Magnesium deficiency and dilated cardiomyopathy diagnosed peripartum

Assessing magnesium status

Mg is predominantly an intracellular cation and accurate assessment of tissue Mg status is difficult. The principal sites of distribution of Mg in humans are in bone (53%), muscle (27%), soft tissue (19%) and red blood cells (0.5%), with only 0.3% of total body Mg in serum.^8–10 Of serum Mg, 30% is protein bound (predominantly to albumin), 50% is ionised and the remainder is complexed with anions including phosphate and citrate. ¹¹ There is no simple, rapid and accurate laboratory test to determine total body magnesium status in humans. ⁵ Measurement of ionised Mg is possible, although difficult to automate, and susceptible to false results without very well-defined sample handling, and probably has little value in addition to serum Mg concentrations.^12,13 Human and animal studies have consistently shown a poor correlation between serum and erythrocyte Mg (eMg) with skeletal muscle Mg concentrations.^14–18 It is therefore possible to have significant depletion of Mg in tissues while demonstrating normal serum and eMg concentrations. ¹⁹ The correlation between lymphocyte Mg and skeletal muscle Mg stores has been inconsistent in studies, measurement is technically difficult, and has high intra-individual variation. ²⁰ Intracellular Mg concentrations range from 5 to 20 mmol/L of which 1–5% is ionised. Mg loading/tolerance tests are a sensitive measure to detect Mg deficiency in individuals with normal renal function. ²¹ Intramuscular ionized Mg measured by phosphorous magnetic resonance spectroscopy was a better clinical measure of Mg status than total serum Mg and has the potential to non-invasively measure Mg content in cardiac muscle, as well as monitoring the effectiveness of Mg supplementation. ²² Haigney et al. demonstrated a strong correlation between intracellular Mg in sublingual epithelial cells obtained by scraping, and myocardial cells obtained by biopsy during cardiopulmonary bypass, while serum Mg correlated poorly with both tissue concentrations. ¹⁹

Spurious hypomagnesaemia may occur with severe hypoalbuminaemia. ¹¹

Magnesium deficiency should be considered irrespective of serum Mg concentration wherever there are typical symptoms or associated electrolyte disorders, particularly in the setting of known acquired or inherited causes of magnesium deficiency. Symptoms of Mg deficiency include neuromuscular irritability (tetany, seizures, movement disorders, paraesthesias), muscle weakness and cramps, and cardiac arrhythmias. Electrolyte disorders associated with Mg deficiency include hypokalaemia, hypocalcaemia and hypophosphataemia, particularly where refractory to replacement therapy. Major risk factors for acquired Mg deficiency include alcohol excess, poorly controlled diabetes mellitus, diarrhoea and malabsorptive syndromes, and medications including proton pump inhibitors, diuretics, antibiotics affecting renal tubular function, calcineurin inhibitors, and platinum agents.

Studies examining differences in prevalence of hypoMg among populations are limited by significant variations in assays used and serum concentrations used to define hypoMg. ²³ Two independent international groups designated 0.85 mmol/L as the low cut-off point defining hypoMg in non-pregnant individuals. ²³

Magnesium physiology in pregnancy

Increased expression of the colonic and renal tubular magnesium transporter genes from 12 weeks’ gestation has been demonstrated compared with non-pregnant controls indicating an increased demand for Mg in pregnancy. ²⁴ Serum Mg declines from a preconception mean of 0.93 mmol/L to a nadir mean of 0.63 mmol/L in the third trimester. ²⁵ Similarly ionised and eMg, and intracellular free Mg in brain and muscle are lower in pregnancy than in non-pregnant controls when measured by NMR spectroscopy.^26,27 After the fifth month of gestation, increasing amounts of Mg are transported from mother to fetus. ⁷ Fetal Mg concentrations are higher than maternal Mg concentrations consistent with a transplacental gradient. Little is known about the mechanism and regulation of placental Mg flux. ²⁸ It has been postulated that maternal–fetal Mg gradient is due to an active transport mechanism, as the gradient is not due to differences in protein binding between mother and fetus. Urinary excretion of Mg rises by approximately 25% during pregnancy. ⁶ In the presence of hypoMg excretion of greater than 1 mmol/day is consistent with renal Mg wasting in non-pregnant individuals. ²⁹ Mg excretion of less than 0.5 mmol/day is suggestive of Mg deficiency in non-pregnant individuals. ³⁰

Conditions manifesting dilated cardiomyopathy and hypomagnesaemia

Conditions which have been reported to manifest hypoMg and dilated cardiomyopathy are summarised in Table 2. Improvement and/or normalization in left ventricular function with Mg therapy has been demonstrated in many of these conditions. The relative effects of hypoMg, hypocalcaemia, hypokalaemia and hypophosphataemia in contributing to LV systolic dysfunction in several of the conditions, however, is unclear.

