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<reference>
Magnesium and the Risk of Cardiovascular Events: A
Meta-Analysis of Prospective Cohort Studies
Xinhua Qu1., Fangchun Jin1., Yongqiang Hao1, Huiwu Li1, Tingting Tang1, Hao Wang2, Weili Yan3,
Kerong Dai1*
1 Shanghai Key Laboratory of Orthopaedic Implant, Shanghai Ninth People’s Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China, 2 Department of
Pharmacology and Biostatistics, Institute of Medical Sciences, Shanghai Jiaotong University School of Medicine, Shanghai, China, 3 Department of Health Policy and
Management, Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland, United States of America

Abstract
Background: Prospective studies that have examined the association between dietary magnesium intake and serum
magnesium concentrations and the risk of cardiovascular disease (CVD) events have reported conflicting findings. We
undertook a meta-analysis to evaluate the association between dietary magnesium intake and serum magnesium
concentrations and the risk of total CVD events.
Methodology/Principal Findings: We performed systematic searches on MEDLINE, EMBASE, and OVID up to February 1,
2012 without limits. Categorical, linear, and nonlinear, dose-response, heterogeneity, publication bias, subgroup, and metaregression analysis were performed. The analysis included 532,979 participants from 19 studies (11 studies on dietary
magnesium intake, 6 studies on serum magnesium concentrations, and 2 studies on both) with 19,926 CVD events. The
pooled relative risks of total CVD events for the highest vs. lowest category of dietary magnesium intake and serum
magnesium concentrations were 0.85 (95% confidence interval 0.78 to 0.92) and 0.77 (0.66 to 0.87), respectively. In linear
dose-response analysis, only serum magnesium concentrations ranging from 1.44 to 1.8 mEq/L were significantly associated
with total CVD events risk (0.91, 0.85 to 0.97) per 0.1 mEq/L (Pnonlinearity = 0.465). However, significant inverse associations
emerged in nonlinear models for dietary magnesium intake (Pnonlinearity = 0.024). The greatest risk reduction occurred when
intake increased from 150 to 400 mg/d. There was no evidence of publication bias.
Conclusions/Significance: There is a statistically significant nonlinear inverse association between dietary magnesium
intake and total CVD events risk. Serum magnesium concentrations are linearly and inversely associated with the risk of total
CVD events.
Citation: Qu X, Jin F, Hao Y, Li H, Tang T, et al. (2013) Magnesium and the Risk of Cardiovascular Events: A Meta-Analysis of Prospective Cohort Studies. PLoS
ONE 8(3): e57720. doi:10.1371/journal.pone.0057720
Editor: German Malaga, Universidad Peruana Cayetano Heredia, Peru
Received September 2, 2012; Accepted January 25, 2013; Published March 8, 2013
Copyright: ß 2013 Qu et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted
use, distribution, and reproduction in any medium, provided the original author and source are credited.
Funding: This study was supported by Fund for National Basic Research Program of China (Grant No. 2012CB619101), Major Basic Research of Science and
Technology Commission of Shanghai Municipality (Grant No. 11DJ1400303), and Key Disciplines of Shanghai Municipal Education Commission (Grant No. J50206).
The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
Competing Interests: The authors have declared that no competing interests exist.
* E-mail: krdai@163.com
. These authors contributed equally to this work.

Current guidelines for the prevention of CVD from the
American Medical Association (AMA) include goals for magnesium intake [14]. These guidelines suggest that magnesium-rich
foods have a positive effect on blood pressure (BP) [14]. Recently,
several literature reviews and editorials have focused on the
relevance of magnesium in CVD. These reviews indicate that the
prevalence of CVD events caused by inadequate magnesium
intake and low serum magnesium concentrations has been
underestimated and that cardiovascular health could be related
to magnesium intake [15–17].
Although higher dietary magnesium intake and serum magnesium concentrations are plausibly linked to a reduced risk of CVD
events, the absence of randomized clinical trials on this topic and
inconsistency among the findings of prospective cohort studies
[18–36] preclude definitive recommendations at present. Metaanalysis is an important tool for revealing trends that might not be

Introduction
Cardiovascular disease (CVD) is a major cause of death and
disability worldwide [1,2]. The prevalence of CVD is increasing
rapidly, and the need for prevention is widely acknowledged [1,3–
5]. Increased physical activity, tobacco control, and weight control
are key steps in the prevention of CVD, but insights into the role of
other lifestyle factors, may contribute to additional prevention
strategies [6–11].
Magnesium is the fourth most abundant mineral found in the
body and is considered to be favorably associated with the risk of
CVD [12]. However, low consumption of magnesium is common
throughout the world. In the United States, the prevalence of
inadequate magnesium intake for adults is about 64% among
males and 67% among females; among individuals aged more
than 71 years, the figure rises to 81% and 82% for males and
females, respectively [13].
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Mg and CVD Events

apparent and should always be used to assess the association
between factors and total CVD events risk [2,37–41]. Moreover,
meta-analyses that focus on the risk of total CVD events are useful
for the establishment of clinical policies and guidelines.
Therefore, we conducted a meta-analysis of prospective studies
for the following purposes: (1) to examine the categorical
association between dietary magnesium intake and serum magnesium concentrations and the risk of total CVD events; (2) to
quantify a dose-response pattern of dietary magnesium intake and
serum magnesium concentrations on total CVD risk; and (3) to
examine the shape of the dose–response relationship by conducting linear and nonlinear dose-response analyses.

for in the analysis, and risk estimates with corresponding
confidence intervals for each category of dietary magnesium
intake and serum magnesium concentrations and/or as a
continuous variable. We extracted the relative risks and 95%
confidence intervals that reflected the greatest degree of control
for potential confounders for use in the main analyses. Our
main outcome was the association with total CVD events,
comprising stroke, coronary heart disease (CHD), and CVD
death [37,38,40].

Data Synthesis and Analysis
We used relative risks as the common measure of association
across studies. Hazard ratios and odds ratios were transformed
into relative risks [45–47]. To summarize the association of
magnesium with the risk of total CVD events, the effect measures
were pooled for the highest vs. lowest categories for dietary
magnesium intake or serum magnesium concentrations. We also
evaluated the dose-response relationship between dietary magnesium intake, serum magnesium concentrations, and total CVD
events. For the included studies where categories were used, we
estimated a relative risk as a continuous variable for a 100 mg/d
increase in dietary magnesium intake and a 0.1 mEq/L increase in
serum magnesium concentrations based on the method described
by Greenland and Longnecker, which takes into account levelspecific relative risks [48,49]. For articles that did not provide
median or mean intakes per category, we assigned the midpoint of
the upper and lower boundaries of each category as the average
intake. When the lowest or highest category was open-ended, we
assumed the open-ended interval length to be the same as the
closest category. We used restricted cubic splines (3 knots at fixed
percentiles of 10%, 50%, and 90% of the distribution) to examine
potential nonlinear dose-response associations between dietary
magnesium intake, serum magnesium concentrations, and the risk
of total CVD events [50,51]. A probability value for nonlinearity
was calculated by testing the null hypothesis that the coefficient of
the second spline is equal to 0 [51].
For the meta-analysis, both a fixed-effects model (weighted with
inverse variance) and a random-effects model were considered
[52]. Heterogeneity between studies was assessed using Cochran
Q statistics and I2 statistics [53]. As suggested by Higgins et al, I2
values of 25%, 50%, and 75% were considered low, moderate,
and high, respectively [54]. For P,0.10 values of the Cochran Q
statistic, it was considered statistical heterogeneity, and a randomeffects model was reported. Subgroup and meta-regression
analyses were used to identify associations between the risk of
total CVD events and relevant study characteristics (individual
CVD outcomes, sex of participants, country of origin, distribution
fractions of magnesium intake or serum magnesium concentrations, magnesium difference, period of follow-up, number of
participants, number of CVD events, and incidence of CVD
events) as possible sources of heterogeneity. Subgroup analysis was
used for classified variables, and meta-regression analysis was used
for continuous variables. Funnel plot asymmetry was used to
detect publication bias, and the Egger regression test was used to
measure funnel plot asymmetry [55]. We also performed the ‘‘trim
and fill’’ procedure to further assess the possible effect of
publication bias in our meta-analysis. This method considers the
possibility of hypothetical ‘‘missing’’ studies that might exist,
imputes their relative risks, and recalculates a pooled relative risk
that incorporates the hypothetical missing studies as though they
actually existed [56,57].
All analyses were conducted using Stata 10 (StataCorp, College
Station, Texas).

