Editor's Note: This is Article of the Month is based on Kannel WB, Feinleib M, McNamara PM, Garrison RJ, Castelli WP. An investigation of coronary heart disease in families. The Framingham offspring study. American J Epidemiol 1979;110:281-90.

Introduction

Hypomagnesemia is thought to be involved in the development of ventricular arrhythmia during reperfusion after acute myocardial infarction. Low magnesium levels potentiate proarrhythmic effects of hypokalemia. Magnesium administration plays a role in the acute management of torsades de pointes. Low serum magnesium is also associated with occurrence of atrial fibrillation (AF) following Coronary Artery Bypass Graft surgery (CABG),¹ although there is conflicting data as to the utility of magnesium administration in the prevention of AF in this clinical setting.^2-4 It is not known whether low levels of magnesium are associated with the development of AF in ambulatory individuals.

Methods

Participants enrolled in the Framingham Offspring Study were analyzed.⁵ The study began in 1971 with 5124 children (or their spouses) of the original Framingham Heart Study, 3,863 of whom underwent the second examination between 1979 and 1983. After exclusion of subjects with no serum magnesium measurement (n=176), prevalent cardiovascular disease (n=155) or AF (n=2), a total of 3,530 participants were included in the analysis.

Participants underwent a complete medical history, physical examination, and laboratory studies. Blood was obtained in the fasting state. All subjects underwent routine surveillance for the development of AF. AF was diagnosed if AF or atrial flutter was found on an outpatient ECG, inpatients medical records or Holter monitor. Follow-up was censored at 20 years.

Cox proportional hazard regression analysis was used to examine the relationship between baseline serum magnesium and incident AF. Magnesium concentrations were analyzed in quartiles. Covariates in the multivariable models included age, sex, body mass index, diabetes mellitus, systolic blood pressure, ratio of total to high-density lipoprotein, smoking status, antihypertensive treatment, hemoglobin, serum albumin, estimated glomerular filtration rate, and alcohol consumption.

Results

Mean age of patients was 44 years; 52% were women. Mean serum magnesium was 1.88 mg/dL. Over a mean follow-up time of 18.6±3.7 years, 228 participants (5%) developed new-onset AF. In age- and sex-adjusted analyses, the risk of incident AF was highest in the lowest quartile of serum magnesium (hazard ratio [HR] compared with the highest quartile, 1.54; 95% CI, 1.06–2.22; P=0.02). No significant difference in the AF risk was observed across the upper 3 quartiles of serum magnesium. There was no association between serum potassium and AF in age- and sex-adjusted (HR per SD of serum potassium, 0.92; 95% CI, 0.81–1.04; P=0.18) or multivariable-adjusted (HR, 0.97; 95% CI, 0.85–1.10; P=0.62) models. Similarly, there was no association between serum calcium and AF in either age- and sex-adjusted (HR per SD of serum calcium, 0.96; 95% CI, 0.84–1.09; P=0.54) or multivariable-adjusted (HR, 0.93, 95% CI, 0.81–1.06; P=0.26) models. There was no association between moderate to heavy alcohol consumption and magnesium concentration (P=0.99). There was no interaction between moderate to heavy alcohol use, magnesium concentration, and the risk of AF (interaction P=0.72).

The age- and sex-adjusted incidence rate of AF was 9.4 per 1000 person-years (95% confidence interval, 6.7–11.9) in the lowest quartile of serum magnesium (≤1.77 mg/dL) compared with 6.3 per 1000 person-years (95% confidence interval, 4.1–8.4) in the highest quartile (≥1.99 mg/dL). In multivariable-adjusted models, individuals in the lowest quartile of serum magnesium were ~50% more likely to develop AF (adjusted hazard ratio, 1.52; 95% confidence interval, 1.00–2.31; P=0.05) compared with those in the upper quartiles. Results were similar after the exclusion of individuals on diuretics.

Conclusions

Low serum magnesium is associated with the development of AF in individuals without cardiovascular disease. Because hypomagnesemia is common in the general population, a link with AF may have potential clinical implications.