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Table 2.

Conditions associated with hypomagnesaemia and dilated cardiomyopathy.

Acquired

Preeclampsiaa

Medication-induced hypomagnesaemia – chemotherapy, proton pump inhibitorsb,4,31

Infection – bacterial sepsis, COVID 19

Diabetic cardiomyopathyb

Alcoholic cardiomyopathy

Eating disordersb,32–34

Genetic

Autosomal dominant hypomagnesaemia with cardiomyopathy (ADKH-RRAGD) /

Hypomagnesaemia 7 2,3

Familial hypomagnesaemia with hypercalciuria and nephrocalcinosis (FHHNC) 35

Primary hypoparathyroidismb,36,37

Gitelman and Bartter syndromes 38,39–42

Vitamin D-deficient Rickets with primary hypomagnesaemiab, 43

Congenital magnesium-losing nephropathy with mitochondrial myopathy 44

Familial primary hypomagnesaemiab, 45

Kearns-Sayre syndromea 46

Autosomal dominant hypocalcaemia type 1b, 47

^a

Peripartum dilated cardiomyopathy. ^bResolution of or improvement in left ventricular function with magnesium therapy.

Preeclampsia, hypomagnesaemia and cardiomyopathy

A systemic review and meta-analysis of 13 observational studies with 11 951 PPCM cases from seven countries found severe preeclampsia, preeclampsia, preeclampsia superimposed upon chronic hypertension, chronic hypertension and gestational hypertension were associated with odds ratios of 13.33, 4.73, 5.77, 4.73 and 3.13 for the development of PPCM. ⁴⁸

A meta-analysis of 14 studies revealed women with pregnancy-induced hypertension had lower concentration of serum Mg, zinc and calcium than healthy pregnant women. ⁴⁹ There is an overexpression for the gene SLC41A1, a Na/Mg exchanger, in placenta from women with preeclampsia (PET) compared with normal placentas, suggesting a change in Mg homeostasis may contribute to the development of PET. ⁵⁰ A pilot study examining serum Mg in pregnant women at a University Teaching Hospital in Benin, West Africa, found that women with hypoMg had an Odds ratio of 22 for preeclampsia compared with normomagnesaemic women. ⁵¹ The presence of hypoMg in women with preeclampsia is associated with increased risks of complications of preeclampsia including posterior reversible encephalopathy syndrome and haemolysis, elevated liver enzymes and low platelet syndrome.^52,53 Mean maternal cerebral and skeletal muscle Mg concentration measured by phosphorous magnetic resonance spectroscopy were lower in women with preeclampsia compared with healthy pregnant and non-pregnant controls.^26,54 In women with preeclampsia, those with visual symptoms had lower cerebral Mg concentration than those without visual symptoms. ⁵⁴

Major methodological difficulties in the interpretation of intervention studies into the role of Mg supplementation in prevention of hypertensive disorders of pregnancy include variations in dietary intake of Mg, and doses and the bioavailability of individual Mg preparations used. A 2014 review of the Cochrane Pregnancy and Childbirth Group's trial register found that Mg supplementation during pregnancy was not associated with a reduction in perinatal mortality, small for gestational age (SGA) or preeclampsia compared with a control group. ⁵⁵ Of the ten randomised trials only two were judged to be of high quality overall, and there was a lack of consistency in the timing, dose and formula of Mg supplements used in individual studies. Additionally, the studies included were not in populations associated with a high prevalence of Mg deficiency. The Brazilian Magnesium trial found that supplementation with oral Mg citrate 150 mg twice a day from 12 to 20 weeks’ gestation was not associated with a reduction in preeclampsia. ⁵⁶ A recent randomised controlled trial of low-risk pregnant women in Iran with serum Mg less than 0.78 mmol/L at 12–14 weeks’ gestation found that supplementation with an effervescent 200 mg Mg preparation for one month, together with a multi-mineral preparation containing 100 mg Mg until the end of pregnancy, was associated with lower risks of preeclampsia, intrauterine growth restriction, pre-term birth, and low birthweight. ⁵⁷

Large, well-designed trials that are sufficiently powered addressing specific considerations including timing of commencement of supplementation, dosage and relevant maternal and neonatal/infant outcomes, in populations with a high incidence of Mg deficiency may be worthwhile.

