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Table of Contents
ORIGINAL ARTICLE
Year : 2019  |  Volume : 8  |  Issue : 1  |  Page : 23-28

Effects of Magnesium Replacement Therapy in Patients with Chronic Stable Heart Failure and Normal Magnesium Level


1 Department of Heart Failure and Transplantation, Rajaei Cardiovascular, Medical and Research Center, Iran University of Medical Sciences, Tehran, Iran
2 Cardiology Department, Shahid Beheshti University of Medical Sciences, Tehran, Iran

Date of Web Publication23-Apr-2019

Correspondence Address:
Dr. Mitra Chitsazan
Vali-Asr Ave., Niyayesh Blvd., Rajaei Cardiovascular, Medical and Research Center, Iran University of Medical Sciences, Tehran
Iran
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/rcm.rcm_29_18

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  Abstract 


Objectives: In the present study, we sought to assess the changes in functional, biochemical, and echocardiographic measurements of heart failure (HF) during a 12-week Mg2+ supplementation in chronic stable HF patients. Methods: Twenty patients with clinically stable New York Heart Association (NYHA) Class I–III systolic HF (echocardiography-derived left ventricular ejection fraction [LVEF] of <40%) and normal magnesium level (1.5–2 mg/dl) were recruited consecutively in this before and after study. The patients received oral Mg2+ (400 mg MgO b.i.d., for a total of 482.6 mg of elemental Mg2+) for a total of 12 weeks. Results: Twenty patients, including 10 (50%) men, with a mean ± standard deviation age of 53 ± 15 years were included. The 6-min walk distance significantly increased from 379 (348–440) m to 583 (506–604) m. High-sensitivity C-reactive protein significantly decreased from 12 (7–14) to 3 (2–4) mg/dL (P < 0.001). N-terminal pro-brain natriuretic peptide also declined from 653 (415–2660.75) to 189.5 (82.5–537.75) ng/dL (P < 0.001). The LVEF and systolic pulmonary artery pressure significantly improved (both P < 0.001). Conclusion: We demonstrated beneficial effects of Mg2+ supplementation in patients with normal magnesium level. We suggest routine Mg2+ supplementation to all HF patients with low-to-normal Mg2+ levels and normal kidney function.

Keywords: Heart failure, magnesium, pro-brain natriuretic peptide


How to cite this article:
Amin A, Chitsazan M, Chitsazan M, Haghighattalab A, Taghavi S, Naderi N. Effects of Magnesium Replacement Therapy in Patients with Chronic Stable Heart Failure and Normal Magnesium Level. Res Cardiovasc Med 2019;8:23-8

How to cite this URL:
Amin A, Chitsazan M, Chitsazan M, Haghighattalab A, Taghavi S, Naderi N. Effects of Magnesium Replacement Therapy in Patients with Chronic Stable Heart Failure and Normal Magnesium Level. Res Cardiovasc Med [serial online] 2019 [cited 2019 Jul 23];8:23-8. Available from: http://www.rcvmonline.com/text.asp?2019/8/1/23/256878




  Introduction Top


A growing body of literature shows the prevalence and significance of altered magnesium metabolism in congestive heart failure (HF). A considerable number of studies have documented lower extracellular and intracellular Mg2+ levels in patients with HF compared with healthy controls.[1],[2],[3],[4],[5] Hypomagnesemia has been found to be associated with higher mortality in HF patients. Increased mortality in HF patients with hypomagnesemia is believed to be related to the development of life-threatening ventricular arrhythmias rather than clinical and hemodynamic compromise. However, recent studies suggest that the beneficial role of Mg2+ supplementation in cardiovascular diseases is beyond its antiarrhythmic role. Mg2+ therapy has been shown to be associated with improved endothelial function and exercise tolerance in patients with coronary artery disease.[6],[7] The beneficial effects of multiple micronutrient supplementations including Mg2+ in HF patients have been shown previously.[8]

However, still, data are lacking regarding the effects of Mg2+ supplementation in HF patients with normal magnesium level. As a result, in the present study, we sought to assess the changes in functional, biochemical, and echocardiographic measurements of HF during a 12-week Mg2+ supplementation in chronic stable HF patients.