Methods
We performed a systematic review of the existing literature,
followed by a meta-analysis of prospective cohort studies according
to the MOOSE guidelines [42] and the PRISMA statement
[43,44].

Data Sources and Searches
We performed a systematic literature search of MEDLINE,
EMBASE, and OVID up to February 1, 2012, without limits. All
searches were performed using medical subject headings (MeSH)
or free text words. We combined search terms for the outcomes
(cardiovascular disease, stroke, cerebral infarction, intracerebral
hemorrhage, subarachnoid hemorrhage, cerebrovascular accident,
myocardial infarction, heart attack, ischemic heart disease,
coronary artery disease, mortality, death, fatality, and fatal), effect
measures (magnesium intake, magnesium supplement, dietary
magnesium, total magnesium, blood magnesium, and serum
magnesium), and risk estimates (odds ratio, relative odds, risk
ratio, relative risk, and hazard ratio). In addition, we handsearched the reference lists of primary studies, review articles, and
clinical guidelines. We inspected the full text of any citation that
appeared relevant. Moreover, we also hand-searched abstract of
meetings related to Nutriology and Cardiology which provided
printed or electronic publications. However, none of these meeting
abstracts was quoted in this study.

Study Selection
Two reviewers independently evaluated studies for inclusion.
Discrepancies between their decisions regarding study inclusion
and interpretation of data were resolved by arbitration, and
consensus was reached after discussion. Studies were included in
the meta-analysis if they met the following criteria: (1) prospective
design; (2) adult population (age, .18 years); (3) the exposure of
interest was intake of magnesium or serum magnesium concentrations; (4) the outcome of interest was CVD events, and (5) the
risk estimates, such as relative risks, odds ratios, or hazard ratios
that could be transformed into relative risks with 95% confidence
interval were reported. Studies that did not meet the inclusion
criteria were excluded during the initial review phase.

Data Extraction
All data were independently abstracted by 2 reviewers using a
standardized data collection form. Discrepancies were resolved
through discussion with other investigators and through
reference to the original articles. The following data were
extracted from each study: the first author’s last name,
publication year, country where the study was performed, year
of follow-up, recruitment time, participant sex and age, sample
size, number of cases, reported outcome, method of outcome
assessment, measure and range of exposure, variables adjusted
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Mg and CVD Events

Results

Association between Serum Magnesium Concentration
and Total CVD Events Risk

The detailed steps of our literature search are shown in
supporting information; see Figure S1. We performed a
systematic literature search of MEDLINE, EMBASE, and
OVID. There were 2478 articles identified from database
search. After evaluations of titles and abstracts, we excluded
2443 studies, 480 of which were duplicates, while another 1963
did not satisfy criteria. Then we retrieved the remaining 35
articles for eligibility, and excluded 16 of them because of crosssectional (n = 13) and using odds ratio without CIs (n = 3). After
the screening and deletion, 19 articles was left and used in this
meta-analysis finally. [18–34]. Agreement between observers
regarding inclusion of studies was considered to be good
(Cohen’s unweighted k = 0.93).

Eight prospective cohort studies [19,25,29–34] with information
on 74,422 participants and over 5884 CVD events were included
in this analysis (Table 3). Individuals in the highest category of
serum magnesium concentration had an approximately 20%
lower risk of total CVD events compared to those in the lowest
concentration category (0.77, 0.66 to 0.87; P,0.001) with
moderate heterogeneity between studies (P = 0.049; I2 = 47%)
(Figure 1). Sensitivity analysis showed that the pooled estimate of
the effects of serum magnesium concentrations on risk of total
CVD events did not vary substantially with the exclusion of any
one study.

Sources of Heterogeneity
Subgroup analysis. Within the subgroup analysis, we
examined location as a possible source of heterogeneity. For
dietary magnesium intake, the relative risks were 0.80 (0.72 to
0.88) for studies conducted in the United States, 0.91 (0.83 to 0.99)
for studies in Europe, and 0.87 (0.76 to 0.97) for studies in Asia;
significant interactions were observed between subgroups
(P = 0.050). For serum magnesium concentrations, this analysis
did not show any significant interaction between location variables
(P = 0.075). For individual CVD outcomes, the relative risks were
0.73 for CHD (0.60 to 0.87), 0.87 for stroke (0.81 to 0.93), and
0.89 for CVD death (0.79 to 0.99) with no interaction between
them (P = 0.060). For serum magnesium concentrations, the
relative risks were 0.64 (0.52 to 0.77) for CVD death and 0.82
(0.73 to 0.92) for CVD and CHD, with a significant interaction
between the subgroups (P = 0.021). We also examined sex as a
possible source of heterogeneity for dietary magnesium intake.
The relative risks were 0.87 (0.74 to 1.00) for males and 0.86 (0.76
to 0.95) for females, with a significant interaction between the
subgroups (P = 0.048). For serum magnesium concentrations, this
analysis did not show any significant interaction between sex
variables (P = 0.797). We also examined distribution fractions of
magnesium assessment as possible sources of heterogeneity. The
results showed that there were no significant interactions between
variables (Table 4).
Meta-regression analysis. Meta-regression analysis indicated no influence of difference in magnesium assessment, length of
follow-up, number of participants or CVD events, or the incidence
of CVD on the inverse association between dietary magnesium
intake, serum magnesium concentrations, and the risk of total
CVD events (Table 5).

Description of Study Characteristics
The characteristics of the included prospective cohort studies
are summarized in Tables 1 and 2. There were 19 prospective
cohort studies with 532,979 participants and over 19,926 CVD
events, including 6668 strokes, 5836 cases of CHD outcomes, and
5339 CVD deaths. The cohorts were from 7 different countries (12
studies from the United States [18–23,25,27,29,30,32,33], 2 from
Sweden [26,28], and 1 each from Finland, France, Germany,
Japan, and China [24,31,34–36]). Nine studies recruited both
male and female participants [19,25,29,30,32–36], whereas 6
recruited only males [18,21,22,24,26,31] and 4 recruited only
females [20,23,27,28]. The age of participants was $25 years.
Study lengths ranged from 7 to 30 years. Eleven of 19 cohort
studies only reported the dietary magnesium intake [18,20–24,26–
28,35,36], 6 only reported the serum magnesium concentration
[29–34], and 2 reported both [19,25].
Most studies used food-frequency questionnaires (FFQs) for
dietary assessment. For dietary magnesium intake, the mean
intakes of magnesium for highest categories were 468 mg/d and
for lowest categories were 223 mg/d. For serum magnesium, the
mean concentrations of serum magnesium for highest categories
were 2.07 mEq/L and for lowest categories was 1.36 mEq/L. The
most frequent confounders that were adjusted for aside from age
included body mass index (BMI), physical activity, smoking status,
alcohol consumption, history of diabetes, dyslipidemia, and BP
status or history of hypertension. Adjustments for potential dietary
confounders varied across individual studies. Fiber intake was
adjusted for in 4 studies [18,22,26,28], and potassium intake was
adjusted for in 3 studies [18,22,27].

