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Summary

This publication from the WHI project was based on data from the observational study cohort and the control arm of the hormone therapy clinical trial [1]. The primary analysis included participants who completed baseline physical examination, demographic, medical history, and self-reported dietary questionnaires, out of which a calculation of the daily magnesium intake was made. The primary outcome was incident hospitalization for heart failure (HF), which was ascertained yearly by medical record abstraction of all self-report hospitalizations. The cohort consisted of 97725 postmenopausal women 50-79 years old, of whom 2153 HF cases were observed over a median follow-up of 8.1 years. The median dietary magnesium intake across quartiles were 149 mg/day for women in the lowest quartile (Q4), 363 mg/day for the highest quartile (Q1) of intake. The non-adjusted Hazard Ratio (HR) of incident hospitalized HF for Q4 was 1.20 (1.06–1.36), compared to the value for Q1, which served as the reference. The corresponding adjusted HR was 1.32 (1.02–1.71). While many parameters and variables were considered and analyzed, the final conclusion was simple “low magnesium intake in a multiracial cohort of postmenopausal women was associated with a higher risk of incident HF, especially HF with reduced ejection fraction”.

Commentary

Magnesium plays an essential role in human physiology, primarily needed in the process of energy production [2]. For some reason, magnesium has not received much public attention in contrast to other nutrients such as calcium, iron, vitamin D and the B complex. Although a large proportion of the population worldwide consume a lower than recommended daily allowance of magnesium [3], blood levels are usually kept within the normal range, and clinical hypomagnesemia is uncommon [4]. The association of magnesium deficiency with cardiovascular risk factors such as hypertension or type 2 diabetes mellitus, or with cardiovascular disease has been well documented [5]. However, a link with HF was scarcely mentioned. A recent systematic review on nutraceuticals in patients with HF did point at magnesium as a relevant potential factor. Nonetheless, it stated that studies were too small or underpowered to accurately appraise clinical outcomes [6]. An earlier publication of data from NHANES III study on a sample comprised of 445 individuals aged 50+ years with congestive HF (54.4% males), concluded that the Prognostic Nutritional Index in participants in the top quintile (higher scores indicating optimal nutritional status) showed significantly greater intakes of magnesium [7]. Despite the large sample size of the WHI study and the sizable number of HF patients, the HRs related to magnesium consumption at Q4 vs. Q1 were not so impressive, reflecting a relatively small difference in absolute numbers between the groups. Needless to point out that a study like WHI, which collected data on a diversified population and analyzing/adjusting for so many variables, casts some doubt on the strength of the results. Unlike the recommendation for older people to keep an optimal dietary intake plus perhaps some supplemental calcium, the situation regarding magnesium is different. National health agencies have dissimilar guides for the desired daily magnesium allowances. For example, the current UK (NHS) recommendation for adult, non-pregnant women aged 19 and over is 270 mg/day [8], whereas the US (NIH) dietary advice for women above age 51 is higher – 320 mg/day [9]. A US survey published back in 2003 provided relevant nutritional data from 4257 participants aged 20 or older [10]. Race differences in mean intake of magnesium were recorded – 256 mg/d among Caucasian women, 202 mg/d among African American women, and 242 mg/d among Mexican American women. Since the natural sources of magnesium lie in leafy and other vegetables and fruits, nuts, brown rice, whole grain bread and dairy products, it is quite evident that racial and ethnical, social and economic parameters influence food consumption habits and thus play a significant role in the amount of daily ingested magnesium. The above WHI findings remind us of the somewhat forgotten pivotal part of magnesium in maintaining the normal function of many bodily organs, and the potential adverse effects of low dietary consumption. However, in my view, the strength of the current findings should be addressed cautiously. Furthermore, the WHI investigators already published their HF results in a 2013 paper, concluding that “among WHI participants with incident HF hospitalization, intakes of Ca, Mg and K were not significantly associated with subsequent mortality” [11]. This statement is in line with the results of the assessment of causality in associations of serum calcium and magnesium levels with HF [12]. In contrast with earlier studies that demonstrated an inverse association between serum magnesium and heart failure risk, “this assessment could not support previous findings suggesting a link between serum calcium and magnesium and heart failure, but this study was underpowered to detect weak associations”. To summarize, the current paper from the WHI “publication factory” is interesting but not that important from the clinical perspective.