A consistent relationship between Mg deficiency, the risk of development of PET, and neurological complications of preeclampsia has been demonstrated. Parenteral Mg prevents seizures and placental abruption in women with PET, and the risk of recurrent seizures in women with eclampsia.^58,59

To date, no association between Mg deficiency and dilated cardiomyopathy complicating PET has been confirmed.

Chemotherapy-induced dilated cardiomyopathy and hypomagnesaemia

Ninety-eight per cent of cases of anthracycline-induced cardiomyopathy occur in the first year following treatment, with only three case reports of onset of symptomatic heart failure described more than five years following treatment.^60,61 A meta-analysis of pregnancies to women with doxorubicin exposure in childhood found 1.7% developed heart failure until 12 months postpartum. ⁶² The risk of PPCM was 55 times greater than the general pregnant population. Daunorubicin-induced cardiomyopathy in rabbits was associated with significant reductions in myocardial Mg and potassium and increased calcium. ⁶³ These changes in myocardial elements were prevented in animals pre-treated with dexrazoxane, proven to prevent anthracycline-induced cardiomyopathy in humans. ⁶⁴ Pre-treatment with Mg oxide nanoparticles also prevents doxorubicin-induced alterations in cardiac and apoptosis-related markers in animal studies. ⁶⁵ In 26 cancer patients observed for seven days with daily clinical and electrocardiographic (ECG) evaluation following initial treatment with doxorubicin or epirubicin, 11 had a fall in eMg. ⁶⁶ Seven of the 11 patients who developed low eMg manifested ECG changes, compared with only one of the 15 patients with normal eMg.

HypoMg due to urine Mg wasting occurs in 8–71% of individuals previously treated with cisplatin, typically with hypocalciuria. ⁶⁷ Preloading with 8 mmol intravenous Mg significantly reduced cisplatin-induced nephrotoxicity in humans with an odds ratio of 0.234. ⁶⁸ Dilated and Takotsubo cardiomyopathy have been described following treatment with cisplatin. ⁶⁹

Sepsis, hypomagnesaemia and cardiomyopathy

Left ventricular systolic function is severely reduced on echocardiography (LVEF <40%) in 20–60% of non-pregnant individuals with septic shock, with resolution of cardiac dysfunction on echocardiography typically occurring within 7–10 days of presentation.^70–72 In the third case cardiac dysfunction persisted for more than six months postpartum, atypical for sepsis as the sole aetiology, and suggestive of PPCM. HypoMg in patients admitted with sepsis to an intensive care unit (ICU) was associated with higher sequential organ failure assessment score, greater length of mean intensive care unit stay, and higher mortality rates (33% vs 4%) than normomagnesaemic septic patients. ⁷³ Soliman et al. found a significantly higher prevalence of septic shock in individuals with low ionised Mg compared with normomagnesaemic individuals (57% vs 11%, p < 0.01) admitted to an ICU. ⁷⁴ Patients who developed low ionised Mg during their ICU stay had higher Acute Physiology and Chronic Health Evaluation II and Sequential Organ Failure Assessment scores at admission, and may have been more likely to develop sepsis due to being more unwell than those with normal ionised Mg. A retrospective cohort study found the use of intravenous magnesium sulphate in patients admitted to an ICU with sepsis was associated with lower ICU and in-hospital mortality, and requirement for renal replacement therapy. ⁷⁵ Magnesium therapy affords significant protection against lipopolysaccharide-induced cardiotoxicity and pyroptotic cell death. ⁷⁶

HypoMg has been detected in 18–61% of individuals admitted to intensive care units, though it is unclear what proportion of these are spurious hypoMg due to hypoalbuminaemia, related to antimicrobial therapy, or represent an epiphenomenon. HypoMg is also associated with an increased risk of disseminated intravascular coagulation in septic patients. ⁷⁷