Association between Dietary Magnesium Intakes and
Total CVD Events Risk

Publication Bias
There was no evidence of publication bias with regard to dietary
magnesium intake or serum magnesium concentrations in relation
to the risk of total CVD events for highest vs. lowest analysis, as
indicated by the Egger test (dietary magnesium intake: P = 0.64;
serum magnesium concentrations: P = 0.41) and the ‘‘trim and fill’’
method (Figure S2).

Thirteen prospective cohort studies [18–28,35,36] with 477,680
participants and over 14,918 CVD events were included in this
analysis (Table 3). The multivariable-adjusted relative risks for
each study and all studies combined for the highest vs. lowest
categories of dietary magnesium intake are shown in Figure 1. In
the meta-analysis, there was a statistically significant inverse
relationship between higher dietary magnesium intake and risk of
total CVD events such that risk of CVD was 15% lower among
individuals with the highest intake of magnesium than among
those with the lowest intake (relative risk 0.85, 95% confidence
interval 0.78 to 0.92; P,0.001). There was moderate heterogeneity across studies (P = 0.060; I2 = 39.2%). Sensitivity analysis
showed that the pooled estimate of the effect of dietary magnesium
intake on risk of total CVD events did not vary substantially with
the exclusion of any one study.
PLOS ONE | www.plosone.org

Dose-response Analysis
Dietary magnesium intake. We assessed the dose-response
relationship between dietary magnesium intake and the risk of
total CVD events. Eleven primary studies [18,20,22–28,35,36]
were included in this dose-response analysis. The summary
relative risk per 100 mg/d was 0.91 (0.86 to 0.96), with moderate
evidence of heterogeneity among studies (P = 0.083, I2 = 38.7%).
There was evidence of a nonlinear association between dietary
magnesium intake and total CVD events risk, Pnonlinearity = 0.024,
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United States, 10

Finnish,13.6

Song (2005)

Larsson (2008)

Japan, 14.7

Larsson (2011)

Zhang (2012)

58,615

34,670

88,375

23,366

14,221

1772

26,556

39,876

39,633

7172

85,764

13,922

43,738

Study Population
(n)
1986

Recruitment Time

1990–1993

1985–1988

1991

1986

1965–1968

1976

1987–1990

1976

1997–1998

Female/Male, 40– 1988–1990
79

Female, 49–83

Female, 30–55

Male, 45–79

Female/Male, 45– 1987–1989
64

Female/Male,
$40

Male, 50–69

Female, 39–89

Male, 40–75

Male, 45–68

Female, 34–59

Female/Male, 45– 1987–1989
64

Male, 40–75

Sex/Age, y

CVD death

Stroke

CVD death

CVD death

Stroke

Stroke

Stroke

CVD

CHD

CHD

Stroke

CHD

Stroke

Outcome(s)

A systematic review of death certificates; and classified
according to ICD-9 (codes 390–459) and ICD-10 (codes
101–199)

Ascertained by Swedish Hospital Discharge Registry and
identified according to ICD-10 (codes I60, I61, I63, I64)

Documented by medical records

Review of Swedish Death and Population Registers
and classified according to ICD-10 (codes I00–I79)

Ascertained by self-report, local hospitals, state vital
statistics offices; and classified according to ICD-9
(codes 430–438)

Ascertained by self-reported; classified according to
ICD-9-CM (codes 430 to 438)

Identified by National Hospital Discharge Register and
the National Register of Causes of Death and classified
according to ICD-8,9,10 (ICD-8 codes 430–434,436; ICD-9
codes 430, 431, 433, 434, 436; ICD-10 codes I60, I61, I63,
and I64)

Confirmed through medical records, autopsy reports,
and death certificates.

Ascertained by self-report and medical records.

Confirmation by the Honolulu Heart Program
Morbidity and Mortality Review Committee.

Ascertained by self-report and medical records;
confirmed according to the criteria of the
National Survey of Stroke.

Ascertained by self-report and medical records, death
certificates; reviewed by members of the ARIC Morbidity
and Mortality Classification Committee

Ascertained by self-report; subclassified according
to the criteria of the National Survey of Stroke.

Outcomes Assessment

CHD = coronary heart disease; CVD = cardiovascular disease; FFQ = food frequency questionnaire; ICD = International Classification of Diseases.
doi:10.1371/journal.pone.0057720.t001

United States, 10

Swedish,10.4

Chiuve (2011)

Swedish, 10

United States, 12

Al-Delaimy (2004)

Kaluza (2010)

United States, 30

Abbott (2003)

United States, 15

United States, 14

Iso (1999)

Ohira (2009)

United States, 7

Liao (1998)

China, 10.6

United States, 8

Ascherio (1998)

Weng (2008)

Location/Followup, y

Source

Table 1. Characteristics of the prospective studies included in the meta-analysis of published studies on magnesium intake and the risk of CVD events.

Validated FFQ

Validated FFQ

FFQ

Validated FFQ

FFQ

FFQ

Validated FFQ

Validated FFQ

Validated FFQ

24-hour dietary recall

Validated FFQ

FFQ

Validated FFQ

Magnesium intake
Assessment

Mg and CVD Events

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3910

14,232

3531

14,221

4035

12,340

13,922

MTB = methylthymol blue; NA = not available.
doi:10.1371/journal.pone.0057720.t002

Germany, 10.1

United States, 12

Peacock (2010)

Reffelmann (2011)

United States, 20

France, 18

Leone (2006)

Khan (2010)

United States, 19

Ford (1999)

United States, 15

United States, 7

Liao (1998)

Ohira (2009)

United States, 10

Gartside (1995)

8251

Location/Follow- Study
up, y
Population(n)

Source

1987–1989

1980–1985

1971–1975

1987–1989

1971–1975

Recruitment
Time

Female/Male, 20–79

Female/Male, 45–64

1997–2001

1987–1989

Female/Male, 44.36101971

Female/Male, 45–64

Male 30–60

Female/Male, $25

Female/Male, 45–64

Female/Male, 25–74

Sex/Age, y

CVD death

CVD death

CVD, CVD
death

Stroke

CVD death

CHD, CVD
death

CHD

CVD

Outcome(s)

Assessed by Sociodemographic and
medical histories; defined with ICD-10
codes I10–I79.

Ascertained by self-report, hospitals,
and death certificates.

Adjudicated by hospital records, medical
office notes, and Framingham clinic
visit notes.

Ascertained by self-report, local
hospitals, state vital statistics offices;
classified according to ICD-9
(codes 430–438).

Determined by the death certificate
classified according to ICD-9 (codes
390–459) and ICD-10 (codes I00–I99).

Determined by the health care facility
records and death certificate; classified
according to ICD-9 (codes 410–414).

Ascertained by self-report and medical
records, death certificates; reviewed by
members of the ARIC Morbidity
and Mortality Classification Committee

Adjudicated by hospital records and
death certificates; classified according
to ICD-9 (codes 390–459).

Outcomes Assessment

Performed on the Siemens Healthcare
Diagnostics using a modification of MTB
complexiometric
procedure.

Performed at visits 1 and 2 and was based on
the procedure of Gindler and Heth using
the metallochromic dye calmagite.

Measured using a standard colorimetric assay.

Based on the procedure of Gindler and Heth
and used the metallochromic dye, calmagite.

Measured by flame atomic absorption
spectrometry.

Measured by atomic absorption
spectrophotometry using the method of
Hansen and Freier.

Measured the procedure of Gindler and Heth,
and used the metallochromic dye calmagite.

NA

Serum magnesium Assessment

Table 2. Characteristics of prospective studies included in meta-analysis of published studies on serum magnesium concentrations and total CVD risk.

