Abstracts
Background:
Ventricular and supraventricular premature complexes (PC) are frequent and usually symptomatic. According to a previous study, magnesium pidolate (MgP) administration to symptomatic patients can improve the PC density and symptoms.
Objective:
To assess the late follow-up of that clinical intervention in patients treated with MgP or placebo.
Methods:
In the first phase of the study, 90 symptomatic and consecutive patients with PC were randomized (double-blind) to receive either MgP or placebo for 30 days. Monthly follow-up visits were conducted for 15 months to assess symptoms and control electrolytes. 24-hour Holter was performed twice, regardless of symptoms, or whenever symptoms were present. In the second phase of the study, relapsing patients, who had received MgP or placebo (crossing-over) in the first phase, were treated with MgP according to the same protocol.
Results:
Of the 45 patients initially treated with MgP, 17 (37.8%) relapsed during the 15-month follow-up, and the relapse time varied. Relapsing patients treated again had a statistically significant reduction in the PC density of 138.25/hour (p < 0.001). The crossing-over patients reduced it by 247/hour (p < 0.001). Patients who did not relapse, had a low PC frequency (3 PC/hour). Retreated patients had a 76.5% improvement in symptom, and crossing-over patients, 71.4%.
Conclusion:
Some patients on MgP had relapse of symptoms and PC, indicating that MgP is neither a definitive nor a curative treatment for late follow-up. However, improvement in the PC frequency and symptoms was observed in the second phase of treatment, similar to the response in the first phase of treatment.
Ventricular Premature Complexes; Arrhythmias, Cardiac; Magnesium
Fundamento:
Extrassístoles (ES) ventriculares e supraventriculares são frequentes e muitas vezes sintomáticas. Segundo estudo prévio, a administração de pidolato de magnésio (PMg) a pacientes sintomáticos pode resultar na melhora da densidade das ES e dos sintomas relacionados.
Objetivo:
Avaliar os resultados dessa intervenção clínica inicial no seguimento tardio de pacientes recebendo PMg ou placebo.
Métodos:
Noventa pacientes com ES, sintomáticos e consecutivos foram randomizados (duplo-cego) para receber PMg ou placebo por 30 dias. Visitas mensais de seguimento (15 meses) foram realizadas para avaliar a sintomatologia e controlar eletrólitos. O Holter de 24 horas foi realizado sempre que sintomáticos, ou duas vezes, independentemente dos sintomas. Na segunda fase do estudo, os pacientes cujos sintomas recidivassem, seja do grupo PMg ou placebo (crossing over), receberam PMg seguindo-se o mesmo protocolo.
Resultados:
Dos 45 pacientes que receberam inicialmente o PMg, 17 (37,8%) apresentaram recidiva dos sintomas em tempo variável nos 15 meses. Os pacientes com recidiva e tratados uma segunda vez apresentaram redução estatisticamente significante na densidade de ES de 138,25/hora (p < 0,001). Os pacientes de crossing reduziram em 247/hora (p < 0,001). Nos pacientes que não apresentaram recidiva, a frequência de ES foi baixa (3 ES/hora). A melhora dos sintomas foi de 76,5% nos retratados e de 71,4% nos de crossing.
Conclusão:
Houve recorrência de sintomas e das ES em alguns pacientes que usaram PMg, deixando claro não ser essa uma forma de tratamento definitivo ou curativo no seguimento tardio. Contudo, houve também melhora na frequência de ES e de sintomas em uma segunda etapa de tratamento, semelhante à resposta na primeira etapa.
Complexos Ventriculares Prematuros; Arritmias Cardíacas; Magnésio
Introduction
The incidence of premature ventricular complexe (PVC) and premature supraventricular complexe (PsVC) increases with age, their prevalence being estimated at as much as 50% of the general population11 Barret PA, Peter CT, Swan HJ, Singh BN, Mandel WJ. The frequency and prognostic significance of electrocardiographic abnormalities in clinically normal individuals. Prog Cardiovasc Dis. 1981;23(4):299-319.
2 De Paula RS, Antelmi I, Vincenzi MA, André CD, Artes R, Grupi CJ, et al. Cardiac arrhythmias and atrioventricular block in a cohort of asymptomatic individuals without heart disease. Cardiology. 2007;108(2):111-6.
3 Rasmussen V, Jensen G, Schnohr P, Hansen JF. Premature ventricular beats in healthy adult subjects 20 to 79 years of age. Eur Heart J. 1985;6(4):335-41.
