Serum magnesium and risk of incident heart failure in older men: The British Regional Heart Study
European Journal of Epidemiology
Serum magnesium and risk of incident heart failure in older men: The British Regional Heart Study
Sasiwarang Goya Wannamethee 0 1 2
Olia Papacosta 0 1 2
Lucy Lennon 0 1 2
Peter H. Whincup 0 1 2
0 Population Health Research Institute, St George's University of London , Cranmer Terrace, London SW17 ORE , UK
1 Department of Primary Care and Population Health, University College London, Royal Free Campus , London NW3 2PF , UK
2 & Sasiwarang Goya Wannamethee
To examine the association between serum magnesium and incident heart failure (HF) in older men and investigate potential pathways including cardiac function, inflammation and lung function. Prospective study of 3523 men aged 60-79 years with no prevalent HF or myocardial infarction followed up for a mean period of 15 years, during which 268 incident HF cases were ascertained. Serum magnesium was inversely associated with many CVD risk factors including prevalent atrial fibrillation, lung function (FEV1) and markers of inflammation (IL-6), endothelial dysfunction (vWF) and cardiac dysfunction [NT-proBNP and cardiac troponin T (cTnT)]. Serum magnesium was inversely related to risk of incident HF after adjustment for conventional CVD risk factors and incident MI. The adjusted hazard ratios (HRs) for HF in the 5 quintiles of magnesium groups were 1.00, 0.72 (0.50, 1.05), 0.85 (0.59, 1.26), 0.76 (0.52, 1.11) and 0.56 (0.36, 0.86) respectively [p (trend) = 0.04]. Further adjustment for atrial fibrillation, IL-6, vWF and FEV1 attenuated the association but risk remained significantly reduced in the top quintile (C 0.87 mmol/l) compared with the lowest quintile [HR 0.62 (0.40, 0.97)]. Adjustment for NT-proBNP and cTnT attenuated the association further [HR 0.70 (0.44, 1.10)]. The benefit of high serum magnesium on HF risk was most evident in men with ECG evidence of ischaemia [HR 0.29 (0.13, 0.68)]. The potential beneficial effect of high serum magnesium was partially explained by its favourable association with CVD risk factors. Further studies are needed to investigate whether serum magnesium supplementation in older adults may protect from the development of HF.
Serum magnesium; Heart failure; Coronary heart disease
Heart failure (HF) is a major epidemic and significant
public health burden in older people. After calcium,
magnesium is the second most common intracellular cation and
is an important electrolyte that plays a major role in
metabolic processes and normal myocardial functioning,
including the regulation of myocyte and endothelial cell
]. The adverse effect of severe magnesium
depletion on ventricular arrhythmias and sudden death
health has long been recognised . Magnesium depletion
is commonly seen in HF patients [
] and is highly prevalent
in the elderly due to reduced intestinal magnesium
absorption and increased urinary magnesium losses [
the early stages of magnesium depletion urinary
magnesium concentrations are low [
]; with more marked
depletion circulating magnesium concentrations (which are
correlated with intracellular magnesium concentrations [
are affected. In recent years there has been growing
evidence that lower circulating magnesium concentrations
within the normal range are associated with increased risk
of developing HF [
]. Experimental and clinical studies
have linked hypomagnesemia to the pathogenesis of
arrhythmias which is a major risk factor for HF [
] and a
few population studies have shown low serum magnesium
to be associated with the development of AF [
Although prospective studies and meta-analyses of
prospective studies have suggested an inverse association
between serum magnesium and risk of CVD [
is limited evidence on the association between serum
magnesium and incident HF in the general population.
However, two studies in middle-aged populations have
shown low serum magnesium to be associated with
increased risk of HF independent of conventional risk
factors for HF and incident MI [
]. The mechanisms
underlying the beneficial effects of higher circulating
magnesium concentrations on HF are not fully understood
but are likely to be multifactorial. It has been suggested but
not tested that this beneficial effect on HF is due to the
beneficial effects of magnesium on the cardiovascular
system, including enhancing endothelial dependent
vasodilation, reducing inflammation, improving lipid and
glucose metabolism and reducing cardiac arrhythmias, all
factors implicated in the pathogenesis of HF [
Whether circulating magnesium is a relevant biological
marker for examining the role of magnesium in HF in older
adults who are at particularly high risk of HF has not been
well studied. We have therefore examined the relationship
between serum magnesium and risk of incident HF in a
large prospective study of older British men and explored
possible mechanisms. We have examined the role of
several potential pathways related to HF not previously
examined including cardiac function, inflammation,
endothelial dysfunction and lung function.