Mg and CVD Events

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Mg and CVD Events

Figure 1. Dietary magnesium intake, serum magnesium concentrations, and the risk of total CVD events. (A) Dietary magnesium
intake; (B) Serum magnesium concentrations. Adjusted relative risks for the association between dietary magnesium intake and serum magnesium
concentrations (highest vs. lowest categories) and the risk of total CVD events were sorted by statistical size, defined by the inverse of the variance of
the relative risks. CI = confidence interval; RR = relative risk. *Male participants. {Female participants. {CVD death outcomes. 1CHD outcomes.
doi:10.1371/journal.pone.0057720.g001

with the greatest reduction for intake between 150 and 400 mg/d
but little evidence of further reduction with higher intake
(Figure 2). Sensitivity analysis showed that the pooled estimate of
the effect of dietary magnesium intake on risk of total CVD events
did not vary substantially with the exclusion of any one study.
Serum magnesium concentration. Five cohort studies
[19,25,30,31,33] were included in the dose-response analysis of
serum magnesium concentrations and the risk of total CVD
events. The summary relative risk of total CVD events for every
0.1 mEq/L increment in serum magnesium concentration was
0.91 (0.85 to 0.97), with moderate heterogeneity among studies
(P = 0.011; I2 = 63.7%). We found no evidence of a nonlinear
relationship between serum magnesium concentrations and total
CVD events risk (Pnonlinearity = 0.465). The dose-response relation
between serum magnesium concentrations and the total CVD
events risk is presented in Figure 2. Sensitivity analysis showed that
the pooled estimate of the effect of serum magnesium concentrations on risk of total CVD events did not vary substantially with
the exclusion of any one study.

including improvement in endothelial function; induction of direct
and indirect vasodilation; improved BP; beneficial effects on
arrhythmias, inflammatory reactions, and platelet aggregation;
and improvement of insulin homeostasis and lipid metabolism
[63–65]. Furthermore, experimental and epidemiological studies
considered that hypertension may serve as an effect modifier of the
magnesium and CVD association [16,17]. According to WHO,
62% of all strokes and 49% of CHD events are attributable to high
BP [66]. A previous meta-analysis of 12 randomized clinical trials
that tested the effects of magnesium supplementation on BP
showed that each 10 mmol/day increase in magnesium was
associated with a 4.3 mm Hg reduction in systolic BP and a
2.3 mm Hg reduction in diastolic BP [67]. In the present metaanalysis, most included cohort studies were adjusted for baseline
BP or hypertension status; only 1 study [18] assessed the impact of
hypertension on the association between dietary magnesium intake
and CVD risk. This study found more pronounced associations
among hypertensive individuals than among non-hypertensive
individuals; this finding supports the beneficial effect of magnesium on CVD outcomes.
Larsson et al [68] conducted a systematic review combining 7
original articles and performed a dose-response meta-analysis to
assess the relationship between magnesium intake and stroke risk.
They determined that an increase of 100 mg a day in magnesium
intake is linearly associated with a 9% decrease in the risk for total
stroke (0.88 to 0.97). However, all but 1 [36] of 7 individual studies
detected non-significant linear trends between magnesium intake
and CVD risk. In contrast to previous meta-analyses, which
showed a linear association between magnesium intake and stroke
risk, we found evidence of a nonlinear inverse association between
magnesium intake and total CVD events risk, with the greatest risk
reduction occurring when intake was increased from low levels.
Our investigation of the shape of the dose-response curve clarifies
this association. This is consistent with the finding of a significant
inverse association in our highest vs. lowest meta-analysis.

Discussion
Principal Findings
The findings from this meta-analysis, based on over 532,979
individuals with over 19,900 cases of CVD events, indicate that
dietary magnesium intake and serum magnesium concentrations
are inversely associated with the risk of total CVD events. A
significant association was found between dietary magnesium and
total CVD events risk in the nonlinear model. The greatest risk
reduction was observed when dietary magnesium intake increased
from 150 mg/d to 400 mg/d. An increase of 0.1 mEq/L in serum
magnesium concentrations was associated with a 9% decrease in
the risk for total CVD events. Analyses stratified by individual
CVD outcomes suggest that adequate dietary magnesium intake
reduces the risk of stroke, CHD, and CVD death equally. Because
of limited information on the individual CVD outcomes, these
results should be interpreted carefully and verified by further
studies.
During the past 8 decades, dietary and serum magnesium levels
have received increased attention and have been the subject of
comprehensive studies in cardiovascular health. Magnesium
deficiency is considered an important risk factor for different
types of CVD. The prevalence of magnesium deficiency is much
higher among patients with CVD than among other patients
[58,59]. However, more than half (nearly 65%) of the United
States population consumes less than the daily requirement of
magnesium from foods [13]. Current guidelines from the World
Health Organization (WHO) and several epidemiological studies
have demonstrated that intake of magnesium from drinking water
may decrease the risk of several types of CVDs [60–62].
Nevertheless, compared to magnesium from dietary sources, the
amount of magnesium consumed from drinking water is negligible.
This fact has weakened the interest in the inclusion of drinking
water in preventive strategies for CVD [15]. Dietary magnesium
intake is an important component for the primary prevention of
CVD.
Several plausible mechanisms have been proposed for the
relationship between magnesium and cardiometabolic benefits,
PLOS ONE | www.plosone.org

Study Strengths and Limitations
To the best of our knowledge, this is the first meta-analysis to
estimate the effect of dietary magnesium intake and serum
magnesium concentrations on the risk of total CVD events and
to include categorical, linear, and nonlinear dose-response metaanalyses. The current meta-analysis had some advantages. First,
the number of total participants and CVD events were substantial,
which significantly increased the statistical power of the analysis.
Second, the quantitative assessment was based on prospective
studies, which minimizes the possibility that our findings resulted
from recall or selection bias. Third, data extraction, data analysis,
and quality assessments of the methods were performed by 2
independent investigators; consistency was checked by arbitrators,
contributing to the accuracy of data in the meta-analysis. Finally,
there were no publication biases in these meta-analyses; therefore,
the entire pooled result may be unbiased.
The possible limitations of our meta-analysis must be considered. First, the quality of the included studies varied, with some
having limited adjustments for potential confounding factors. Our
study is also subject to confounding factors that could be innate in
the included cohorts, which is an inherent weakness of all
observational studies and meta-analyses. Although most studies
7

March 2013 | Volume 8 | Issue 3 | e57720

Persons

PLOS ONE | www.plosone.org

8

Female

Female

Male Female 23,083
35,532

Chiuve(2011)

Larsson(2011)

Zhang(2012)

Male
Female

Liao(1998)

6155 7767

Female/Male 8251

Gartside (1995)

Serum Magnesium Concentrations

34,670

88,375

23,366

Male

Kaluza(2010)

26,556

Male/Female 14,221

Male

Larsson(2008)

39,876

Ohira(2009)

Female

Song(2005)

39,633

Female/Male 1772

Male

Al-Delaimy (2004)

85,764

7172

Weng(2008)

Female

Male

Abbott(2003)

Male Female 6155 7767

Liao(1998)

Iso(1999)

Male

43,738

Cohort
(n)

Ascherio(1998)

Dietary Magnesium Intake

Source

CHD

Total CVD events

CVD death

Stroke

CVD death

CVD death

Stroke

Stroke

Stroke

Total CVD events

CHD

CHD

Stroke

CHD

Stroke

Classification
of CVD

0.92 (0.80, 1.07)

0.66 (0.46, 0.95)

1.25 (0.96, 1.61)

0.80 (0.75, 1.13)

223 96

492

0.84 (0.53,1.31)
0.55 (0.27, 1.14)

0.68 (0.54,0.87)

Quartile(IV vs. I)

Thirds(III v I)

Quintile(V vs. I)

Quintile(V vs. I)

Quartile(IV vs. I)

Thirds(III v I)

Quartile(IV vs. I)

Quartile(IV vs. I)

Quintile(V vs. I)

0.87(0.77,0.97) {
0.68 (0.45, 1.04)

Quintile(V vs. I)

Quintile(V vs. I)

Quintile(V vs. I)

Quintile(V vs. I)

Quartile(IV vs. I)

Quintile(V vs. I)

Comparison

1.00 (0.82–1.23)

0.82 (0.65, 1.05)

0.59(0.40,0.91)

0.80 (0.63, 1.01)

0.69 (0.45, 1.0)
1.32 (0.68, 2.5)

0.92 (0.58, 1.46)

RR (95% CI)
of CVD

1343 1347 1.02 (0.85, 1.22)
0.82 (0.69, 0.97)

1680

505

819

557

132

3281

1037

1449

1431

690

223 96

328

No. of
CVD

Table 3. Detailed outcomes of each the published studies included in the meta-analysis.