4 Wajngarten M, Grupi C, Bellotti GM, Da Luz PL, Azul LG, Pileggi F. Frequency and significance of cardiac rhythm disturbances in healthy elderly individuals. J Electrocardiol. 1990;23(2):171-6.-55 Hiss RG, Averill KH, Lamb LE. Electrocardiographic findings in 67,375 asymptomatic subjects. III. Ventricular rhythms. Am J Cardiol. 1960;6:96-107.. The long-term prognosis is benign, but, when symptomatic, such premature complexe (PC) can be uncomfortable or even disabling. Several pharmacological and non-pharmacological measures for their clinical control have been suggested. However, under certain conditions, the results are limited or the risk-benefit relationship is arguable.
Magnesium (Mg) is an alkaline earth metal that participates in several metabolic processes, such as reactions in ATP generation. It is the second intracellular cation and the fourth cation of the human body66 Swaminathan R. Magnesium metabolism and disorders. Clin Biochem Rev. 2003;24(2):47-66.
7 Wu J, Carter A. Magnesium: the forgotten electrolyte. Aust Prescr. 2007;30:102-5.
8 Gums JG. Magnesium in cardiovascular and other disorders. Am J Health Syst Pharm. 2004;61(15):1569-76.-99 Gums JG, Stier-Carson D, Hedrix GH, Weart GH, De Oca GM. Effect of magnesium and potassium on cardiac function: the role of spironolactone. J Pharm Technol. 1990;6:10-4.. That metal plays a significant role in maintaining proper cardiac rhythm, because of its action on the Na/K- ATPase pump66 Swaminathan R. Magnesium metabolism and disorders. Clin Biochem Rev. 2003;24(2):47-66.,77 Wu J, Carter A. Magnesium: the forgotten electrolyte. Aust Prescr. 2007;30:102-5. and its interaction with calcium1010 Huskisson E, Maggini S, Ruf M. The role of vitamins and minerals in energy metabolism and well-being. J Int Med Res. 2007;35(3):277-89.. Approximately half of the body Mg is within soft tissue cells, while the other half is within bone tissue88 Gums JG. Magnesium in cardiovascular and other disorders. Am J Health Syst Pharm. 2004;61(15):1569-76.,1111 Elin RJ. Magnesium: the fifth but forgotten electrolyte. Am J Clin Pathol. 1994;102(5):616-22.. Less than 1% of Mg is found in the blood, and approximately 0.3%, in the serum1212 Elin RJ. Laboratory tests for the assessment of magnesium status in humans. Magnes Trace Elem. 1991;92(2-4):172-81.,1313 Arnaud MJ. Update on the assessment of magnesium status. Br J Nutr. 2008;99 Suppl 3:S24-36.. Thus, total body Mg has a weak correlation with its serum levels, which can be normal in the presence of low intracellular values1414 Arsenian MA. Magnesium and cardiovascular disease. Prog Cardiovasc Dis. 1993;35(4):271-310.,1515 Purvis JR, Movahed A. Magnesium disorders and cardiovascular diseases. Clin Cardiol. 1992;15(8):556-68..
The Mg intake has decreased in the past century88 Gums JG. Magnesium in cardiovascular and other disorders. Am J Health Syst Pharm. 2004;61(15):1569-76., probably due to the increased consumption of processed foods88 Gums JG. Magnesium in cardiovascular and other disorders. Am J Health Syst Pharm. 2004;61(15):1569-76.,1414 Arsenian MA. Magnesium and cardiovascular disease. Prog Cardiovasc Dis. 1993;35(4):271-310.,1616 Kawano Y, Matsuoka H, Takishita S, Omae T. Effects of magnesium supplementation in hypertensive patients: assessment by office, home, and ambulatory blood pressures. Hypertension. 1998;32(2):260-5., which can be a risk factor for Mg deficiency. That deficiency can be associated with cardiovascular disease, such as cardiac arrhythmias88 Gums JG. Magnesium in cardiovascular and other disorders. Am J Health Syst Pharm. 2004;61(15):1569-76.. In selected patients, based on a simple treatment strategy, antiarrhythmics drugs, which can be harmful or poorly tolerated under certain circumstances, can be avoided. Recently, we have shown that Mg pidolate (MgP), after a 30-day continuous supplementation, can decrease ectopic beats and improve related symptoms1717 Falco CN, Grupi C, Sosa E, Scanavacca M, Hachul D, Lara S, et al. Successful improvement of frequency and symptoms of premature complexes after oral magnesium administration. Arq Bras Cardiol. 2012;98(6):480-7.. Based on those initial findings, we assessed the outcome of this cohort of patients in the late follow-up.
