasma magnesium concentration and ventricular arrhythmias occurring in the second or third week after myocardial infarction. In one study, for example, the mean plasma magnesium concentration was 1.83 mg/dL (0.76 mmol/L) in patients with no abnormal rhythms, 1.68 mg/dL (0.7 mmol/L) in those with multifocal ventricular premature complexes (VPCs), and 1.55 mg/dL (0.65 mmol/L) in those with unsustained ventricular tachycardia [10]. Thirteen patients with complex arrhythmias and hypomagnesemia received intravenous magnesium over 24 hours; a normal rhythm was restored in 10.

A related issue is the possible protective effect of doubling the normal plasma magnesium concentration in patients with suspected acute myocardial infarction. The main rationale behind this regimen is that mild hypermagnesemia protects the myocardium from ischemia-reperfusion injury, at least in part by promoting restoration of high-energy phosphates. Some studies have suggested that magnesium may be beneficial if given before reperfusion with thrombolysis or angioplasty. However, a randomized clinical trial (MAGIC) specifically designed to test the role of magnesium found no benefit to magnesium infusion [11].

Magnesium may also be associated with atherosclerosis. Mendelian randomization is a method to reduce confounding by using genetic risk variants as instrumental variables of an exposure. In a Mendelian randomization study of over 180,000 individuals in the CARDIoGRAMplusC4D dataset, a genetic predisposition to a higher serum magnesium level was associated with reduced risk of coronary artery disease [12].

HEART FAILURE — An increased incidence of hypomagnesemia has been found repeatedly in patients with heart failure and may be due in part to diuretic therapy [13]. A role for magnesium depletion in sudden death has been suggested but not proven. As an example, in a prospective study involving over 1000 patients with class III or IV heart failure, no correlation was found between hypomagnesemia at the beginning of the study and survival at a median follow-up of six months [14]. However, measurements were not made later in the study, and all patients were receiving digoxin, diuretics, and an angiotensin-converting enzyme (ACE) inhibitor, any or all of which may have altered magnesium balance during the course of the study. In another study of ambulatory patients with chronic heart failure, serum magnesium levels less than or equal to 2 mEq/L were associated with an increased risk of both all-cause (hazard ratio 1.23) and cardiovascular (hazard ratio 1.38) mortality [15]. Although data from smaller clinical trials suggest potential benefits from magnesium supplementation in patients with heart failure [16,17], the utility of such therapy remains unclear.

Evidence from one observational study has suggested an association between serum magnesium level and the risk for heart failure. In an analysis of 14,709 patients enrolled in the Atherosclerosis Risk in Communities (ARIC) cohort, a total of 2250 incident heart failure events occurred over a median of 20.6 years [18]. After adjusting for demographic factors such as age, sex, race, and center, patients in the lowest quintile of serum magnesium (0.5 to 1.4 mEq/L) had a 2.6-fold higher risk of incident heart failure compared with those in the highest quintile (1.8 to 3.1 mEq/L).

The association between dietary magnesium intake and heart failure was evaluated in a meta-analysis of 40 cohort studies including more than 1 million patients [19]. During the follow-up period, which ranged from 4 to 30 years, 701 cases of heart failure were reported. Increasing dietary magnesium intake was associated with a 22 percent reduction in the risk of heart failure per 100 mg/day increment (relative risk [RR] 0.78, 95% CI 0.69-0.89). As these were all observational studies, the results of this meta-analysis may have been limited by residual confounding, particularly due to other dietary components that may be correlated with magnesium intake. By contrast, in a study of UK Biobank participants, genetically predicted magnesium levels were not associated with heart failure, suggesting that the link between magnesium and heart failure may not be causal [20].

Additional prospective studies are needed to investigate the possible utility of magnesium supplementation in the prevention of heart failure.