§1.8 vs. !1.5

§1.74 vs. ,1.62

294 vs. 173 (median)
274 vs. 175 (median)

373 vs. 267 (median)

383 vs. 235 (median)

§481 vs. ,426

.367 vs. ,186

.282.2 vs. ,242.6

575 vs. 382 (median)

433 vs. 255 (median)

453 vs. 261 (median)

340–1138 vs. 50.3–186

381 vs. 211 (median)

Range: 39.9–485.1

452 vs. 243 (median)

The highest vs.
lowest categories*

Age, race, ARIC field center, smoking status, cigarette-years, alcohol drinking,
PA, education, fibrinogen, total cholesterol, HDL-C, triglycerides, WHR, diuretic
use status, hormone replacement, SBP and diabetes status.

Age, sex, quetelet index, PA, exercise, sedimentation rate, dietary iron, smoking,
maximum weight, alcohol, and riboflavin.

BMI, smoking status, ethanol intake, history of hypertension, history of diabetes,
sports time, walking time, educational status and perceived mental stress, and
for women, menopausal status and hormone replacement therapy.

Age, smoking status, pack-years of smoking, educational, BMI, PA, history of
diabetes and hypertension, aspirin use, family history of MI, and intakes of total
energy, alcohol, protein, cholesterol, total fiber, and folate.

Age, BMI, history of CVD, total calories, smoking, parental history of myocardial
infarction, alcohol, PA, use of aspirin, postmenopausal hormones, diuretics,
calcium, potassium, and vitamin D, hypertension, diabetes, and
hypercholesterolemia.

Age, marital, education, self-reported health status, smoking status, PA, WHR,
dietary fiber, saturated fatty acid, phosphorus, alcohol, vitamin D, calcium and
intake.

Age, BMI, sex, race-field center, smoking, LDL-C, HDL-C, fibrinogen, vWf,
education. SBP, antihypertensive medication, and diabetes.

Age, sex, smoking, area, central obesity, BMI, diabetes mellitus, physical activity,
hypertension, use of antihypertensive drug, self-report heart disease,
apolipoprotein B, hypercholesterolemia, hypertriglyceridemia, fibrinogen,
plasminogen and alcohol intake

Age, BMI, supplementation group, smoking, BP, serum total cholesterol, serum
HDL-C, histories of diabetes and CHD,PA, alcohol, and total energy.

Age, BMI, randomized treatment assignment, total energy, smoking, PA, alcohol,
multivitamin use, postmenopausal hormone use, history of diabetes,
hypertension, hypercholesterolemia, and MI.

Age, BMI, time period, energy intake, history of diabetes, history of high
cholesterol, smoking status, aspirin intake, family history of MI, vitamin E,
alcohol, PA, and nutrient variables (trans fatty acid, total protein, cereal fiber,
folate, omega 3 fatty acid, potassium).

Age, BMI, the confounding dietary variable(s), total cholesterol, hypertension,
diabetes, PA, smoking status, and alcohol intake.

Age and smoking status.

Age, race, ARIC field center, smoking status, cigarette-years, alcohol drinking,
PA, education level, fibrinogen, total cholesterol, HDL-C, triglycerides, WHR,
diuretic use status, hormone replacement, SBP and diabetes status

Age, total intake of energy, potassium and fiber, smoking, alcohol consumption,
history of hypertension, hypercholesterolemia, parental history of myocardial
infarction, profession, BMI and PA.

Factors Controlled for in Multivariate Analysis

Mg and CVD Events

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PLOS ONE | www.plosone.org

had adjusted for age, BMI, BP, and physical activity for CVD
events, confounding by known and unknown risk factors cannot be
excluded as a potential explanation for the observed findings
[6,69]. Moreover, it is difficult to completely rule out that the
possibility that other nutrients or specific effects of magnesium and
other potentially beneficial food components co-existing in the
same foods were responsible for the observed association.
Second, some degree of misclassification of exposure may have
weakened the strength of the association. Because of the selfadministered FFQ of dietary magnesium intake, errors are
inevitable. In addition, only 1 report updated the information
about dietary magnesium assessment during follow-up [22]. Such
errors may have been present in other studies that assessed dietary
magnesium at baseline only, which could lead to an underestimation of the relative risk estimates.
Third, due to the lack of data, it is difficult to explain the
correlation of dietary magnesium intake with serum magnesium
concentrations. In the current systematic review, only 1 study
provided information about the inter-relationship between dietary
magnesium intake, serum magnesium concentrations, and CVD
risk [25]. That study found that individuals in the group with both
dietary and serum magnesium greater than the median (serum
magnesium = 1.6 mEq/L; dietary magnesium = 241 mg/d) had
an approximately 35% lower risk of ischemic stroke than did those
in the group with less than median values of both dietary and
serum magnesium (relative risk 0.64, 95% confidence interval 0.48
to 0.85), but not in the groups with either dietary or serum
magnesium below the median.
Finally, heterogeneity may have been introduced because of
methodological differences between studies. After the subgroup
and meta-regression analysis, we founded location, sex, and
individual CVD outcomes as possible sources of heterogeneity.
Although these issues may have reduced the strength of the
conclusions drawn in these meta-analyses, visual inspection of
forest plots in our meta-analysis suggests that there is considerable
consistency in the relative risks across the studies.

BMI = body mass index; HDL-C = high density lipoprotein cholesterol; LDL-C = low density lipoprotein cholesterol; MI = myocardial infarction; PA = physical activity; SBP = systolic blood pressure; WHR = waist/hip ratio.
*Mg/d for dietary magnesium intake and mEq/L for serum magnesium concentrations.
{
Recalculate from primal studies.
doi:10.1371/journal.pone.0057720.t003

Age, sex, diabetes, smoking status, BMI, glomerular filtration rate, arterial
hypertension, use of calcium antagonists, beta blocker, diuretics, statins, and
ACE and angiotensin-receptor inhibitors.
Reffelmann (2011) Male/
Female

3910

CVD death

NA

NA
Intergroup
difference
0.60(0.41,0.88) {

Age, race, sex, field center, HDL, LDL, TG, serum K, heart rate- adjusted QT
interval, PA, smoking, pack-years, ETOH intake, education, diabetes,
hypertension, and diuretics use.
Male/
Female
Peacock(2010)

14,232

CVD death

264

§1.75 vs. !1.5
Quartile(IV vs. I)
0.62 (0.42–0.93)

Age, sex, BMI, diabetes, SBP, smoking status, hypertension treatment,
glomerular filtration rate hemoglobin, serum albumin, and total/HDL ratio.
Male/
Female
Khan (2010)

3531

Total CVD events

554

NA
Quartile(IV vs. I)
0.91 (0.72, 1.17)

Age, BMI, sex, race-field center, smoking, LDL-C, HDL-C, fibrinogen, vWf,
education. SBP, antihypertensive medication, and diabetes.
Male/
Female
Ohira(2009)

14,221

Stroke

557

§1.8 vs. !1.5
Quartile(IV vs. I)
1.04 (0.82, 1.32)

Age, BMI, smoking status, alcohol consumption, PA, LDL, HDL, cholesterol,
triglycerides, diabetes, and CVD history.
Range: 0.477–3.538{
Thirds(III v I)
Male
Leone(2006)

4035

CVD death

56

0.6 (0.2–1.2)

Age, sex, race, education, smoking status, cholesterol, SBP, diabetes,
antihypertensive medication, BMI, PA, and alcohol consumption.
§1.77 vs. ,1.59
Quartile(IV vs. I)
0.92 (0.79, 1.07)
0.69 (0.52, 0.90)
Female/
Male
Ford(1999)

12,340

CHD CVD death

2637
1005

{

Comparison
Persons
Source

Table 3. Cont.