This study was aimed at: 1) assessing the late clinical outcome of patients initially treated with placebo and/or MgP; 2) assessing whether patients with arrhythmia relapse in a 15-month follow-up, when treated for the second time, have the same response of the first treatment; and 3) assessing the response of patients to MgP after initially receiving placebo.
Methods
This study's methodology has been previously described when assessing the 30-day results1717 Falco CN, Grupi C, Sosa E, Scanavacca M, Hachul D, Lara S, et al. Successful improvement of frequency and symptoms of premature complexes after oral magnesium administration. Arq Bras Cardiol. 2012;98(6):480-7.. In the first state of the treatment, ninety consecutive symptomatic patients were randomized (double-blind) to receive either 3.0 g/day of MgP, the equivalent of 260 mg of the Mg element, or placebo, for 30 days. All patients underwent transthoracic echocardiography, and had normal kidney function (Cockcroft-Gault formula) and structurally normal heart1818 Helou R. Should we continue to use the Cockcroft-Gault formula? Nephron Clin Pract. 2010;116(3):c172-85..
The serum levels of Mg, sodium, calcium and potassium were measured before and on the 15th and 30th day after randomization. The follow-up visits were monthly conducted to assess symptoms by using a specific questionnaire. As previously described1717 Falco CN, Grupi C, Sosa E, Scanavacca M, Hachul D, Lara S, et al. Successful improvement of frequency and symptoms of premature complexes after oral magnesium administration. Arq Bras Cardiol. 2012;98(6):480-7., the questionnaire was elaborated with the following questions: 1- failures or "leaps", like a 'somersault' in the chest; 2- cough with palpitations; 3- dizziness; 4- dyspnea; 5- sweating and/or chest pain. According to the frequency of symptoms, points were attributed, which resulted in a score, and a two-point drop was considered a criterion of improvement. In addition, a categorical classification was conducted by asking the patients whether the symptoms improved, the answers being merely "yes" or "no" (Figure 1). In the long-term follow-up, all patients underwent 24-hour Holter monitoring twice, independently of symptoms, to assess the PC frequency. In addition, Holter monitoring (3 channels) was performed whenever symptoms appeared (before and 30 days of use of MgP).
This figure shows the score system to assess improvement of symptoms before and after the drugs in both groups (placebo and magnesium pidolate).
In the second phase of the study, the patients with symptom relapse, of both the treatment and placebo groups ("crossing over"), received MgP for 30 more days, according to the same protocol.
Statistical analysis
The densities of PC in both phases of treatment (pre- and post-intervention) were measured by using mean, standard deviation, median, minimum and maximum values1919 Kirkwood BR, Sterne JAC. Essential medical statistics. 2nd ed. Massachusetts, USA: Blackwell Science; 2006.
The PC densities were compared between times of treatment and between treatments by using repeated-measures two-way analysis of variance (ANOVA)2020 Singer JM, Andrade DF. (2000). Analysis of longitudinal data. In: Handbook of statistics. Volume 18: bio-environmental and public health statistics. eds. P.K. Sen and C.R. Rao. Amsterdam: North Holland. 115-160.. A correlation matrix of symmetrical components was calculated between asssessments2020 Singer JM, Andrade DF. (2000). Analysis of longitudinal data. In: Handbook of statistics. Volume 18: bio-environmental and public health statistics. eds. P.K. Sen and C.R. Rao. Amsterdam: North Holland. 115-160.. Multiple comparisons by using Bonferroni adjustment2121 Kuntner M, Nachtsheim C, Neter J, Li W. Applied linear statistical models. 4th ed. Illinois, USA: McGraw Hill / Irwin; 1996. were performed between the treatment times, and contrast was created to assess whether the improvement in the first treatment (pre-post 1st treatment) differed from that in the second treatment (pre-post 2nd treatment).