TORSADES DE POINTES — Hypomagnesemia increases the risk of a unique form of polymorphic ventricular tachycardia called torsades de pointes. The risk is particularly increased in patients taking class IA or class III antiarrhythmic drugs. (See "Acquired long QT syndrome: Definitions, pathophysiology, and causes", section on 'Metabolic abnormalities'.)

The American Heart Association Guidelines for Cardiopulmonary Resuscitation and Emergency Cardiac Care include a recommendation that magnesium sulfate be added for the management of torsades de pointes, severe hypomagnesemia, or refractory ventricular fibrillation [21,22]. Treatment is aimed at accelerating the heart rate and/or shortening the QT interval. Intravenous magnesium is now regarded as the treatment of choice even when hypomagnesemia is not present [23]. (See "Overview of the acute management of tachyarrhythmias", section on 'Polymorphic ventricular tachycardia'.)

CARDIOPULMONARY BYPASS — Hypomagnesemia may both develop during cardiopulmonary bypass and predispose to arrhythmias [24]. The causes of hypomagnesemia in this setting are unclear. Possible contributing factors include hemodilution, increased fractional excretion by the kidney, chelation by free fatty acids and/or citrate, and enhanced cellular uptake induced by increasing circulating levels of catecholamines.

Several randomized controlled trials have examined the effect of magnesium sulfate supplementation on arrhythmias after cardiac surgery. Meta-analyses of these trials have also been performed. This issue is discussed elsewhere in detail. (See "Atrial fibrillation and flutter after cardiac surgery" and "Atrial fibrillation and flutter after cardiac surgery", section on 'Ineffective or possibly effective therapies'.)

INTENSIVE CARE UNIT — Hypomagnesemia is extremely common in patients in the intensive care unit. As an example, a study of admissions to a surgical intensive care unit in 2011 found that hypomagnesemia was present in 33 percent of patients [25]. Although hypomagnesemia in critically ill patients is likely multifactorial, the use of proton pump inhibitors (PPIs, which are commonly given to patients in the intensive care unit) has been shown to increase the risk of hypomagnesemia in a large meta-analysis of data from 109,798 patients [26].

Hypomagnesemia in the intensive care unit is frequently associated with hypokalemia and hypocalcemia [27,28] (see "Hypomagnesemia: Clinical manifestations of magnesium depletion") and may be associated with increased mortality. In one study, for example, hypomagnesemia present on admission to the intensive care unit was associated with a mortality rate approximately twice that of comparably ill, normomagnesemic patients [28]. It has not been shown, however, that treatment with magnesium supplementation would improve the outcome.

CORONARY ARTERY DISEASE — Several large prospective epidemiologic studies have examined the relationship between the serum magnesium concentration and the subsequent development of coronary artery disease (CAD) [29-32]. Each suggests that a low serum magnesium may be a risk factor for coronary disease.

One study, for example, examined and followed a cohort of 13,922 individuals aged 45 to 64 years old and over for four to seven years as part of the Atherosclerosis Risk in Communities (ARIC) study [31]. The relative risk of CAD across quartiles of serum magnesium in females was 1 (in the lowest quartile), 0.92, 0.48, and 0.44. The data in males showed a similar trend but was less striking and did not achieve statistical significance. Both males and females who developed CAD had lower mean baseline serum magnesium concentration than the disease-free controls. How a low serum magnesium might predispose to CAD is not known. However, it may be related to its effects on endothelial function. Support for this comes from one study of 50 patients with CAD that found that oral magnesium therapy (30 mmol/day for 30 days) improved endothelial function and exercise tolerance compared with placebo [33]. (See "Coronary endothelial dysfunction: Clinical aspects".)

One observational study has suggested an association between low serum magnesium and mortality from CAD. In a population-based analysis of 9820 patients followed for a median of 8.7 years, lower serum magnesium level (<0.80 mmol/L) was associated with an increased risk of CAD mortality (hazard ratio [HR] 1.36, 95% CI 1.09-1.69) as well as sudden cardiac death (SCD; HR 1.54, 95% CI 1.12-2.11) [34]. Although low serum magnesium was also associated with accelerated subclinical atherosclerosis (as evidenced by increased carotid intima-media thickness) and increased QT interval, adjustment for these factors did not change the relationship between serum magnesium and CAD mortality or SCD.

