Magnesium Disorders and Prognosis in Heart Failure: A Systematic Review : Cardiology in Review

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Magnesium Disorders and Prognosis in Heart Failure: A Systematic Review

Voultsos, Petros MD, MSc*; Bazmpani, Maria-Anna MD, MSc*; Papanastasiou, Christos A. MD, MSc*; Papadopoulos, Christodoulos E. MD, PhD; Efthimiadis, Georgios MD, PhD*; Karvounis, Haralambos MD, PhD*; Kalogeropoulos, Andreas P. MD, PhD‡,§; Karamitsos, Theodoros D. MD, PhD*

Author Information
doi: 10.1097/CRD.0000000000000397

Abstract

Magnesium is an intracellular cation, often overlooked in everyday clinical practice. It is involved in essential biochemical reactions of cellular metabolism, including the regulation of muscular function, endothelial cell function, myocardial excitability, and activation of sodium-potassium adenosine triphospate synthase.1,2 Magnesium uptake may reduce the risk of arrhythmias and vasoconstriction that are common in heart failure (HF) patients.2 Additional magnesium actions in the cardiovascular system include the reduction of systemic vascular resistance, dilation of coronary arteries,3 improvement of myocardial metabolism, reduction of platelet aggregation,4 stabilization of cellular membranes,5 and protection of myocardial cells caused by circulating catecholamines.6

As magnesium is mainly an intracellular ion, measurements in serum or plasma may not reflect the overall magnesium homeostasis. In other words, normal serum magnesium levels may coexist with a reduction in intracellular magnesium. In fact, reduction in intracellular magnesium is more common than hypomagnesemia in HF.7–10 Normal serum magnesium values are 0.7–1.2 mmol/L.11 Hypomagnesemia can be categorized according to serum magnesium concentration levels as follows: mild (0.6–0.7 mmol/L), moderate (0.5–0.6 mmol/L), and severe (<0.5 mmol/L).12

Magnesium deficiency (hypomagnesemia) is a common finding in HF13 and has been associated with increased mortality due to cardiac arrhythmias, coronary vasoconstriction, and progressive reduction of cardiac contractility.14 It plays a key role in the occurrence and progression of arrhythmias, especially those caused by abnormal stimulus production due to pathological automation and triggering activity.15–17 Hypermagnesemia, on the other hand, is less frequent in HF. The most common cause of hypermagnesemia is chronic renal failure,18 mainly because the kidneys are the major route of magnesium elimination and excessive magnesium intake, contained in dietary supplements.19 Hypermagnesemia can also lead to cardiovascular effects, including hypotension and various cardiac arrhythmias.20

Taking into consideration the pleiotropic effects of magnesium in the cardiovascular system, the current systematic review aims to investigate the association of serum magnesium levels with cardiovascular mortality, all-cause mortality, and HF hospitalizations and ventricular arrhythmias in patients with HF and reduced ejection fraction (HFrEF).

MATERIALS AND METHODS

Literature Search

This systematic review was conducted in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines.21

PubMed and Scopus online databases were searched from inception up to September 30, 2020, for relevant studies. The search algorithm composed of relevant text words and medical subject headings that combined serum magnesium, HF, cardiovascular mortality, and morbidity-related terms. Search terms were combined with “Boolean operators” either as free text terms or as controlled “MeSH terms.” The reference lists of the included studies were manually searched for further eligible studies. The detailed search strategy that was used is presented in the Supplemental Digital Content 1 (https://links.lww.com/CIR/A31).

Inclusion Criteria

A study was considered to be eligible, if the following inclusion criteria were fulfilled: (1) included adult patients (≥18 years old), (2) explored the effect of serum magnesium on mortality and/or morbidity in HF patients, and (3) published in any language. All definitions of hypomagnesemia were included, irrespective of the cutoff limit used in individual studies. Two authors (P.V., M.-A.B.) independently assessed the eligibility of the potentially included studies. Any discrepancies were resolved via consensus with the involvement of a third reviewer (T.D.K.).

Data Extraction and Quality Assessment

A prespecified form was used to extract the following demographics and baseline characteristics of the included studies: patient follow-up time, type of HF, gender, mean age, body mass index, history of myocardial infarction, underlying diseases or comorbidities (eg, diabetes, hypertension, chronic kidney disease), left ventricular ejection fraction, New York Heart Association functional classification, and serum magnesium concentration. The quality of evidence in the included studies was assessed independently by 2 reviewers (P.V., M.-A.B.) using the Quality in Prognosis (QUIPS) tool.22 The following key domains were appraised as low, moderate, or high risk of bias: study participation, study attrition, prognostic factor measurement, outcome measurement, study confounding, statistical analysis, and reporting.