  Methods Top


Study design and population

Twenty patients with clinically stable New York Heart Association (NYHA) Class I–III systolic HF (echocardiography-derived left ventricular ejection fraction [LVEF] of <40%) and normal magnesium level (1.5–2 mg/dl) were recruited consecutively from the Heart Failure and Transplant Clinic of Rajaei Cardiovascular, Medical and Research Center, Tehran, Iran, from June 2017 to September 2017. Patients with a history of chronic kidney disease, cirrhosis, peripheral vascular diseases, pregnancy, chronic diarrhea, inflammatory bowel disease, malabsorption disorders, and arrhythmias were excluded. Patients were also excluded if they were taking Mg2+ supplements, steroids, and nonsteroidal anti-inflammatory drugs. Patients had been receiving optimized anti-HF therapy [adequate doses of diuretics and neurohormonal blockades including beta-blockers and angiotensin-converting enzyme inhibitors (or angiotensin receptor blockers) and aldosterone antagonists] according to the latest guidelines on HF,[9],[10] and none of them had been hospitalized, had emergency visits, or changed medical therapy during the 3 preceding months. Moreover, patients were kept on the same medical regimen (including the type and dose of the medications) during all the study period.

Study protocol

The study was designed as an interventional before and after study. At study entry, the subjects' clinical history was reviewed, and physical examination, echocardiography, 6-min walk test (6MWT), and biochemical measurements were performed. In addition to their background therapy for HF, patients received oral Mg2+ (400 mg MgO b.i.d., for a total of 482.6 mg of elemental Mg2+). Patients were visited every 2 weeks, and drug toleration as well as probable side effects was evaluated. At the end of the 12th week, all patients were reevaluated by the same investigators with examining biomedical indices, exercise parameters, and echocardiographic assessment.

The present study was conducted in accordance with the ethical guidelines of the Declaration of Helsinki. Institutional Review Boards at Rajaei Cardiovascular, Medical and Research Center approved the study protocol, and written informed consent was obtained from all patients.

Assessment of exercise capacity

NYHA functional class of patients was assessed by the same investigator evaluating patients at rest, dressing, walking, and climbing the stairs. NYHA Classes range from I (no symptoms) to IV (symptoms at rest). Functional capacity of patients was also assessed using the 6MWT, conducted in a flat straight 30 m corridor according to the latest guideline provided by the American Thoracic Society.[11] The distance walked in 6 min is expressed in meters.

Blood sampling and analysis

Basal blood samples were taken at 08:00 h from an antecubital vein after a 30-min rest in supine position. Blood samples were collected in the morning after an overnight fast and immediately processed on the same day. Plasma N-terminal pro-brain natriuretic peptide (NT-proBNP) levels were measured using the ELISA method (BioMedia-Corp, Bratislava-Slovakia). Serum magnesium level was measured using colorimetric method. Normal magnesium level was defined as 1.5–2 mEq/L.

Echocardiography

All patients underwent a complete echocardiographic examination with a commercially available system (Vivid™ 7, GE Healthcare, Horten, Norway). The LV end-systolic and end-diastolic volume and LVEF were measured by the modified biplane Simpson's method from the apical four-and two-chamber views.[12] M-mode LV dimensions were obtained from the parasternal long-axis view. All measurements were averaged over three consecutive beats.

Statistical analysis

All analyses were conducted by Statistical Package for the Social Sciences software, version 19 (SPSS Inc., Chicago, IL, USA). All data initially were analyzed using the Kolmogorov-Smirnov test to assess for normality. Categorical variables are presented as numbers and percentages and quantitative ones as means ± standard deviation (SD). Categorical data were compared by the Chi-square test; quantitative variables by the Student's t- test, the Mann-Whitney U-test, and the Kruskal–Wallis test, as appropriate. All P values were two-tailed, and P < 0.05 was considered statistically significant.