The improvement in symptoms was described at each treatment phase in both groups of patients, and McNemar tests1919 Kirkwood BR, Sterne JAC. Essential medical statistics. 2nd ed. Massachusetts, USA: Blackwell Science; 2006 were performed to assess whether there was difference in the improvement percentages in each treatment. The results were illustrated by using graphs of mean profiles with the respective standard errors. The 5% significance level was adopted for all tests. The SPSS software, version 20.0, was used for statistical analysis.
Results
The 90 patients participating in the first phase of treatment were followed up for 15 months. Table 1 shows the outcome of the first intervention. Of the 45 patients initially randomized to receive MgP, 41 (91.1%) were asymptomatic after the first month assessment, and four relapsed. In subsequent months, more 13 patients relapsed, adding to a total of 17 relapses (37.8%). All patients were treated again. The relapse time varied during the 15-month follow-up, and no statistically significant relapse concentration in a certain time was observed.
Outcome of the first intervention with Magnesium pidolate (MgP) versus placebo (shown as median)
Frequency of premature complexes
The relapsing patients (17 in the MgP group) who were retreated had a mean reduction in the PC density of 138.25/hour in both treatments (p < 0.001). No mean difference was observed in the PC density improvement between the successful initial treatment and that after relapse (p = 0.159), that is, patients using MgP repeated the response of the first treatment: significant improvement in symptoms and in PC (Table 2 and Figure 2).
The median value of PVC/day after the first treatment was 3, and was 1872 on Holter monitoring after relapse. After the new intervention, this frequency decreased to 280 (p < 0.001). Regarding PsVC, the median after the first treatment was 14 PsVC/day, 15 on Holter monitoring after relapse, increasing to 38 after treatment (p < 0.102) (Table 3). The density of PC/hour after the first treatment was 10.3, increasing to 126.1 on relapse, and decreasing to 50.2 after the new treatment (p < 0.001) (Tables 3 and 4).
Only three patients relapsed twice, being retreated, and two of them responded similarly, with improvement in symptoms and in PC frequency. Only one patient relapsed three times, and had a good response after the retreatments. The patients who did not relapse had a low PC frequency on Holter monitoring, with a median of 3 PC/hour (Table 3).
Of the 45 patients treated with placebo in the first phase, 6 (13.3%) improved their symptoms and 39 (86.7%) remained symptomatic. Of those 39, 21 agreed to receive MgP and were selected for crossing-over. Patients who did not agree to receive MgP were excluded from the analysis. The crossing-over patients had a statistically significant mean reduction in the PC density when using MgP (p < 0.001), while, when on placebo, no change in density was observed (p > 0.999). The mean improvement in PC density was 247/hour, greater in the treatment with MgP than in the first treatment with placebo (p < 0.001) (Table 2 and Figure 3).
Mean profiles of density of extrasystoles in each treatment in patients of the placebo group undergoing crossing-over.
The median of PVC decreased from 2508/day to 689/day (p < 0.001), and that of PsVC, from 4/day to 1/day (p < 0.015) (Table 3). The density of PC/hour was 264.8 in the pre-treatment phase, dropping to 48 after the use of MgP (crossing-over) (Tables 3 and 4).
On Holter monitoring, PVC were more frequent, originating mainly (71%) from the outflow tract of the ventricles.
Symptoms
In relapsing patients, the improvement in symptoms of both treatments was statistically the same (p = 0.125) (Table 5). All 17 relapsing patients improved their symptoms in the first treatment, while 76.5% improved their symptoms in the relapse treatment. Similar response was obtained in the score of symptoms and in the categorical response of symptom improvement ('yes' or 'no').
The patients using placebo in the initial treatment and MgP in the second one (crossing-over) had a statistically greater improvement in symptoms with the second treatment (14.3% versus 71.4%, respectively; p < 0.001) (Table 5).
Improvement in symptoms of each group of patients for each treatment, and results of the marginal association test
No significant changes in the measurements of serum Mg, potassium and calcium were observed during the study. No side effects were observed in the long-term follow-up.
Discussion
The follow-up results show that the improvement in symptoms by using MgP was maintained (76.5%) in the relapsing group as compared with the initial treatment. The group using placebo initially (crossing-over) had a 71.4% improvement in symptoms with MgP versus a 14.3% improvement with placebo.
The use of MgP was effective in reducing PC. However, because that is mainly a symptomatic treatment and because the mechanism of PC is multifactorial, symptoms and PC relapsed in approximately 38% of the cases, indicating that MgP is neither a definitive nor a curative treatment in late follow-up. However, the patients who could use MgP again improved their frequency of PC and mainly their symptoms, the latter being this study's major objective, because the group treated had a structurally normal heart.