Subjects and methods
The British Regional Heart Study is a prospective study
involving 7735 men aged 40–59 years drawn from one
general practice in each of 24 British towns, who were
screened between 1978 and 1980 [
]. The population
studied was socio-economically representative and
comprised predominantly white Europeans ([ 99%). In
1998–2000, all surviving men, then aged 60–79 years,
were invited for a 20th year follow-up examination, on
which the current analyses are based. Ethical approval was
obtained from all relevant local research ethics committees.
All men completed a mailed questionnaire providing
information on their lifestyle and medical history, had a
physical examination and provided a fasting blood sample.
The samples were frozen and stored at - 20 C on the day
of collection and transferred in batches for storage at
- 70 C until analysis, carried out after no more than one
freeze–thaw cycle. 12 lead electrocardiograms (ECG) were
recorded using a Siemens Sicard 460 instrument and were
analyzed at the University of Glasgow ECG core
laboratory using Minnesota Coding definitions. Men were asked
whether a doctor had ever told them that they had angina or
MI, HF or stroke; details of their medications were
recorded at the examination including use of BP lowering drugs
(BNF code 3.1). 4252 men (77% of available survivors)
attended for examination. Of these 4088 men provided
fasting blood samples and 4031 men had blood
measurement of serum magnesium.
Cardiovascular risk factor measurements at 1998–2000
Anthropometric measurements including body weight and
height were carried out. Details of measurement and
classification methods for smoking status, physical activity,
social class, alcohol intake, blood pressure, lung function,
and blood lipids in this cohort have been described
]. Serum magnesium was measured with an
enzymatic colorimetric assay using a Hitachi 747 automated
analyser. C-reactive protein (CRP) was assayed by ultra
sensitive nephelometry (Dade Behring, Milton Keynes,
UK); interleukin 6 (IL-6) was measured with ELISA (R&D
Systems, Oxford, UK). von Willebrand factor (VWF)
antigen was measured with enzyme-linked immunosorbent
assays (DAKO, High Wycombe, UK). Predicted
glomerular filtration rate (eGFR) (measure of renal
function) was estimated from serum creatinine using the
equation eGFR = 186 9 (Creatinine/
88.4)-1.154 9 (Age)-0.203 . Chronic kidney disease
(CKD) was defined as eGFR \ 60 ml/min per 1.73 m
Nterminal pro-brain natriuretic peptide (NT-proBNP) was
determined using the Elecsys 2010 (Roche Diagnostics,
Burgess Hill, UK) [
]. Cardiac Troponin T (cTnT) was
measured by a high sensitivity method on an e411 (Roche
Diagnostics, Burgess Hill, UK) using the manufacturers
calibrators and quality control material. The low control
coefficient of variation (CV) was 6.6%, and high control
CV 3.0%, and the assay limit of detection was 3 pg/ml.
Evidence of myocardial ischaemia on ECG was based on
Minnesota codings 1.1–1.3 (definite, probable or possible
myocardial infarction) or 4.1–4.4 and 5.1–5.3 (definite,
probable or possible myocardial ischaemia).
Electrocardiographic left ventricular hypertrophy (LVH) was defined
according to relevant Minnesota codes (codes 3.1 or 3.3).
Atrial fibrillation (AF) was defined according to Minnesota
codes 8.3.1 and 8.3.3.
All men have been followed up from initial examination
(1978–1980) for cardiovascular morbidity [
followup has been achieved for 99% of the cohort. In the present
analyses, all-cause mortality and morbidity events are
based on follow-up from re-screening in 1998–2000 at
mean age 60–79 years to June 2014, a mean follow-up
period of 15 years (range 14–16 years). Survival times
were censored at date of HF, death from any cause or end
of the study follow-up period (June 2014), whichever
occurred first. Evidence of non-fatal MI and HF was
obtained by ad hoc reports from general practitioners
supplemented by biennial reviews of the patients’ practice
records (including hospital and clinic correspondence)
through to the end of the study period. Incident non-fatal
HF was based on a confirmed doctor diagnosis of HF from
primary care records and confirmed by a review of
available clinical information from primary and secondary care
records (including symptoms, signs, investigations,
treatment response) to ensure that the diagnosis was consistent
with current recommendations on HF diagnosis [
incidence and determinants of HF cases identified using
this process have already been reported and are consistent
with results from other studies [
16, 17, 19
]. Incident HF
included both incident non-fatal HF and death from HF
(ICD 9th revision code 428 or ICD10th revision I28).