  Results Top


Patient demographics

Twenty patients with ischemic (n = 4 [20%]) and idiopathic dilated cardiomyopathy (n = 16 [80%]) including 10 (50%) males and 10 (50%) females with a mean ± SD age of 53 ± 15 (range 20–85) were included. Baseline patient characteristics are depicted in [Table 1].
Table 1: Baseline characteristics of the study population

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Mg2+ serum level increased from 1.63 ± 0.27 to 2.90 ± 0.17 mEq/L (P < 0.001).

Effects of magnesium on exercise tolerance

The NYHA class significantly improved (P < 0.001). Four patients (20%) improved from NYHA Class III to NYHA Class II. Four patients (20%) improved from NYHA Class III to NYHA Class I. Nine patients (45%) improved from NYHA Class II to NYHA Class I. One patient (5%) deteriorated from NYHA Class III to Class IV. Two patients (10%) remained in their previous NYHA Class (Class II).

The 6-min walk distance (6MWD) significantly increased from 379 (348–440) to 583 (506–604) m [Figure 1].
Figure 1: Change in 6MWD. (a) Distribution of 6MWD before Mg2+ replacement. (b) Distribution of 6MWD after Mg2+ replacement. 6MWD: 6-min walk distance

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Effects of magnesium on laboratory measurements

High-sensitivity C-reactive protein (Hs-CRP) significantly decreased from 12 (7–14) to 3 (2–4) mg/dL (P < 0.001) [Figure 2]. NT-proBNP also declined from 653 (415–2660.75) to 189.5 (82.5–537.75) ng/dL (P < 0.001) [Figure 3].
Figure 2: Change in hs-CRP. (a) Distribution of hs-CRP before Mg2+ replacement. (b) Distribution of hs-CRP after Mg2+ replacement. Hs-CRP: High-sensitivity C-reactive protein

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Figure 3: Change in NT-proBNP. (a) Distribution of NT-proBNP before Mg2+ replacement. (b) Distribution of NT-proBNP after Mg2+ replacement. NT-proBNP: N-terminal pro-brain natriuretic peptide

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Effects of magnesium on echocardiography parameters

The changes in the assessed echocardiographic parameters are provided in [Table 2]. The LVEF [Figure 4] and systolic pulmonary artery pressure (SPAP) significantly improved (both P < 0.001).
Table 2: The changes in echocardiographic measures

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Figure 4: Change in LVEF. (a) Distribution of LVEF before Mg2+ replacement. (b) Distribution of LVEF after Mg2+ replacement. LVEF: Left ventricular ejection fraction

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  Discussion Top


In the present study, we assessed the beneficial role of long-term Mg2+ supplementation, if any, in HF patients with normal magnesium level. The main finding of our study was that a 12-week trial of Mg2+ therapy in these patients seems to improve exercise capacity, as reflected by 6MWD. It decreases NT-proBNP level in clinically stable HF patients with optimal antifailure medications. Mg2+ supplementation is associated with a significant improvement in LVEF and SPAP. Mg2+ was well tolerated and there were no serious side effects attributable to Mg2+ being seen.