Cohort
(n)

Classification
of CVD

No. of
CVD

RR (95% CI)
of CVD

The highest vs.
lowest categories*

Factors Controlled for in Multivariate Analysis

Mg and CVD Events

Implications and Directions for Future Research
In the United States, the Recommended Dietary Allowance of
magnesium set by the National Institute of Health for men and
women aged 31–70 years is 420 and 320 mg/d, respectively. The
approximate magnesium content of some foods is as follows:
156 mg in 1 cup cooked spinach, 142 mg in 1 cup cooked
soybeans, 122 mg in 2 rectangular biscuits of shredded wheat
cereal, and 100 mg in 1 oz roasted peanuts [68,70]. According to
a recent report by WHO, 17.3 million deaths occurred due to
CVD in 2008, and this figure will rise to 23.6 million by 2030 [71].
Given that the mortality for total CVD events is 1 in 5, a 15%
reduction in the rate of CVD by increasing dietary magnesium
intake throughout the population could avert 1–2.5 million deaths
from CVD each year [72].
On the basis of this meta-analysis, we believe that future
research in the following areas would offer important insights.
First, there is a compelling need for the investigation of the interrelationship between dietary magnesium intake, serum magnesium
concentrations, and CVD. To gain information from a mechanistic perspective, an objective assessment of total body magnesium stores and intracellular magnesium concentrations is required
[15]. The role of dietary magnesium intake and serum magnesium
concentrations should be explained by such an objective
assessment. Moreover, several well-designed cohort studies, where
both magnesium intake and serum magnesium levels are obtained,
with adequate control for confounding factors should be considered. Second, multicenter, double-blinded, placebo-controlled
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Mg and CVD Events

Table 4. Subgroup analysis to investigate differences between studies included in meta-analysis.

Subgroup

Cohorts (n) RR (95% CI)

Q

I2(%)

P value

0.575

P value for heterogeneity
between subgroups

Dietary Magnesium Intake
Individual CVD outcomes
Stroke

7

0.87 (0.81, 0.93)

4.76

0

CHD

3

0.73 (0.60, 0.87)

3.63

17

0.305

CVD death

3

0.89 (0.79, 0.99)

10.95

73

0.012

Male

7

0.87 (0.74, 1.00)

14.34

58

0.026

Female

6

0.86 (0.76, 0.95)

6.79

26

0.237

United States

8

0.80 (0.72, 0.88)

9.70

18

0.287

Europe

3

0.91 (0.83, 0.99)

4.84

59

0.089

2

0.87 (0.76, 0.97)

4.60

57

0.100

Quintile

8

0.87 (0.82, 0.93)

10.53

24

0.230

Quartile

4

0.74 (0.80, 0.90)

2.63

0

0.621

0.060

Sex
0.048

Location

Asian

0.050

Distribution fractions
0.187

Serum Magnesium concentrations
Individual CVD outcomes
CVD & CHD

4

0.82 (0.73, 0.92)

6.82

41

0.145

CVD death

4

0.64 (0.52, 0.77)

0.42

0

0.935

Male & Female

6

0.79 (0.72, 0.88)

15.24

61

0.018

Only male

2

0.75 (0.44, 1.06)

0.55

0

0.458

United States

6

0.80 (0.73, 0.88)

13.81

49

0.055

Europe

2

0.78 (0.71, 0.81)

0.00

0

1.000

Quartile

5

0.84 (0.75, 0.92)

0.09

46

0.087

Thirds

2

0.67 (0.52, 0.83)

11.04

0

0.766

0.021

Sex
0.797

Location
0.075

Distribution fractions
0.069

doi:10.1371/journal.pone.0057720.t004

randomized trials should be performed for gaining a better
understanding of any causal relationships between magnesium and
CVD, especially for sex-specific associations or for individuals at
high risk of CVD. Third, it is also important to gain a better
understanding of the mechanisms underlying cardiometabolic
changes in response to magnesium intake. Investigation of
biological and genetic markers may offer additional insights into
the role of magnesium in the etiology of CVD.

Conclusions
In summary, findings from this meta-analysis indicate that
dietary magnesium intake and serum magnesium concentrations
are inversely associated with the risk of total CVD events. Serum
magnesium concentrations ranging from 1.44 mEq/L to
1.8 mEq/L are associated with linear decreases in the risk of
total CVD events. There is a nonlinear inverse association
between intake of dietary magnesium and total CVD events risk,

Table 5. Meta-regression analysis.

Dietary Magnesium Intake
Coefficient

SE

Serum Magnesium Concentrations
P Value

95% CI

Coefficient

SE

P Value

95% CI

Magnesium difference

0.001

0.000

0.797

20.001 to 0.002 21.821

0.993

0.318

214.441 to 10.800

Length of follow-up

20.008

0.013

0.585

20.037 to 0.022 20.164

0.111

0.377

21.571 to 1.242

No. of participants

20.002

0.002

0.411

20.005 to 0.003 20.445

0.243

0.319

23.538 to 2.648

No. of CVD events

0.106

0.104

0.335

20.130 to 0.342 0.396

0.219

0.322

22.385 to 3.176

Incidence of CVD

20.021

0.025

0.431

20.078 to 0.036 20.470

0.272

0.334

23.923 to 2.983

doi:10.1371/journal.pone.0057720.t005

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Mg and CVD Events

Figure 2. Dose-response relationship between dietary magnesium intake and serum magnesium concentrations and the risk of
total CVD events. Relative risk (solid line) with 95% confidence interval (long dashed lines) for the association of dietary magnesium intake and
serum magnesium concentrations with risk of total CVD events in a restricted cubic spline random-effects meta-analysis. The short dashed line
represents the simpler linear model. The lowest values of 152 mg/d of dietary magnesium and 1.44 mEq/L of serum magnesium were used to reestimate all relative risks.
doi:10.1371/journal.pone.0057720.g002

PLOS ONE | www.plosone.org

11

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Mg and CVD Events

with the greatest reduction in risk occurring when the intake is
increased from 150–400 mg/d. If further interventional randomized controlled trials demonstrate these beneficial effects, new
pathways would be opened up for the primary prevention of CVD.

serum magnesium concentrations and the risk of total
CVD events.
(DOC)

Author Contributions
Supporting Information

Conceived and designed the experiments: XQ KD. Performed the
experiments: XQ FJ KD. Analyzed the data: XQ FJ HL HW. Wrote
the paper: XQ YH TT WY KD.

Figure S1 Flowchart of the study selection process.