The men were divided into five approximately equally
sized groups based on the quintile distribution of serum
magnesium in all men without HF or MI. Cox proportional
hazards model was used to assess the multivariate-adjusted
hazards ratio (HR) in a comparison of the five magnesium
groups using the lowest quintile as the reference group as
well as in a 1 SD increase in serum magnesium. In the
multivariate analysis smoking (never, long-term
ex-smokers (C 15 years), recent ex-smokers (\ 15 years), and
current smokers], social class (manual vs non-manual),
physical activity (inactive, occasionally active, light,
moderate and at least moderately vigorous), heavy drinking
(C 35 drinks/week), use of antihypertensive drugs (yes/
no), diabetes (yes/no) and LVH (yes/no) were fitted as
categorical variables. The proportional hazards assumption
was examined using time-varying covariates, calculating
interactions of predictor variables and a function of
survival time and including them in the models. Examination
of time-varying covariates indicated no violation of the
proportionality assumption. Restricted cubic splines were
used to visually depict the association between magnesium
and incident HF. The distributions of NT-proBNP, cTnT,
IL-6 and CRP were skewed and log transformation was
used to normalise these factors. To evaluate whether serum
magnesium predicted HF independent of incident MI
during follow-up we adjusted for incident MI by fitting MI as a
time dependent covariate. To calculate the excess risk
explained by the mediating factors we compared the
regression models with and without the mediating factors.
The percent excess risk explained by the mediator is
obtained by a ratio where the numerator included the
difference between the unadjusted (total effect) and the
adjusted (direct effect) relative risks and the denominator
includes the unadjusted excess risk (total effects) [
We excluded men with prior doctor diagnosis of HF or
myocardial infarction (MI) (N = 508) at examination
leaving 3523 men for analysis. Men with MI have very
high HF incidence rates (17.40/1000/person-yrs vs 6.31/
1000/per-yrs) and high prevalence of renal dysfunction
which is known to influence serum magnesium levels [
Therefore to reduce confounding by complications of MI
we excluded these men.
The mean (SD) serum magnesium in the 3523 men was
0.80 (0.07) mmol/L (range 0.48–1.06 mmol/L). 236 men
(6.7%) had hypomagnesimia (\ 0.70 mmol/l). During the
mean follow-up period of 15 years there were 268 incident
HF events (6.38/1000 person-years), 171 incident
nonfatal MI (4.06/1000 person-years) and 429 incident CHD
events (fatal CHD or non-fatal MI) (10.19/1000
personyears), in the 3523 men without MI or HF.
Table 1 shows baseline characteristics for each of the 5
magnesium groups. Low magnesium was significantly and
strongly associated with increased BMI, heavy drinking,
AF, renal dysfunction, use of antihypertensive drugs,
HOMA-IR, CRP, IL-6, vWF, cTnT and NT-proBNP.
Table 2 shows the association between serum magnesium
and biological markers that may play a role in the
association of magnesium and HF, adjusted for age and BMI in
all men and excluding those with CKD. With the exception
of CRP, the inverse association between serum magnesium
and the CV risk factors remained after adjustment for age
and BMI and upon exclusion of those with CKD.
Serum magnesium and incident coronary heart disease
Serum magnesium showed no association with incident
CHD events. The age adjusted hazards ratio (95%CI) for
the quintiles of serum magnesium were 1.00, 0.86 (0.64,
1.16), 0.86 (0.63, 1.17), 0.92 (0.68, 1.24) and 0.97 (0.71,
1.31) respectively (p trend = 0.99).