Measured Outcomes

The outcomes of interest were as follows: (1) cardiovascular mortality (ie, sudden death, acute HF, myocardial infarction, and nonfatal stroke); (2) all-cause mortality; and (3) cardiovascular morbidity (ie, hospitalization for HF, ventricular arrhythmias).

RESULTS

Study Selection and Study Characteristics

In total, 8 studies encompassing 13,539 HF patients met our inclusion criteria and were included in the review.19,23–29 A detailed flowchart of study selection is presented in Figure 1. Four were randomized clinical trials,25,27–29 while the rest were observational studies.19,23,24,26

F1
FIGURE 1.:
PRISMA flowchart. The study selection process is reported according to the Preferred Recording Items for Systematic Reviews and Meta-analyses guidelines. PRISMA indicates Preferred Reporting Items for Systematic Reviews and Meta-Analyses.

Five studies were conducted in the United States,24–28 2 in Europe23,29 and 1 in Israel.19 The percentage of males ranged from 51.2% to 75.3% among the included studies, with a mean age varying from 63.3 to 74.3 years. HFrEF and chronic kidney disease rates ranged from 51.3% to 85.5% and 23.2% to 46.4%, respectively. Patients with New York Heart Association functional class III and IV were included in most studies. Details about baseline characteristics are presented in Table 1. Assessment of risk of bias in individual studies can be found in Supplemental Digital Content 2 (https://links.lww.com/CIR/A32).

TABLE 1. - Characteristics of Selected Studies
References Year of Publication Length of Follow-Up N Age, yr Male Sex, % Hypomagnesemic, % Hypermagnesemic, % Outcomes Diabetes, % AH, % ICM, % CKD, % Mean LVEF NYHA ≥ III, % Mg (Normal Range)
Gottlieb et al 26 1990 24 mo 199 64 72.4 19.1 13.6 1, 2 NA NA 51.3 NA 19.0% 81.4 1.60–2.10 mEq/L
Eichhorn et al 27 1993 20 mo 1068 63.3 59.2 18.6 22.7 1, 2 NA NA 55.2 NA 21.2% 100.0 1.60–1.80 mEq/L
Madsen et al 23 1997 24.5 mo 190 66.0 72 40 17.4 1, 2 NA 17.9 66.0 23.2 34.5% 45.8 0.81–0.89 mmol/L
Ceremuzyński et al 29 2000 10 d 78 67.0 51.2 38.5 NA 3 NA 51.2 85.8 NA 31.0% 87.2 0.65–1.05 mmol/L
Cohen et al 19 2003 43 mo 404 74.3 56.4 12.4 4.6 1 43.6 NA NA 40.3 36.5% 39.1 0.77–1.08 mmol/L
Adamopoulos et al 28 2009 36 mo 1120 63.5 74.8 52.8 NA 1, 2, 3 46.4 47.5 64.4 46.4 32.0% 30.1 >2.00 mEq/L
Vaduganathan et al 25 2013 9.9 mo 1982 65.6 75.3 22.3 21.2 1, 2, 3 37.5 71.4 70.4 27.1 27.6% 39.9 1.90–2.20 mg/dL
Naksuk et al 24 2017 108 mo 8498 67.0 62.2 42.8 28.7 1, 2 NA NA NA NA NA NA 2.0 to <2.20 mg/dL
Continuous variables are presented as mean ± SD. Categorical variables are presented as percentages (%).
AH indicates arterial hypertension; CKD, chronic kidney disease; ICM, ischemic cardiomyopathy; LVEF, left ventricular ejection fraction; Mg, magnesium; N, No. participants; NA, not available data; NYHA, New York Heart Association; SD, standard deviation; 1, all-cause mortality; 2, cardiovascular mortality; 3, morbidity of heart failure patients.

To assess the effect of serum magnesium concentration on mortality and morbidity, 6 studies compared hypomagnesemia and hypermagnesemia with normomagnesaemia19,25–27,29 and 2 studies compared hypomagnesemia with normomagnesaemia.23,28