(DOC)
Trim and fill funnel plot for meta-analysis of
the association between dietary magnesium intake and

Figure S2

References
23. Song Y, Manson JE, Cook NR, Albert CM, Buring JE, et al. (2005) Dietary
magnesium intake and risk of cardiovascular disease among women.
Am J Cardiol 96: 1135–1141.
24. Larsson SC, Virtanen MJ, Mars M, Mannisto S, Pietinen P, et al. (2008)
Magnesium, calcium, potassium, and sodium intakes and risk of stroke in male
smokers. Arch intern med 168: 459–465.
25. Ohira T, Peacock JM, Iso H, Chambless LE, Rosamond WD, et al. (2009)
Serum and dietary magnesium and risk of ischemic stroke: the Atherosclerosis
Risk in Communities Study. Am J Epidemiol 169: 1437–1444.
26. Kaluza J, Orsini N, Levitan EB, Brzozowska A, Roszkowski W, et al. (2010)
Dietary calcium and magnesium intake and mortality: a prospective study of
men. Am J Epidemiol 171: 801–807.
27. Chiuve SE, Korngold EC, Januzzi JL, Jr., Gantzer ML, Albert CM (2011)
Plasma and dietary magnesium and risk of sudden cardiac death in women.
Am J Clin Nutr 93: 253–260.
28. Larsson SC, Virtamo J, Wolk A (2011) Potassium, calcium, and magnesium
intakes and risk of stroke in women. Am J Epidemiol 174: 35–43.
29. Gartside PS, Glueck CJ (1995) The important role of modifiable dietary and
behavioral characteristics in the causation and prevention of coronary heart
disease hospitalization and mortality: the prospective NHANES I follow-up
study. J Am Coll Nutr 14: 71–79.
30. Ford ES (1999) Serum magnesium and ischaemic heart disease: findings from a
national sample of US adults. Int J Epidemiol 28: 645–651.
31. Leone N, Courbon D, Ducimetiere P, Zureik M (2006) Zinc, copper, and
magnesium and risks for all-cause, cancer, and cardiovascular mortality.
Epidemiology 17: 308–314.
32. Khan AM, Sullivan L, McCabe E, Levy D, Vasan RS, et al. (2010) Lack of
association between serum magnesium and the risks of hypertension and
cardiovascular disease. Am Heart J 160: 715–720.
33. Peacock JM, Ohira T, Post W, Sotoodehnia N, Rosamond W, et al. (2010)
Serum magnesium and risk of sudden cardiac death in the Atherosclerosis Risk
in Communities (ARIC) Study. Am Heart J 160: 464–470.
34. Reffelmann T, Ittermann T, Dorr M, Volzke H, Reinthaler M, et al. (2011) Low
serum magnesium concentrations predict cardiovascular and all-cause mortality.
Atherosclerosis 219: 280–284.
35. Weng LC, Yeh WT, Bai CH, Chen HJ, Chuang SY, et al. (2008) Is ischemic
stroke risk related to folate status or other nutrients correlated with folate intake?
Stroke 39: 3152–3158.
36. Zhang W, Iso H, Ohira T, Date C, Tamakoshi A (2012) Associations of dietary
magnesium intake with mortality from cardiovascular disease: The JACC study.
Atherosclerosis 221: 587–595.
37. Levitan EB, Song Y, Ford ES, Liu S (2004) Is nondiabetic hyperglycemia a risk
factor for cardiovascular disease? A meta-analysis of prospective studies. Arch
intern med 164: 2147–2155.
38. Holmes MV, Perel P, Shah T, Hingorani AD, Casas JP (2011) CYP2C19
genotype, clopidogrel metabolism, platelet function, and cardiovascular events: a
systematic review and meta-analysis. JAMA 306: 2704–2714.
39. Thompson AM, Hu T, Eshelbrenner CL, Reynolds K, He J, et al. (2011)
Antihypertensive treatment and secondary prevention of cardiovascular disease
events among persons without hypertension: a meta-analysis. JAMA 305: 913–
922.
40. Wang L, Manson JE, Song Y, Sesso HD (2010) Systematic review: Vitamin D
and calcium supplementation in prevention of cardiovascular events. Ann Intern
Med 152: 315–323.
41. Pittas AG, Chung M, Trikalinos T, Mitri J, Brendel M, et al. (2010) Systematic
review: Vitamin D and cardiometabolic outcomes. Ann Intern Med 152: 307–
314.
42. Stroup DF, Berlin JA, Morton SC, Olkin I, Williamson GD, et al. (2000) Metaanalysis of observational studies in epidemiology: a proposal for reporting. Metaanalysis Of Observational Studies in Epidemiology (MOOSE) group. JAMA
283: 2008–2012.
43. Liberati A, Altman DG, Tetzlaff J, Mulrow C, Gotzsche PC, et al. (2009) The
PRISMA statement for reporting systematic reviews and meta-analyses of studies
that evaluate healthcare interventions: explanation and elaboration. BMJ 339:
b2700.

1. Chavkin W, Elman D (1997) Mortality from cardiovascular causes among blacks
and whites in New York City. N Engl J Med 336: 1321; author reply 1321–1322.
2. Qu X, Huang X, Jin F, Wang H, Hao Y, et al. (2011) Bone mineral density and
all-cause, cardiovascular and stroke mortality: A meta-analysis of prospective
cohort studies. Int J Cardiol.
3. Mosca L, Benjamin EJ, Berra K, Bezanson JL, Dolor RJ, et al. (2011)
Effectiveness-based guidelines for the prevention of cardiovascular disease in
women–2011 update: a guideline from the American Heart Association. J Am
Coll Cardiol 57: 1404–1423.
4. Wu S, Feng B, Li K, Zhu X, Liang S, et al. (2012) Fish Consumption and
Colorectal Cancer Risk in Humans: A Systematic Review and Meta-analysis.
Am J Med 125: 551–559 e555.
5. Cheng TO (2012) Cardiovascular health, risks and diseases in contemporary
China. Int J Cardiol 154: 233–242.
6. Ferket BS, Colkesen EB, Visser JJ, Spronk S, Kraaijenhagen RA, et al. (2010)
Systematic review of guidelines on cardiovascular risk assessment: Which
recommendations should clinicians follow for a cardiovascular health check?
Arch Intern Med 170: 27–40.
7. De Backer G, Ambrosioni E, Borch-Johnsen K, Brotons C, Cifkova R, et al.
(2003) European guidelines on cardiovascular disease prevention in clinical
practice. Third Joint Task Force of European and Other Societies on
Cardiovascular Disease Prevention in Clinical Practice. Eur Heart J 24: 1601–
1610.
8. LaBresh KA, Ellrodt AG, Gliklich R, Liljestrand J, Peto R (2004) Get with the
guidelines for cardiovascular secondary prevention: pilot results. Arch Intern
Med 164: 203–209.
9. (2003) Routine vitamin supplementation to prevent cancer and cardiovascular
disease: recommendations and rationale. Ann Intern Med 139: 51–55.
10. Tanne JH (2012) US citizens score poorly on ratings of cardiovascular risk
factors. BMJ 344: e22.
11. Chen Y, McClintock TR, Segers S, Parvez F, Islam T, et al. (2012) Prospective
investigation of major dietary patterns and risk of cardiovascular mortality in
Bangladesh. Int J Cardiol.
12. Weisinger JR, Bellorin-Font E (1998) Magnesium and phosphorus. Lancet 352:
391–396.
13. Moshfegh A, Goldman J, Cleveland L (2005) What we eat in America,
NHANES 2001–2002: Usual nutrient intakes from food compared to Dietary
Reference Intakes: US Department of Agriculture, Agricultural Research
Service. pp. 1–56.
14. Lipsky MS, Mendelson M, Havas S, Miller M (2008) American Medical
Association guide to preventing and treating heart disease: essential information
you and your family need to know about having a healthy heart: Wiley.
15. Song Y, Liu S (2012) Magnesium for cardiovascular health: time for
intervention. Am J Clin Nutr 95: 269–270.
16. Rosanoff A, Weaver CM, Rude RK (2012) Suboptimal magnesium status in the
United States: are the health consequences underestimated? Nutr Rev 70: 153–
164.
17. Houston M (2011) The role of magnesium in hypertension and cardiovascular
disease. J Clin Hypertens (Greenwich) 13: 843–847.
18. Ascherio A, Rimm EB, Hernan MA, Giovannucci EL, Kawachi I, et al. (1998)
Intake of potassium, magnesium, calcium, and fiber and risk of stroke among US
men. Circulation 98: 1198–1204.
19. Liao F, Folsom AR, Brancati FL (1998) Is low magnesium concentration a risk
factor for coronary heart disease? The Atherosclerosis Risk in Communities
(ARIC) Study. Am Heart J 136: 480–490.
20. Iso H, Stampfer MJ, Manson JE, Rexrode K, Hennekens CH, et al. (1999)
Prospective study of calcium, potassium, and magnesium intake and risk of
stroke in women. Stroke 30: 1772–1779.
21. Abbott RD, Ando F, Masaki KH, Tung KH, Rodriguez BL, et al. (2003)
Dietary magnesium intake and the future risk of coronary heart disease (the
Honolulu Heart Program). Am J Cardiol 92: 665–669.
22. Al-Delaimy WK, Rimm EB, Willett WC, Stampfer MJ, Hu FB (2004)
Magnesium intake and risk of coronary heart disease among men. J Am Coll
Nutr 23: 63–70.