Previous studies suggest that mechanisms such as chronic or aggressive thiazide and loop diuretic therapy; activation of the renin-angiotensin-aldosterone axis; decreased oral intake; “dilutional” reduction in extracellular concentration; chronic hypokalemia; and chronic digitalis therapy are probable etiologies of hypomagnesemia in HF patients.[13],[14],[15],[16],[17],[18],[19],[20],[21],[22],[23] However, it was shown that Mg2+ intake is below the Recommended Dietary Allowance (RDA) and/or Dietary Reference Intakes (DRI) both in HF patients and healthy controls.[24] Gorelik et al. found no significant difference in the dietary intake of Mg between HF patients and controls.[25]

The majority of the previous research regarding the role of magnesium in chronic HF has been evaluated the association between hypomagnesemia and occurrence of significant life-threatening ventricular arrhythmias and sudden death.[3],[26]

Hypomagnesemia has been found to be associated with higher mortality in HF patients. Adamopoulos et al. in a propensity-matched population of ambulatory chronic HF patients showed that serum magnesium level of 2 mEq/L or less was associated with increased cardiovascular mortality but not with increased cardiovascular hospitalization.[27] They concluded that this might be explained by the fact that most of these deaths were likely sudden in nature. They linked this increased rate of cardiovascular deaths to the life-threatening ventricular arrhythmias. However, there is no general consensus in the previous literature regarding the role of hypomagnesemia in increasing the mortality in HF patients. Eichhorn et al. in patients with mild-to-moderate HF demonstrated that serum magnesium level does not appear to be an independent risk factor for sudden death or death due to all causes.[28]

Fuentes et al. evaluated effects of acute and chronic oral magnesium supplementation on endothelial function, exercise capacity, and quality of life in 22 patients with symptomatic HF.[29] They found no significant differences between the treatment and placebo arms with respect to daily Mg2+ intake, Minnesota Living with HF questionnaire score, 6-min walk, Mg2+ level, or hemodynamic parameters from baseline at 1 week or 3 months. However, they showed that the small artery elasticity decreased in patients who did not take Mg2+, whereas there it significantly improved in patients receiving Mg2+ supplementations.

Witte et al. showed that long-term multiple micronutrient supplementation (including calcium, magnesium, zinc, copper, selenium, Vitamin A, thiamine, riboflavin, Vitamin B6, folate, Vitamin B12, Vitamin C, Vitamin E, Vitamin D, and coenzyme Q10) can improve LV volumes, LVEF, and quality of life scores in elderly patients with systolic HF.[8]

In accordance with our findings, Almoznino-Sarafian et al. showed that oral Mg2+ supplementation to HF patients significantly attenuates blood levels of CRP concomitantly with a significant elevation of intracellular Mg level.[30] Moreover, data from the National Health and Nutrition Examination Survey 1999–2000 suggests that cardiovascular patients receiving regular and prolonged Mg2+ supplementation are likely to have lower CRP levels.[31]

Whatever the cause, both hypomagnesemia and intracellular magnesium depletion are common electrolyte abnormalities in HF patients. The importance of this electrolyte derangement and replacement strategy in patients with low to low-normal values remains controversial.

Study limitations

As a before and after study in a small number of HF patients, the main limitations of our study are the limited sample size and also the lack of a placebo arm. We attributed all changes seen in biochemical and echocardiographic parameters to magnesium replacement, while these might be affected by a variety of confounders which are only amenable to be assessed through comparisons by a well-matched placebo arm. Definitely, the results provided by a larger group of HF patients in a randomized, double-blind, placebo-controlled study would be more reliable to ascertain the beneficial role of long-term magnesium therapy in HF patients. Despite inherent limitations of such study design, this study provided additional evidence on the beneficial role of magnesium supplementation in clinically stable HF patients with normal magnesium level. To further elucidate the potential of magnesium therapy to be an adjuvant therapy in HF patients, future well-designed randomized, double-blind, placebo-controlled trials with larger sample sizes are suggested.


  Conclusion Top


We demonstrated that Mg2+ supplementation in patients with normal magnesium level for 12 weeks is associated with significant improvement in LV systolic function, NT-proBNP and hs-CRP serum levels, and exercise tolerance, suggesting potential mechanisms by which Mg2+ could safely benefit chronic stable HF patients with normal magnesium level receiving optimal antifailure medications. We suggest routine Mg2+ supplementation to all HF patients with low-to-normal Mg2+ levels and normal kidney function.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
  References Top

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