Amos Pines
Sackler School of Medicine, Tel-Aviv University, Tel-Aviv, IsraelThe Hebrew University Hadassah Medical School, Jerusalem, Israel

References

  1. Wu WC, Huang M, Taveira TH, Roberts MB, Martin LW, Wellenius GA, Johnson KC, Manson JE, Liu S, Eaton CB. Relationship between dietary magnesium intake and incident heart failure among older women: the WHI. J Am Heart Assoc. 2020 Apr 7;9(7):e013570.
    https://www.ncbi.nlm.nih.gov/pubmed/32192409
  2. de Baaij JH, Hoenderop JG, Bindels RJ. Magnesium in man: implications for health and disease. Physiol Rev. 2015 Jan;95(1):1-46.
    https://www.ncbi.nlm.nih.gov/pubmed/25540137
  3. US Department of Agriculture, Agricultural Research Service. Usual Nutrient Intake from Food and Beverages, by Gender and Age, What We Eat in America, NHANES 2013-2016; 2019.
    https://www.ars.usda.gov/ARSUserFiles/80400530/pdf/usual/Usual_Intake_gender_WWEIA_2013_2016.pdf
  4. Ahmed F, Mohammed A. Magnesium: the forgotten electrolyte – a review on hypomagnesemia. Med Sci (Basel). 2019 Apr 4;7(4).
    https://www.ncbi.nlm.nih.gov/pubmed/30987399
  5. Rosique-Esteban N, Guasch-Ferré M, Hernández-Alonso P, Salas-Salvadó J. Dietary magnesium and cardiovascular disease: a review with emphasis in epidemiological studies. Nutrients. 2018 Feb 1;10(2).
    https://www.ncbi.nlm.nih.gov/pubmed/29389872
  6. Hopper I, Connell C, Briffa T, De Pasquale CG, Driscoll A, Kistler PM, Macdonald PS, Sindone A, Thomas L, Atherton JJ. Nutraceuticals in patients with heart failure: a systematic review. J Card Fail. 2020;26:166-179.
    https://www.ncbi.nlm.nih.gov/pubmed/31704198
  7. Sattler ELP, Ishikawa Y, Trivedi-Kapoor R, Zhang D, Quyyumi AA, Dunbar SB. Association between the Prognostic Nutritional Index and dietary intake in community-dwelling older adults with heart failure: findings from NHANES III. Nutrients. 2019 Oct 31;11(11).
    https://www.ncbi.nlm.nih.gov/pubmed/31683657
  8. Public Health England. Government Dietary Recommendations Government recommendations for energy and nutrients for males and females aged 1 – 18 years and 19+ years.2016.
    https://assets.publishing.service.gov.uk/government/uploads/system/uploads/attachment_data/file/618167/government_dietary_recommendations.pdf
  9. US Department of Health and Human Services. National Institutes of Health. Office of Dietary Supplements. Magnesium. March 24 2020.
    https://ods.od.nih.gov/factsheets/Magnesium-HealthProfessional/
  10. Ford ES, Mokdad AH. Dietary magnesium intake in a national sample of US adults. J Nutr. 2003;133:2879-82.
    https://www.ncbi.nlm.nih.gov/pubmed/12949381
  11. Levitan EB, Shikany JM, Ahmed A, Snetselaar LG, Martin LW, Curb JD, Lewis CE. Calcium, magnesium and potassium intake and mortality in women with heart failure: the Women’s Health Initiative. Br J Nutr. 2013;110:179-85.
    https://www.ncbi.nlm.nih.gov/pubmed/23199414
  12. Helte E, Åkesson A, Larsson SC. Assessing causality in associations of serum calcium and magnesium levels with heart failure: a two-sample Mendelian randomization study. Front Genet. 2019 Oct 23;10:1069.
    https://www.ncbi.nlm.nih.gov/pubmed/31708976

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