Results of Individual Studies

Cardiovascular Mortality

Seven studies reported data on Cardiovascular (CV) mortality.19,23–28 In 4 studies, hypomagnesemia was found to be an independent predictor of CV mortality.19,25,26,28 More specifically, in the study of Gottlieb et al,26 patients with hypomagnesemia had increased risk of sudden cardiac death compared with patients with normal or higher serum magnesium levels (P < 0.05). In the study of Madsen et al,23 hypomagnesemia was significantly associated with increased risk of sudden cardiac death (hazard ratio [HR], 4.0; confidence interval [CI], 1.4–11.3; P = 0.0091). Adamopoulos et al28 also reported that hypomagnesemia had a statistically significant association with an increased mortality (HR, 1.38; 95% CI, 1.04–1.83; P = 0.024). Along those lines, Cohen et al19 showed that patients with hypomagnesemia were more likely to experience increased mortality compared with those with normal serum magnesium, while hypermagnesemia was not an independent prognostic factor for survival, after adjustment for age, congestive HF, and renal disease. On the other hand, 3 studies did not show statistically significant association between CV mortality and hypomagnesemia, especially after adjusting for confounders.24,25,27

All-Cause Mortality

Four studies reported data on all-cause mortality.24,25,27,28 Hypermagnesemia was associated with increased risk of all-cause mortality in the study by Naksuk et al,24 which showed that patients with hypermagnesemia had higher death rates, compared with patients with normal serum magnesium (odds ratio, 1.8; 95% CI, 1.25–2.59). However, in the other 3 studies, magnesium levels were not found to significantly affect mortality.25,28

Ventricular Arrhythmias and Hospitalizations

Two studies reported data on cardiovascular morbidity, referring to ventricular arrhythmias and HF hospitalizations.28,29 Ceremuzyński et al29 reported a significant decrease in the number of ventricular ectopic beats (P < 0.0001), ventricular bigeminy (P < 0.003), and the number of nonsustained ventriuclar tachycardia episodes (P < 0.01), after correction of hypomagnesemia with intravenous magnesium administration. On the other hand, Adamopoulos et al28 did not find a significant association of serum magnesium levels with cardiovascular morbidity and hospitalizations for HF (HR, 1.14; 95% CI, 0.94–1.39; P = 0.182) or with all-cause morbidity and hospitalizations (HR, 1.18; 95% CI, 0.99–1.42; P = 0.068). Summary of results on cardiovascular mortality, all-cause mortality, and cardiovascular morbidity are presented in Table 2.

TABLE 2. - Summary of Results
References Cardiovascular Mortality All-Cause Mortality Morbidity
Gottlieb et al, 26 1990 Patients with hypomagnesemia had increased risk of sudden cardiac death compared with patients with normal or higher serum magnesium levels (P < 0.05)
Eichhorn et al, 27 1993 Change in serum magnesium concentration is not an independent prognostic factor for sudden death and cardiovascular death (RR, 1.16; CI, 0.79–1.70) No statistically significant difference between patients with hypermagnesemia and patients with normal magnesium levels as well as between patients with hypomagnesemia and normomagnesaemia
Madsen et al, 23 1997 Hypomagnesemia was considered a prognostic factor for sudden cardiac death (HR, 4.0; CI, 1.4–11.3; P = 0.0091), especially in combination with ventricular tachycardia
Ceremuzyński et al, 29 2000 Intravenous magnesium administration resulted in a statistically significant decrease in the number of ventricular ectopic beats (P < 0.0001), ventricular bigeminy (P < 0.003), and the number of episodes of nonsustained ventricular tachycardia
Cohen et al, 19 2003 Hypomagnesemia has a prognostic role in mortality of heart failure patients (P = 0.009)
Adamopoulos et al, 28 2009 Hypomagnesemia had a statistically significant association with an increase in mortality (HR, 1.38; 95% CI, 1.04–1.83; P = 0.024) Nonstatistically significant difference in mortality of patients with low serum magnesium levels compared with patients with normal serum magnesium levels (HR, 1.23; 95% CI, 0.97–1.57; P = 0.089) Nonstatistically significant association of serum magnesium levels with cardiovascular morbidity and hospitalizations for heart failure (HR, 1.14; 95% CI, 0.94–1.39; P = 0.182) or with all-cause morbidity and hospitalizations (HR, 1.18; 95% CI, 0.99–1.42; P = 0.068)
Vaduganathan et al, 25 2013 Serum magnesium levels are not an independent prognostic factor (HR, 1.01; 95% CI, 0.79–1.30; P = 0.9) Serum magnesium levels are not an independent prognostic factor (HR, 0.94; 95% CI, 0.69–1.28; P = 0.7)
Naksuk et al, 24 2017 No statistically significant association was found between serum magnesium levels and sudden cardiac death in coronary care patients Magnesium levels >2.4 mg/dL are an independent predictor of mortality for patients with heart failure
CI indicates confidence interval; HR, hazard ratio; RR, relative risk.

DISCUSSION

In this systematic review, low serum magnesium levels appear to be associated with increased mortality due to cardiovascular causes, but not with all-cause mortality or cardiovascular morbidity in patients with HFrEF. On the other hand, hypermagnesemia is more likely an indicator of comorbidities that affect prognosis rather than an independent prognostic marker in patients with HF.