However, contrasting findings were reported in a post hoc analysis of the EPHESUS trial, in which 6632 patients with myocardial infarction and left ventricular dysfunction were randomly assigned to eplerenone or placebo [35]. Of the 5371 patients with a post-baseline magnesium measurement, 4 percent had hypomagnesemia at baseline, and 13 percent developed hypomagnesemia over a median of 16 months. Although baseline hypomagnesemia was associated with an increased risk of the composite of all-cause mortality and all-cause hospitalization (HR 1.24, 95% CI 1.03-1.50), its impact on cardiovascular mortality was not significant after adjustment for covariates.

The association of magnesium intake (rather than serum levels) and CAD has been examined in two large prospective female cohorts [29,36]. Neither showed a significant association with CAD. However, the larger of the two studies documented an inverse association with fatal CAD; compared with those in the lowest quintile of intake, females in the highest had a relative risk for fatal CAD during 28 years of follow-up of 0.61 (95% CI 0.45-0.84) [29]. The efficacy of magnesium supplementation in preventing CAD remains to be established.

ATRIAL FIBRILLATION — As mentioned above, hypomagnesemia is associated with atrial fibrillation following cardiac surgery. In addition, hypomagnesemia may increase the risk of atrial fibrillation in the general population without known cardiovascular disease [37]. In the Framingham Offspring Study, for example, individuals in the lowest compared with the highest quartile of serum magnesium were 50 percent more likely to develop atrial fibrillation during 20 years of follow-up. By Mendelian randomization, genetically predicted serum magnesium levels were found to be inversely associated with atrial fibrillation, suggesting a causal relationship [38]. However, not all studies have confirmed this association. Among 2513 participants in the Atherosclerosis Risk in Communities (ARIC) study who had ambulatory electrocardiogram monitoring, hypomagnesemia was not associated with atrial fibrillation after adjusting for cardiovascular risk factors [39].

SUMMARY

●Overview – Mild hypomagnesemia is a common electrolyte abnormality, particularly in older adults and among patients with heart failure, due to diuretic therapy. Data suggest that mild magnesium depletion predisposes to cardiac arrhythmias when it occurs in the setting of an acute ischemic event, congestive heart failure, torsades de pointes, after cardiopulmonary bypass, or in the acutely ill patient in the intensive care unit. (See 'Introduction' above and 'Heart failure' above.)

●Acute ischemic heart disease – Patients with acute myocardial infarction who have mild hypomagnesemia appear to have an increased frequency of ventricular arrhythmias particularly in the first 24 hours. The administration of intravenous magnesium may reduce the frequency of potentially fatal ventricular arrhythmias. (See 'Acute ischemic heart disease' above.)

●Torsades de pointes – Hypomagnesemia increases the risk of torsades de pointes, particularly in patients taking class IA or class III antiarrhythmic drugs. (See 'Torsades de pointes' above.)

●Cardiopulmonary bypass – Hypomagnesemia may both develop during cardiopulmonary bypass and predispose to arrhythmias. Possible contributing factors include hemodilution, increased fractional excretion by the kidney, chelation by free fatty acids and/or citrate, and enhanced cellular uptake induced by increasing circulating levels of catecholamines. (See 'Cardiopulmonary bypass' above.)

●Other cardiovascular disease – A low serum magnesium may be a risk factor for heart failure (see 'Heart failure' above), coronary disease (see 'Coronary artery disease' above), and atrial fibrillation (see 'Atrial fibrillation' above) in the general population.

ACKNOWLEDGMENT — The UpToDate editorial staff acknowledges Zalman S Agus, MD, who contributed to an earlier version of this topic review.