Serum magnesium and incident heart failure
In contrast to incident CHD, serum magnesium was
inversely associated with risk of incident HF events after
adjustment for CV risk factors; age, smoking status, social
class, physical activity, heavy drinking, BMI, systolic
Mean and SD; *Geometric mean and interquartile range
Heavy drinking = C 35 drinks/week
AF atrial fibrillation, LVH left ventricular hypertrophy, FEV1 forced expiratory volume in 1 s, CRP c-reactive protein, IL-6 interleukin 6, vWF
von Willebrand factor, NT-pro BNP N-terminal pro-brain natriuretic peptide, cTnT cardiac troponin T
blood pressure, HDL cholesterol, use of antihypertensive
treatment, diabetes, eGFR and LVH with risk significantly
reduced in those in the highest quintile (Table 3). Figure 1
shows the continuous association between serum
magnesium and risk of HF after these adjustments. The
Figure shows that risk declined at levels above 0.85 (* top
quintile). Exclusion of men on diuretics made little
difference to the association (Table 3). Since serum
magnesium showed no association with incident CHD (fatal
CHD/non-fatal MI), adjustment for incident non-fatal MI
made little difference to the findings (Table 3). The inverse
associations with HF were attenuated after further
adjustment for AF, IL-6, vWF and lung function (Table 3:
models 2–4) but risk remained significantly reduced in
those with elevated serum magnesium. Further adjustment
for cardiac markers NT-proBNP and cTnT attenuated the
association further (Table 3;models 5 and 6). However, the
reduced risk seen in the top quintile was strengthened and
significant when men with CKD were excluded (Table 3).
We calculated the percent excess risk explained by
established risk factors and potential mediators. The
reduced risk explained by established risk factors (Model
1) was 12% [(0.5–0.56)/(0.5–1)*100]. Prevalent AF, lung
function (FEV1), IL-6 and vWF together explained about
14% of the reduced risk [(0.56–0.62/(0.56–1)*100] and
cardiac markers (cTnT and NT-proBNP) explained a
Quintile 1 used as the reference group
Model 1 adjusted for age, smoking, social class, physical activity heavy drinking, BMI, HDL-C, diabetes, use of antihypertensive drugs, systolic
blood pressure, eGFR and LVH
Model 2 adjusted for model 1 and AF
Model 3 adjusted for model 2 and IL-6 and vWF
Model 4 adjusted for model 3 and FEV1
Model 5 adjusted for Model 4 and cTnT
Model 6 adjusted for model 5 and NT-proBNP
further 21% of the reduced risk [(0.62–0.70)/0.62–1)*100].
Overall, approximately 32% of the reduced risk of HF seen
for elevated magnesium appeared to be explained by AF,
IL-6, vWF and cardiac markers (NT-proBNP, cTnT)
combined (Model 6) after adjustment for the established
risk factors [(0.56–0.70)/(0.56–1)*100].
We further examined the association between serum
magnesium and HF risk separately in men with and without
Fig. 1 Association of serum magnesium (mmol/l) with risk of
incident heart failure: magnesium modelled as restricted cubic splines
with knots at the 5th (0.68 mmol/l) 20th, 40th, 60th, 80th and 95th
(0.92 mmol/l) percentiles adjusted for age, smoking, physical activity,
social class, BMI, diabetes, antihypertensive treatment, eGFR, LVH,
heavy drinking and systolic blood pressure
ECG evidence of myocardial ischemia (Table 4). The
inverse association between serum magnesium and HF risk
was somewhat more evident in those with evidence of
myocardial ischaemia on ECG (N = 784) although a
formal test for interaction was not significant (p = 0.21) after
adjustment for factors in model 1. The association between
magnesium and incident HF in those with evidence of
ischaemia was not due to their higher risk of developing MI
as adjustment for incident MI made little difference to the
findings (Table 4).
Calcium and HF
Serum calcium showed no association with incident HF.
The age adjusted hazards ratio for the increasing quintiles
of calcium were 1.00, 1.12 (0.77, 1.64), 1.03 (0.72, 1.48),
0.83 (0.55, 1.26) and 1.08 (0.75, 1.57) respectively.
In this study of older British men without history of MI or
HF, serum magnesium was inversely associated with
incident HF, with risk significantly reduced in those with
high serum magnesium levels (upper quintile). The vast
majority of these men (99%) in the top quintile of the study
population had levels within the normal range
(\ 0.95 mmol/L) [
]. This potentially beneficial effect of
high serum magnesium was more evident in those with
evidence of myocardial ischaemia on ECG. No association
was seen between serum magnesium concentration and
incident CHD. Our findings confirm the previous 2 reports
of the inverse association between serum magnesium and
] and extend the findings to older adults without
prevalent MI. We also investigated several potential
pathways including inflammation, endothelial dysfunction,
cardiac function and lung function not previously assessed.