Perspective

The authors present evidence suggesting that there may be a relationship between hypomagnesemia and the development of AF in a general population cohort with no baseline cardiovascular disease. The authors observed a nonlinear association between serum magnesium and AF, with subjects in the lowest quartile of serum magnesium (≤1.77 mg/dL) being ~50% more likely to develop AF compared to those in the upper quartiles. This study is remarkable, because it is the first cohort study to suggest such an interaction exists outside of the cardiac post-operative setting. The strengths of this study include the large sample size, long follow-up, standardized measurement of serum magnesium performed at a single laboratory, and a robust adjudication of events. As the investigators obtained a direct measurement of the magnesium level, rather than rely on nutritional diaries, there are no issues of recall bias, which often times plagues such studies. Unfortunately, only the baseline serum magnesium was measured and its levels may have varied over the span of 20 years.

Magnesium has well described electrophysiological properties on cardiac myocytes. It is involved in the function of the sodium-potassium adenosine triphosphatase enzyme, which controls the movement of sodium and potassium across the cell membrane. It also antagonizes the L-type and T-type calcium channels in the atria.⁶ Intravenous administration of magnesium prolongs sinoatrial conduction time, atrioventricular nodal refractory period, and PR and AH intervals^,7,8 and low serum magnesium increases sinus node automaticity.⁹ Intravenous magnesium can improve rate control in AF and facilitate maintenance of sinus rhythm.¹⁰ The precise mechanism of how low levels of magnesium may contribute to AF remains unknown. Additionally, serum magnesium levels do not correlate well with intracellular magnesium levels, the fact which presents a challenge to establishing a definitive relationship between serum hypomagnesemia and AF.¹¹ Causality between low magnesium and future AF cannot be inferred from this study, but the findings do present an attractive hypothesis. Should these findings be confirmed in future studies, the public health implications would be significant.

References

1. Zaman AG, Alamgir F, Richens T, Williams R, Rothman MT, Mills PG. The role of signal averaged P wave duration and serum magnesium as a combined predictor of atrial fibrillation after elective coronary artery bypass surgery. Heart 1997;77:527-31.
2. Cook RC, Humphries KH, Gin K, et al. Prophylactic intravenous magnesium sulphate in addition to oral {beta}-blockade does not prevent atrial arrhythmias after coronary artery or valvular heart surgery: a randomized, controlled trial. Circulation 2009;120:S163-9.
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5. Kannel WB, Feinleib M, McNamara PM, Garrison RJ, Castelli WP. An investigation of coronary heart disease in families. The Framingham offspring study. American J Epidemiol 1979;110:281-90.
6. Wu JY, Lipsius SL. Effects of extracellular Mg2+ on T- and L-type Ca2+ currents in single atrial myocytes. The American journal of physiology 1990;259:H1842-50.
7. Kulick DL, Hong R, Ryzen E, et al. Electrophysiologic effects of intravenous magnesium in patients with normal conduction systems and no clinical evidence of significant cardiac disease. Am Heart J 1988;115:367-73.
8. DiCarlo LA, Jr., Morady F, de Buitleir M, Krol RB, Schurig L, Annesley TM. Effects of magnesium sulfate on cardiac conduction and refractoriness in humans. J Am Coll Cardiol 1986;7:1356-62.
9. Op't Hof T, Mackaay AJ, Bleeker WK, Jongsma HJ, Bouman LN. Differences between rabbit sinoatrial pacemakers in their response to Mg, Ca and temperature. Cardiovasc Res 1983;17:526-32.
10. Onalan O, Crystal E, Daoulah A, Lau C, Crystal A, Lashevsky I. Meta-analysis of magnesium therapy for the acute management of rapid atrial fibrillation. Am J Cardiol 2007;99:1726-32.
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Keywords: Atrial Fibrillation, Atrial Flutter, Blood Pressure, Body Mass Index, Coronary Artery Bypass, Diabetes Mellitus, Diuretics, Glomerular Filtration Rate, Hypokalemia, Magnesium, Myocardial Infarction, Potassium, Sodium, Sodium-Potassium-Exchanging ATPase, Torsades de Pointes

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