PLOS ONE | www.plosone.org

12

March 2013 | Volume 8 | Issue 3 | e57720

Mg and CVD Events

44. Moher D, Liberati A, Tetzlaff J, Altman DG (2009) Preferred reporting items for
systematic reviews and meta-analyses: the PRISMA statement. BMJ 339: b2535.
45. Zhang J, Yu KF (1998) What’s the relative risk? A method of correcting the odds
ratio in cohort studies of common outcomes. JAMA 280: 1690–1691.
46. McNutt LA, Wu C, Xue X, Hafner JP (2003) Estimating the relative risk in
cohort studies and clinical trials of common outcomes. Am J Epidemiol 157:
940–943.
47. Ronksley PE, Brien SE, Turner BJ, Mukamal KJ, Ghali WA (2011) Association
of alcohol consumption with selected cardiovascular disease outcomes: a
systematic review and meta-analysis. BMJ 342: d671.
48. Orsini N, Bellocco R, Greenland S (2006) Generalized least squares for trend
estimation of summarized dose–response data. Stata J 6: 40–57.
49. Greenland S, Longnecker MP (1992) Methods for trend estimation from
summarized dose-response data, with applications to meta-analysis.
Am J Epidemiol 135: 1301–1309.
50. Larsson SC, Orsini N, Wolk A (2010) Vitamin B6 and risk of colorectal cancer: a
meta-analysis of prospective studies. JAMA 303: 1077–1083.
51. Larsson SC, Orsini N, Wolk A (2011) Dietary potassium intake and risk of
stroke: a dose-response meta-analysis of prospective studies. Stroke 42: 2746–
2750.
52. DerSimonian R, Laird N (1986) Meta-analysis in clinical trials. Control Clin
Trials 7: 177–188.
53. Higgins JP, Thompson SG, Deeks JJ, Altman DG (2003) Measuring
inconsistency in meta-analyses. BMJ 327: 557–560.
54. Higgins JP, Thompson SG (2002) Quantifying heterogeneity in a meta-analysis.
Stat Med 21: 1539–1558.
55. Egger M, Davey Smith G, Schneider M, Minder C (1997) Bias in meta-analysis
detected by a simple, graphical test. BMJ 315: 629–634.
56. Sutton AJ, Duval SJ, Tweedie RL, Abrams KR, Jones DR (2000) Empirical
assessment of effect of publication bias on meta-analyses. BMJ 320: 1574–1577.
57. Peters JL, Sutton AJ, Jones DR, Abrams KR, Rushton L (2007) Performance of
the trim and fill method in the presence of publication bias and between-study
heterogeneity. Stat Med 26: 4544–4562.
58. Burch GE, Giles TD (1977) The importance of magnesium deficiency in
cardiovascular disease. Am Heart J 94: 649–657.

PLOS ONE | www.plosone.org

59. Fox CH, Mahoney MC, Ramsoomair D, Carter CA (2003) Magnesium
deficiency in African-Americans: does it contribute to increased cardiovascular
risk factors? J Natl Med Assoc 95: 257–262.
60. Yang CY, Chiu HF (1999) Calcium and magnesium in drinking water and the
risk of death from hypertension. Am J Hypertens 12: 894–899.
61. Yang CY (1998) Calcium and magnesium in drinking water and risk of death
from cerebrovascular disease. Stroke 29: 411–414.
62. Cotruvo JA, Bartram J, WHO (2009) Calcium and magnesium in drinkingwater: public health significance: World Health Organization.
63. Chakraborti S, Chakraborti T, Mandal M, Mandal A, Das S, et al. (2002)
Protective role of magnesium in cardiovascular diseases: a review. Mol Cell
Biochem 238: 163–179.
64. Adamopoulos C, Pitt B, Sui X, Love TE, Zannad F, et al. (2009) Low serum
magnesium and cardiovascular mortality in chronic heart failure: a propensitymatched study. Int J Cardiol 136: 270–277.
65. Sanjuliani AF, de Abreu Fagundes VG, Francischetti EA (1996) Effects of
magnesium on blood pressure and intracellular ion levels of Brazilian
hypertensive patients. Int J Cardiol 56: 177–183.
66. Organization WH (2002) The world health report 2002: reducing risks,
promoting healthy life: World Health Organization.
67. Jee SH, Miller ER, 3rd, Guallar E, Singh VK, Appel LJ, et al. (2002) The effect
of magnesium supplementation on blood pressure: a meta-analysis of
randomized clinical trials. Am J Hypertens 15: 691–696.
68. Larsson SC, Orsini N, Wolk A (2012) Dietary magnesium intake and risk of
stroke: a meta-analysis of prospective studies. Am J Clin Nutr 95: 362–366.
69. Mitka M (2006) Guidelines update: aggressively target cardiovascular risk
factors. JAMA 296: 30–31.
70. NIH, Office of dietary supplements. Dietary supplement fact sheet: Magnesium.
Available: http://odsodnihgov/factsheets/magnesium/, Accessed: 2009, Sep 1.
71. WHO (2011) Global Atlas on cardiovascular disease prevention and control;
Shanthi Mendis PP, Bo Norrving, editor: World Health Organization.
72. Strazzullo P, D’Elia L, Kandala NB, Cappuccio FP (2009) Salt intake, stroke,
and cardiovascular disease: meta-analysis of prospective studies. BMJ 339:
b4567.

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</reference>

<statements>
1. A meta-analysis of prospective studies reported that higher dietary magnesium intake and higher serum magnesium concentrations are inversely associated with total CVD events. The greatest reduction in risk was observed when intake increased from about 150 mg/day to 400 mg/day, and a 0.1 mEq/L increase in serum magnesium was associated with roughly a 9% lower risk of total CVD events.
2. A meta-analysis of randomized trials reported that magnesium supplementation at a median dose of around 368–400 mg/day for about three months reduced systolic blood pressure by roughly 2–5 mm Hg and diastolic blood pressure by about 1.5–2 mm Hg, as well as improving triglycerides and HDL cholesterol. These changes are modest but potentially meaningful at the population level.
3. Magnesium stands out as the metal ion with the most consistent observational, genetic, and mechanistic support for a protective role in cardiovascular disease, and supplementation appears to improve some cardiovascular risk factors and surrogate markers in certain populations. However, large randomized trials with hard endpoints (MI, stroke, CVD mortality) are still needed before magnesium supplementation can be widely recommended as a primary preventive therapy.
</statements>

Begin the assessment now. Output only the JSON list, without any conversational text or explanations.