Serum magnesium related inversely to prevalent AF, lung
function (FEV1) and markers of inflammation (IL-6),
endothelial dysfunction (vWF) and cardiac dysfunction
(cTnT, NT-proBNP), all markers of pathways involved in
the pathogenesis of HF. It was estimated that about 32% of
the reduced risk of HF associated with higher serum
magnesium levels within the normal range was to some
extent mediated by these multiple pathways after taking
ECG not available in 11 men
Model 1 adjusted for age, smoking, social class, physical activity, heavy drinking, BMI, HDL-C, diabetes, use of antihypertensive drugs, systolic
blood pressure, eGFR and LVH
into account potential confounders and established
conventional CVD risk factors.
Serum magnesium and incident CHD
Although serum magnesium was related to many risk
factors for CVD, we observed no association with CHD.
The lack of association between circulating magnesium
concentrations and incident CHD has been reported
] and is consistent with the results of a
metaanalysis, reporting no association between serum
magnesium and CVD in men.  It is suggested that urinary
magnesium excretion may be a more useful marker of
plasma magnesium than plasma concentrations in relation
to CHD [
]. Nevertheless we have observed an
association between circulating serum magnesium and incident
Serum magnesium and inflammation
It has been hypothesized that the association between
serum magnesium and HF may be acting through
]. Several lines of experimental evidence
have suggested that higher magnesium intake may have
beneficial effects on endothelial dysfunction and reducing
inflammatory cytokine production . We have observed
an inverse relationship between circulating serum
magnesium and vWF (a marker of endothelial dysfunction) and
IL-6 (a pro-inflammatory cytokine and a marker of
inflammation) after taking BMI into account, in line with
other populations studies [
]. However, we observed
only weak associations with CRP a marker of low-grade
chronic inflammation, which is keeping with the evidence
that magnesium generally has not been found to affect
markers of chronic low-grade inflammation . However,
the association between serum magnesium and HF was not
explained by IL-6 or vWF in multivariate analysis.
Magnesium levels may be impacted by renal function and
diuretics. However the association was seen even after
exclusion of men with diuretics and was stronger when
men with CKD were excluded.
Potential pathways relating serum magnesium concentration and HF
The association between circulating magnesium
concentration and HF but not CHD suggests non-ischaemic
mechanisms specific to HF are particularly important.
Magnesium is known to have antiarrhythmic properties [
High levels of circulating magnesium may protect against
the development of cardiac arrhythmias and left ventricular
hypertrophy. We observed an inverse association between
serum magnesium and prevalent AF, with prevalence
decreased at levels above 0.83 mmol/l (2 mg/dl). These
findings are consistent with the results of a recent
prospective study which showed that risk of AF increased
below a threshold of 1.9 mg/dl [
]. However, in the present
study, the inverse association between serum magnesium
and HF remained after adjustment for prevalent AF. Low
magnesium has been shown to be associated with the
development of AF [
], which in turn may lead to
increased risk of HF.
Magnesium may have a direct beneficial effect on the
pulmonary vasculature. Clinical studies have shown that
magnesium infusion decreases pulmonary vascular
resistance and pulmonary artery pressure [
associated with right ventricular structural abnormalities
which could lead to clinical HF. In the present study, serum
magnesium related inversely and strongly to lung function
(FEV1) which is a strong predictor of HF risk . Higher
lung function in participants with high normal serum
magnesium levels partially explained the reduced risk of
HF seen in these men. Thus pulmonary function may be
one of the pathways by which high levels of magnesium is
beneficially related to HF.
Another possible pathway linking circulating
magnesium concentrations and HF is coronary artery calcification
(CAC). CAC has been shown to be associated with left
ventricular diastolic dysfunction a major cause of HF with
preserved ejection fraction in the elderly [
studies have shown CAC to be associated with increased
risk of incident HF [
]. Animal and experimental
models have shown that magnesium prevents vascular
calcification in aortic vascular smooth muscle cells
]. Serum magnesium has been shown to be inversely
related to CAC in the general population [
]. We have
shown a significant association between magnesium and
cTnT which has shown to be strongly associated with the
presence of CAC  and adjustment for cTnT attenuated
the magnesium-HF association further suggesting that
CAC may be another mechanism by which magnesium
may protect against HF. Moreover, age has shown to be the
predominant risk factor for CAC [
] and asymptomatic
CHD is known to be associated with increased risk of CAC
]. The finding that the protective effect of high serum
magnesium was particularly evident in men with evidence
of myocardial ischaemia suggests that magnesium may
delay the progression of CAC in these high risk older men.