RRAGD gene variants

In 2021 Schlingmann et al. described heterozygous variants in the RRAGD gene which induce a constitutive activation of mechanistic target of rapamycin resulting in tubulopathy associated with hypoMg due to renal Mg wasting, hypokalaemia, and renal salt wasting. ³ Hypercalciuria, hypochloraemia, nephrocalcinosis and polyuria were variable features. ³ Six of eight children from unrelated families with tubulopathy had early-onset severe dilated cardiomyopathy, three of whom underwent cardiac transplantation.

Trepiccione et al. subsequently identified 23 individuals from 11 families affected by gain-of-function variants of the RRAGD gene. ² The renal phenotype for most of the variants (S76L, I221 K, P119R, P119L) typically manifests in the second decade of life occasionally preceded by dilated cardiomyopathy in childhood. Polyhydramnios and pre-term delivery were described for patients carrying the I221K- and S76L/W-RRAGD variants. The P88L variant, however, is associated with dilated cardiomyopathy and sudden cardiac death manifesting in adulthood. None of the four females with P88L variants presented with major complications during pregnancy. Standard potassium and magnesium supplements were effective in managing carpopedal spasm and tetany, though it is unclear as to whether this treatment had any impact on LV systolic function.

In 2006 Ahmed et al. had described a case of a woman at 27 weeks’ gestation with newly diagnosed dilated cardiomyopathy, hypermagnesuric hypoMg, hypercalciuria and polyuria, who in retrospect may have a RRAGD gene variant. ⁷⁸

Potential mechanisms in Mg deficiency contributing to dilated cardiomyopathy

Mg is involved in oxidative and inflammatory responses through neutralizing free radicals of oxygen and reducing inflammation by regulating the expression of nuclear factor kappa B.^79,80 Mg deficiency leads to a pro-inflammatory state with excessive production of oxygen-derived free radicals, which may overwhelm tissue antioxidant capacity with subsequent oxidative tissue destruction. Cellular ATP is significantly reduced in low-Mg mouse hearts. Mishra demonstrated that Mg-deficient rats have fewer cardiac mitochondria than control rats. ⁸¹ Human studies have also described abnormalities of cardiac mitochondria with hypoMg. ⁴⁴

HypoMg is associated with increased levels of catecholamines. Animals fed a Mg-deficient diet demonstrated a dramatic increase in myocardial injury following exposure to isoprenaline. ⁸² Isolated perfused rat hearts with low-Mg demonstrated a 20–37% reduction in coronary blood flow, a 25–50% reduction in cardiac output and stroke volume, 3- to 4-fold elevations in lactate production, and eventual irreversible cardiac failure. ⁸³ Mg reduces catecholamine release from both adrenal medulla and peripheral adrenergic nerve terminals, and is a highly effective alpha-adrenergic antagonist and antiarrhythmic in the setting of high-dose epinephrine infusions. ⁸⁴ Magnesium infusions have been shown to be effective in the perioperative management of phaeochromocytoma, as well as in reversing systolic dysfunction with both dilated and Takotsubo cardiomyopathy with phaeochromocytoma crisis.^84–87

Hypomagnesaemia may be associated with hypokalaemia, hypocalcaemia and hypophosphataemia, which may affect cardiac function.

Mg deficiency and PPCM – geographical associations

Attempts to test for a possible relationship between incidences of hypoMg, dietary Mg intake, and PPCM among populations are significantly limited by a lack of data regarding prevalence of hypoMg globally, variations in assays and se Mg defining hypoMg, and heterogeneity of populations studied ²³ (Table 3). A strong correlation, however, was found between incidence of PPCM and dietary Mg intake (r = 0.713).

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Table 3.

Global incidences of PPCM, hypomagnesaemia, and dietary Mg intake – countries listed from highest to lowest incidence PPCM.