It is worth noting that the patients initially treated with placebo also improved significantly their symptoms and frequency of PC after using MgP. This confirms that Mg administration is really better than placebo use.
The Mg reduces irregular heartbeats, and Mg deficiency should always be considered a potential factor for cardiac arrhythmias2222 Tong GM, Rude RK. Magnesium deficiency in critical illness. J Intensive Care Med. 2005;20(1):3-17.. One hypothesis of the pathophysiological mechanisms relates to the fact that low Mg levels lead to an increase in intracellular calcium and sodium, and to a decrease in intracellular potassium77 Wu J, Carter A. Magnesium: the forgotten electrolyte. Aust Prescr. 2007;30:102-5.,88 Gums JG. Magnesium in cardiovascular and other disorders. Am J Health Syst Pharm. 2004;61(15):1569-76.. Those changes in ionic loads cause membrane potential flotations, destabilizing atrial and ventricular myocardium, causing arrhythmias.
The Framingham study2323 Khan AM, Lubitz SA, Sullivan LM, Sun JX, Levy D, Vasan RS, et al. Low serum magnesium and the development of atrial fibrillation in the community: the Framingham Heart Study. Circulation. 2013;127(1):33-8. has shown that low Mg levels are associated with the development of atrial fibrillation in individuals with no cardiovascular disease. Patients at intensive care units should undergo intravenous replacement of Mg for arrhythmias not responding to conventional drugs, such as torsades de pointes1515 Purvis JR, Movahed A. Magnesium disorders and cardiovascular diseases. Clin Cardiol. 1992;15(8):556-68., and arrhythmias caused by digitalis intoxication2424 Iseri LT, Allen BJ, Brodsky MA. Terapia de magnesio en arritmias cardiacas en medicina de cuidados críticos. Revista de Cuidados Intensivos em Medicina. 2005;20(1):3-17.. Similarly to hypomagnesemia, digitalis inhibits the Na/K ATPase pump, increasing intracellular calcium and the contraction power of cardiomyocytes, PC being one of the most common arrhythmias in digitalis intoxication. The Mg deficiency caused by diuretic treatment in heart failure is associated with a higher incidence of arrhythmias, such as ventricular ectopy66 Swaminathan R. Magnesium metabolism and disorders. Clin Biochem Rev. 2003;24(2):47-66.,88 Gums JG. Magnesium in cardiovascular and other disorders. Am J Health Syst Pharm. 2004;61(15):1569-76.,2525 Ceremuzynski L, Gebalska J, Wolk R, Makowska E. Hypomagnesemia in heart failure with ventricular arrhythmias. Beneficial effects of magnesium supplementation. J Intern Med. 2000;24(1):78-86.. High concentrations of catecholamines can lead to the exit of intracellular Mg to the extracellular compartment, resulting in Mg reduction in the tissues, causing arrhythmias, especially in cardiac surgeries and in congestive heart failure patients66 Swaminathan R. Magnesium metabolism and disorders. Clin Biochem Rev. 2003;24(2):47-66..
According to Kleivay and Milne2626 Klevay LM, Milne DB. Low dietary magnesium increases supraventricular ectopy. Am J Clin Nutr. 2002;75(3):550-4., the recommended daily Mg intake is 320 mg/day. Higher daily doses might be required by patients on diuretics, more prone to Mg level reduction, and, thus, with a higher potential and more susceptible to the development of ES2626 Klevay LM, Milne DB. Low dietary magnesium increases supraventricular ectopy. Am J Clin Nutr. 2002;75(3):550-4.. Martynov and Akatova2727 Martynov Al, Akatova EV. Fifteen years experience of the use of magnesium preparations in patients with mitral valve prolapse. Kardiologiia. 2011;51(6):60-5. have followed up, for 15 years, 31 patients with mitral valve prolapse, who, during that time, regularly used Mg preparations for three months, twice a year. A reduction in the following parameters were observed: mean and maximum heart rate; number of tachycardia episodes; QT interval duration; and incidence of paroxysmal supraventricular tachycardia and PC. In addition, improvements in quality of life and in sympathetic tone were observed.