Magnesium supplementation trials
The finding that low serum magnesium is associated with
several adverse CVD risk factors is supported by
randomised control trials. Systematic reviews of magnesium
supplementation trials provide evidence as to the benefits
of magnesium supplementation in reducing metabolic
CVD risk factors including blood pressure and glucose as
well as CRP levels [
]. Two recent trials have shown
magnesium supplementation to improve vascular function
]. The MAGICAL-CKD trial is now underway in
investigating whether magnesium supplementation can
prevent the progression of CAC in subjects with chronic
kidney disease . However, magnesium
supplementation trials on mortality outcome, largely conducted in high
risk patients with acute MI have been inconclusive [
While one observational study has reported an inverse
association between dietary magnesium intake and risk of
HF hospitalisation [
], a magnesium supplementation trial
has yet to be conducted in generally healthy older adults
with respect to HF outcome.
Strengths and limitations
The strengths of this study reflect its representativeness as a
cohort, with a wide range of HF risk factors measured and
high follow up rates. However, it was based on an older,
predominantly white, male population of European origin,
so that the results cannot be generalized directly to women,
to younger populations or to other ethnic groups. The
current findings are based on doctor diagnosed HF, which
is likely to underestimate the true incidence of HF in this
study population. However, the other risk factor
associations to HF risk in this report and in our previous report on
obesity, NT-proBNP and lung function and HF [
16, 17, 19
generally accord with prior data and therefore suggest
potential external validity for our findings. Information on
echocardiographic measurements was not available and we
were not therefore able to differentiate between systolic
and diastolic HF. Serum magnesium concentration is
maintained within a narrow range and values in the normal
range may not fully reflect total body magnesium stores
], although serum magnesium correlates well with
intracellular magnesium levels [
]. Thus serum levels may
represent the nutritional status of magnesium in the body.
We had no measurements of urinary magnesium excretion,
which has been suggested as a better indicator of dietary
magnesium intake [
]. Serum magnesium was only
measured at a single point in time, so that the strength of its
association with HF may have been underestimated.
Adjustments were based on measurements at examination
and we had no information on incident AF which is
associated with serum magnesium and HF risk. This was a
prospective observation study and we cannot establish
causality. Mendelian randomisation studies are needed to
test for any evidence for a direct causal association
between serum magnesium and HF.
Conclusion and implications
High normal levels of serum magnesium were associated
with significantly reduced risk of incident HF in older men
which was partially explained by its favourable association
with several potential pathways in HF including AF,
inflammation, endothelial dysfunction, lung function and
cardiac dysfunction. Serum magnesium may be modifiable
by magnesium intake raising the possibility that
magnesium may be a modifiable risk factor for HF. Intervention
trials are needed to confirm whether magnesium
supplementation in older adults, in particular those with evidence
of myocardial ischaemia, would reduce the risk of HF.
Funding The British Regional Heart Study is supported by a British
Heart Foundation (BHF) Programme Grant (RG/13/16/30528).
Compliance with ethical standards
Conflict of interest The authors declare that they have no conflict of
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1. Enselberg CD , Simmons HG , Mintz AA . The effects of magnesium upon cardiac arrhythmias . Am Heart J . 1950 ; 39 : 703 - 12 .
2. De Baaij JHF , Hoenderop JGJ , Bindels RJM . Magnesium in man: implications for health and disease . Physiol Rev . 2015 ; 95 : 1 - 46 .
3. Barbagallo M , Belvedere M , Dominguez LJ . Magnesium homeostasis and aging . Magn Res . 2009 ; 22 : 235 - 46 .
4. Larsson S. Urinary magnesium excretion as a marker of heart disease risk . Am J Clin Nutr . 2013 ; 97 : 1159 - 60 .
5. Misialek JR , Lopez FL , Lutsey PL , Huxley RR , Peacock JM , Chen LY , Soliman EZ , Agarwal SK , Alonso A . Serum and dietary magnesium and incidence of atrial fibrillation in whites and in African Americans-Atherosclerosis Risk in Communities (ARIC) study . Circ J . 2013 ; 77 ( 2 ): 323 - 9 .
6. Khan AM , Lubitz SA , Sullivan LM , Sun JX , Levy D , Vasan RS , Magnani JW , Ellinor PT , Benjamin EJ , Wang TJ . Low serum magnesium and the development of atrial fibrillation in the community: the Framingham Heart Study . Circulation . 2013 ; 127 : 33 - 8 .