Country 88	Incidence PPCM	Incidence Mg deficiency	Mean dietary intake magnesium women
Nigeria	1:100	16.2% pregnant women serum Mg < 0.5 mmol/L 51	79 mg/day 89
Haiti	1:300	Drinking water severely deficient in Mg (< 0.3 mmol/L) 90	No data
China	1:350–1:900	73% pregnant women serum Mg < 0.75 mmol/L 91	238 mg/day 92
Pakistan	1:840	31% pregnant women serum Mg < 0.75 mmol/L 93	No data
USWhiteAfrican American	1:1500–1:40001:440–1:670	No data20% non-pregnant urban African American population se Mg < 0.62 mmol/L (71% female) 94	256 mg/day diet alone 95 390 mg/day with supplements202 mg/day 95
South Africa	1:1000	No data	260 mg/day (Black) 96 280 mg/day (White)
India	1:1340	43.6% rural pregnant women serum Mg < 0.74 mmol/L 97	No data
Denmark	1:10 000	No data	360 mg/day 98
Japan	1:15 000	No data	320 mg/day 99
Russian Federation	No data	34% pregnant women serum Mg < 0.65 mmol/L 100 65.5% pregnant women serum Mg < 0.8 mmol/L 100	No data

PPCM: peripartum cardiomyopathy.

Potential implications for management

A single-centre, randomised placebo-controlled double-blind study of 79 non-pregnant patients with severe congestive heart failure (NYHA IV) receiving optimal medical therapy found the use of magnesium orotate as adjuvant therapy improved survival, clinical symptoms, and patient quality of life. ¹⁰¹

Mineralocorticoid receptor antagonists are not effective in increasing se Mg concentration. Amiloride and sodium-glucose transporter 2 inhibitors (SGLT2i) increase serum Mg by reducing renal Mg loss, through increasing reabsorption in the distal nephron. ¹⁰² Amiloride was shown to increase lymphocyte intracellular free Mg in patients treated with furosemide compared with furosemide alone. ¹⁰³ SGLT2i reduces mortality, rehospitalisation, and adverse cardiac outcomes in individuals with heart failure with reduced ejection fraction. ¹⁰⁴ No studies have specifically examined the use of SGTL2i or amiloride in PPCM or the efficacy of amiloride in cardiac failure.

A study examining improvements in intracellular tissue Mg with intravenous Mg therapy demonstrated greater improvement with doses of Mg larger than 40 mmol/24 h. ¹⁹ Up to 160 mmol of intravenous Mg may be required over five days to correct deficiency. ¹⁰⁵

Animal studies have not demonstrated teratogenicity with amiloride. Amiloride use has been described in only ten human pregnancies in the management of Gitelman, Liddle and Geller syndromes, and primary aldosteronism, without adverse maternal or fetal outcomes.^106–109 SGTL2i have been shown to cross the placental barrier in ex-vivo human placental perfusion models with a maximal fetal to maternal concentration of 0.38–0.67. ¹¹⁰ The adjusted risk for any and cardiac major congenital malformation following periconception use of SGLT2i referenced against insulin use were 1.13 and 0.98 respectively. ¹¹¹

Women with PPCM may be treated with dopamine agonists, or be advised against breastfeeding, although a study demonstrated that lactation was not associated with lower rates of myocardial recovery with PPCM. ¹¹² Only one human case report has described the use of amiloride during breastfeeding, without adverse neonatal effects. While SGLT2i are ∼ 90% protein bound in plasma, and therefore unlikely to pass into breastmilk in clinically significant amounts, there is no published information to date regarding the safe use of SGTL2i with breastfeeding.

Future research possibilities

Retrospective studies of databases of individuals with PPCM or idiopathic dilated cardiomyopathy in pregnancy examining serum Mg, and myocardial Mg from autopsy or myocardial biopsy specimens may be helpful. Retrospective studies of women with preeclampsia complicated by PPCM comparing outcomes with and without parenteral Mg therapy may be informative. Prospective studies involving non-invasive measurement of myocardial or skeletal muscle Mg using phosphorous magnetic resonance spectroscopy (MRS), or alternatively measurement of sublingual epithelial cell Mg by energy-dispersive x-ray analysis, may provide information regarding tissue Mg concentration in PPCM and dilated cardiomyopathy in pregnancy. Prospective randomised double-blinded trials of intravenous Mg at a dose of at least 40 mmol/day for up to five days comparing outcomes in treatment groups and placebo control may be worthwhile. Genetic testing for RRAGD variations from retrospective databases as well as in future cases of dilated cardiomyopathy and PPCM may also be informative.