Serum Magnesium and Prognosis in Heart Failure

Hypomagnesemia is an important electrolyte disturbance since it carries a high prevalence among patients with HF.30 Several pathophysiological mechanisms along with medicinal agents lead to magnesium deficiency. Anorexia and reduced intestinal absorption limit magnesium intake. In addition, activation of the neurohormonal and renin-angiotensin system results in the stimulation of aldosterone and antidiuretic hormone secretion, which in turn, due to sodium and water retention, promote extracellular volume growth, which prevents the renal tubes from reabsorbing magnesium, and thus, causes the loss of magnesium from the urine.13,20,31–33 Loop diuretics, thiazides, and digoxin, commonly administered to HF patients, prevent magnesium reabsorption in different nephron segments, and cause significant urine magnesium loss.19 Intracellular magnesium influx, caused by metabolic acidosis and increased secretion of catecholamines, common conditions that occur in congestive HF, contribute to the establishment of hypomagnesemia and are responsible for possible arrhythmias.34 Importantly, the myocardium of HF patients is a susceptible substrate for arrhythmia development and hypomagnesemia may potentially cause or aggravate malignant rhythm disturbances and sudden cardiac death.

Low serum magnesium levels seem to have a direct predictive role in mortality of patients with HF. A clear association between hypomagnesemia and sudden cardiac death has been reported by 4 of the included studies in this systematic review.19,23,28,31 The largest and most recent study was conducted by Adamopoulos et al.28 In their study, the presence of hypomagnesemia was associated with increased long-term cardiovascular mortality in a propensity-matched cohort of HF patients. However, no statistically significant association of serum magnesium levels with hospitalizations of HF was found. Therefore, the increased mortality of patients with hypomagnesemia may be attributed to arrhythmic events and sudden cardiac death. Three studies reported neutral findings regarding the prognostic significance of serum magnesium levels and cardiovascular mortality.24,25,27 However, it should be noted that the prognostic role of serum magnesium levels was not the primary endpoint of both the EVEREST (Efficacy of Vasopressin Antagonism in Heart Failure: Outcome Study With Tolvaptan) and the PROMISE (Prospective Randomized Milrinone Survival Evaluation) study. Furthermore, the results by Naksuk et al24 should be interpreted with caution since their study had a retrospective design.

Hypermagnesemia, on the other hand, is usually encountered among HF patients of older age, lower body weight and renal failure. Hypermagnesemia may have various effects on the neurological and cardiovascular system, such as mental disorders, neuromuscular dysfunction, hypotension, and cardiac arrhythmias, which are dangerous in the context of congestive HF.13,20,35 However, based on the results of this systematic review, no robust associations of hypermagnesemia and cardiovascular mortality can be suggested. Only 1 study reported an increased all-cause mortality in patients admitted to the cardiac care unit with acute decompensated HF and elevated serum magnesium levels.24

Interestingly, in the PROMISE study, a significant increase in mortality was initially observed in the group of patients with hypermagnesemia compared with the group of patients with normal magnesium levels, however, adjustment for baseline clinical parameters showed no statistically significant difference between the groups of patients in terms of all-cause mortality. Similar results were reported by Cohen et al.19 Therefore, although hypermagnesemia was associated with poorer prognosis, it does not appear to be the underlying cause of increased mortality, but most likely is an indicator of comorbidities that affect prognosis of patients with HF.

Limitations

Our systematic review has some limitations. First, the number of studies that fulfilled the inclusion criteria is small, and inevitably, there is significant heterogeneity in methodology. Specifically, there is heterogeneity in the main and secondary endpoints of the selected studies as well as the therapeutic approaches and clinical characteristics of patients. Additionally, different methods of measurement and normal ranges for normal serum magnesium were used among the included studies. Finally, most of magnesium is intracellular, and its levels are not reflected by estimation of magnesium concentration in the serum, as it corresponds to less than 1% of the body’s total magnesium. Therefore, intracellular magnesium depletion may exist, although serum magnesium is within normal range.

Clinical Implications

HF patients are prone to develop magnesium abnormalities, and hypomagnesemia appears to be a predisposing factor for life-threatening ventricular arrhythmias and/or sudden cardiac death. It is logical to suggest that HF patients with hypomagnesemia may benefit from magnesium supplementation or aldosterone antagonists with caution for overcorrection. Future studies are needed to shed light on the role of magnesium in HF mortality and determine the safe limits of serum magnesium, especially for patients with HF.

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Keywords:

heart failure; magnesium; prognosis; mortality

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