More recently, Del Gobbo et al2828 Del Gobbo LC, Song Y, Poirier P, Dewailly E, Elin RJ, Egeland GM. Low serum magnesium concentrations are associated with a high prevalence of premature ventricular complexes in obese adults with type 2 diabetes. Cardiovasc Diabetol. 2012;11(1):23. have assessed obese adults with type 2 diabetes, and have shown that low serum Mg levels were associated with a high prevalence of PVC.
Our previous study, assessing 60 individuals with PVC and PsVC, has shown an improvement in the frequency of arrhythmia and mainly in symptoms1717 Falco CN, Grupi C, Sosa E, Scanavacca M, Hachul D, Lara S, et al. Successful improvement of frequency and symptoms of premature complexes after oral magnesium administration. Arq Bras Cardiol. 2012;98(6):480-7.. Our current results indicate a significant improvement in PVC of the outflow tract. Right ventricular outflow tract is the most common origin of PVC in patients without structural heart disease2929 Darrieux FC, Scanavacca MI, Hachul DT, Melo SL, D'Ávilla AB, Grupi CJ, et al. Radiofrequency catheter ablation of premature ventricular contractions originating in the right ventricular outflow tract. Arq Bras Cardiol. 2007;88(3):265-72.. That site might have remnant cells of the neural crest and of adrenergic modulation. The Mg reduction in those cells might be related to sympathetic modulation, more evident in the ventricles.
All those studies have shown that Mg intake can be a practical alternative to treat some arrhythmias. Considering its low cost, its efficacy and safety, the increase in daily Mg intake should be considered for symptomatic patients with PC and a structurally normal heart.
Limitations
Intracellular Mg was not measured, but the measurement of serum Mg levels has shown that supplementation to be safe and effective. The specific score for symptoms has not been validated, because it does not exist in the literature. However, a categorical assessment ('yes' or 'no') has also been performed, showing a good correlation between the reduction in PC frequency and improvement in symptoms. In addition, this study was not aimed at preventing life-threatening arrhythmias. These data should not be used to justify the treatment of patients for that purpose, especially those with heart diseases.
Conclusion
Some patients on MgP had relapse of symptoms and PC, indicating that MgP is neither a definitive nor a curative treatment in late follow-up. However, improvement in the PC frequency and symptoms was observed in the second phase of treatment, after relapse, being similar to the response in the first phase of treatment. Treatment with MgP, even after the first phase with placebo, improved the symptoms and PC density of the population studied (structurally normal heart).
The increase in daily Mg intake should be considered for patients with PC and structurally normal heart.
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Sources of FundingThere were no external funding sources for this study.
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Study AssociationThis article results from the continuation of the doctoral dissertation by Cristina Nádja M. Lima De Falco, from Faculdade de Medicina da Universidade de São Paulo.
Acknowledgements
We thank Prof. Dr. Dalmo Moreira and Prof. Dr. Ricardo Alkmim Teixeira for their precious suggestions in the first phase of this project, Prof. Dr. Antônio Carlos Pereira Barretto and Prof. Dr. Alfredo J. Mansur for all the encouragement, and Rogério Ruscitto Prado for his support in the statistical analysis.
References
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1Barret PA, Peter CT, Swan HJ, Singh BN, Mandel WJ. The frequency and prognostic significance of electrocardiographic abnormalities in clinically normal individuals. Prog Cardiovasc Dis. 1981;23(4):299-319.
-
2De Paula RS, Antelmi I, Vincenzi MA, André CD, Artes R, Grupi CJ, et al. Cardiac arrhythmias and atrioventricular block in a cohort of asymptomatic individuals without heart disease. Cardiology. 2007;108(2):111-6.
-
3Rasmussen V, Jensen G, Schnohr P, Hansen JF. Premature ventricular beats in healthy adult subjects 20 to 79 years of age. Eur Heart J. 1985;6(4):335-41.
-
4Wajngarten M, Grupi C, Bellotti GM, Da Luz PL, Azul LG, Pileggi F. Frequency and significance of cardiac rhythm disturbances in healthy elderly individuals. J Electrocardiol. 1990;23(2):171-6.
-
5Hiss RG, Averill KH, Lamb LE. Electrocardiographic findings in 67,375 asymptomatic subjects. III. Ventricular rhythms. Am J Cardiol. 1960;6:96-107.
-
6Swaminathan R. Magnesium metabolism and disorders. Clin Biochem Rev. 2003;24(2):47-66.
-
7Wu J, Carter A. Magnesium: the forgotten electrolyte. Aust Prescr. 2007;30:102-5.
-
8Gums JG. Magnesium in cardiovascular and other disorders. Am J Health Syst Pharm. 2004;61(15):1569-76.
-
9Gums JG, Stier-Carson D, Hedrix GH, Weart GH, De Oca GM. Effect of magnesium and potassium on cardiac function: the role of spironolactone. J Pharm Technol. 1990;6:10-4.
-
10Huskisson E, Maggini S, Ruf M. The role of vitamins and minerals in energy metabolism and well-being. J Int Med Res. 2007;35(3):277-89.
-
11Elin RJ. Magnesium: the fifth but forgotten electrolyte. Am J Clin Pathol. 1994;102(5):616-22.
-
12Elin RJ. Laboratory tests for the assessment of magnesium status in humans. Magnes Trace Elem. 1991;92(2-4):172-81.
-
13Arnaud MJ. Update on the assessment of magnesium status. Br J Nutr. 2008;99 Suppl 3:S24-36.
-
14Arsenian MA. Magnesium and cardiovascular disease. Prog Cardiovasc Dis. 1993;35(4):271-310.
-
15Purvis JR, Movahed A. Magnesium disorders and cardiovascular diseases. Clin Cardiol. 1992;15(8):556-68.
-
16Kawano Y, Matsuoka H, Takishita S, Omae T. Effects of magnesium supplementation in hypertensive patients: assessment by office, home, and ambulatory blood pressures. Hypertension. 1998;32(2):260-5.
-
17Falco CN, Grupi C, Sosa E, Scanavacca M, Hachul D, Lara S, et al. Successful improvement of frequency and symptoms of premature complexes after oral magnesium administration. Arq Bras Cardiol. 2012;98(6):480-7.
-
18Helou R. Should we continue to use the Cockcroft-Gault formula? Nephron Clin Pract. 2010;116(3):c172-85.
-
19Kirkwood BR, Sterne JAC. Essential medical statistics. 2nd ed. Massachusetts, USA: Blackwell Science; 2006
-
20Singer JM, Andrade DF. (2000). Analysis of longitudinal data. In: Handbook of statistics. Volume 18: bio-environmental and public health statistics. eds. P.K. Sen and C.R. Rao. Amsterdam: North Holland. 115-160.
-
21Kuntner M, Nachtsheim C, Neter J, Li W. Applied linear statistical models. 4th ed. Illinois, USA: McGraw Hill / Irwin; 1996.
-
22Tong GM, Rude RK. Magnesium deficiency in critical illness. J Intensive Care Med. 2005;20(1):3-17.
-
23Khan AM, Lubitz SA, Sullivan LM, Sun JX, Levy D, Vasan RS, et al. Low serum magnesium and the development of atrial fibrillation in the community: the Framingham Heart Study. Circulation. 2013;127(1):33-8.
-
24Iseri LT, Allen BJ, Brodsky MA. Terapia de magnesio en arritmias cardiacas en medicina de cuidados críticos. Revista de Cuidados Intensivos em Medicina. 2005;20(1):3-17.
-
25Ceremuzynski L, Gebalska J, Wolk R, Makowska E. Hypomagnesemia in heart failure with ventricular arrhythmias. Beneficial effects of magnesium supplementation. J Intern Med. 2000;24(1):78-86.
-
26Klevay LM, Milne DB. Low dietary magnesium increases supraventricular ectopy. Am J Clin Nutr. 2002;75(3):550-4.
-
27Martynov Al, Akatova EV. Fifteen years experience of the use of magnesium preparations in patients with mitral valve prolapse. Kardiologiia. 2011;51(6):60-5.
-
28Del Gobbo LC, Song Y, Poirier P, Dewailly E, Elin RJ, Egeland GM. Low serum magnesium concentrations are associated with a high prevalence of premature ventricular complexes in obese adults with type 2 diabetes. Cardiovasc Diabetol. 2012;11(1):23.
-
29Darrieux FC, Scanavacca MI, Hachul DT, Melo SL, D'Ávilla AB, Grupi CJ, et al. Radiofrequency catheter ablation of premature ventricular contractions originating in the right ventricular outflow tract. Arq Bras Cardiol. 2007;88(3):265-72.
Publication Dates
-
Publication in this collection
11 Nov 2014 -
Date of issue
Dec 2014
History
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Received
20 July 2014 -
Reviewed
17 Aug 2014 -
Accepted
21 Aug 2014