7. Markovits N , Kurnik D , Halkin H , Margalit R , Bialik M , Lomnicky Y , Loebstein R . Database evaluation of the association between serum magnesium levels and the risk of atrial fibrillation in the community . Int J Cardiol . 2016 ; 205 : 142 - 6 .
8. Del Gobbo LC , Imamura F , Wu JH , de Oliveira Otto MC , Chiuve SE , Mozaffarian D . Circulating and dietary magnesium and risk of cardiovascular disease: a systematic review and meta-analysis of prospective studies . Am J Clin Nutr . 2013 ; 98 ( 1 ): 160 - 73 .
9. Qu X , Jin F , Hao Y , Li H , Tang T , Wang H , Yan W , Dai K. Magnesium and the risk of cardiovascular events: a meta-analysis of prospective cohort studies . PLoS One . 2013 ; 8 ( 3 ): e57720 .
10. Kieboom BC , Niemeijer MN , Leening MJ , van den Berg ME , Franco OH , Deckers JW , Hofman A , Zietse R , Stricker BH , Hoorn EJ . Serum magnesium and the risk of death from coronary heart disease and sudden cardiac death . J Am Heart Assoc . 2016 ; 5 ( 1 ): e002707 .
11. Lutsey PL , Alonso A , Michos ED , Loehr LR , Aston BC , Coresh J , Folsom AR . Serum magnesium, phosphorous, and calcium are associated with risk of incident heart failure: the Atherosclerosis Risk in Communities (ARIC) Study . Am J Clin Nutr . 2014 ; 100 : 756 - 64 .
12. Kunutsor SK , Khan H , Laukkanen JA . Serum magnesium and risk of new onset heart failure in men: the Kuopio Ischemic Heart Disease Study . Eur J Epidemiol . 2016 ; 31 : 1035 - 43 .
13. Shechter M. Magnesium and cardiovascular system . Magn Res . 2010 ; 23 : 60 - 72 (Review).
14. Lennon LT , Ramsay SE , Papacosta O , Shaper AG , Wannamethee SG , Whincup PH . Cohort Profile Update: The British Regional Heart Study 1978 - 2014 : 35 years follow-up of cardiovascular disease and ageing . Int J Epidemiol . 2015 ; 44 : 826 - 826g .
15. Wannamethee SG , Lowe GDO , Whincup PH , et al. Physical activity and hemostatic and inflammatory variables in elderly men . Circulation . 2002 ; 105 : 1785 - 90 .
16. Wannamethee SG , Shaper AG , Whincup PH , et al. Obesity and risk of incident heart failure in older men with and without preexisting coronary heart disease: does leptin have a role?' . J Am Coll Cardiol . 2011 ; 58 : 1870 - 7 .
17. Wannamethee SG , Shaper AG , Papacosta O , Lennon L , Welsh P. Whincup PH Lung function and airway obstruction: associations with circulating markers of cardiac function and incident heart failure in older men-the British Regional Heart Study . Thorax . 2016 ; 71 : 526 - 34 .
18. Levy AS , Bosch JP , Lewis JB , Greene T , Rogers N , Roth D. A more accurate method to estimate glomerular filtration rate from serum creatinine: a new prediction equation . Modification of Diet in Renal Disease Study Group. Ann Intern Med . 1999 ; 130 : 461 - 70 .
19. Wannamethee SG , Welsh P , Whincup P , Lennon L , Papacosta O , Sattar N. N-terminal pro brain natriuretic peptide but not copeptin improves prediction of heart failure over other routine clinical risk parameters in older men with and without cardiovascular disease: population-based study . Eur J Heart Fail . 2014 ; 16 : 25 - 32 .
20. McMurray JJ , Adamopoulos S , Anker SD , Auricchio A , Bo¨ hm M , Dickstein K , Falk V , Filippatos G , Fonseca C , Gomez-Sanchez MA , Jaarsma T , Køber L , Lip GY , Maggioni AP , Parkhomenko A , Pieske BM , Popescu BA , Rønnevik PK , Rutten FH , Schwitter J , Seferovic P , Stepinska J , Trindade PT , Voors AA , Zannad F , Zeiher A. ESC Committee for Practice Guidelines. ESC Guidelines for the diagnosis and treatment of acute and chronic heart failure 2012: the task force for the diagnosis and treatment of acute and chronic heart failure 2012 of the European Society of Cardiology. Developed in collaboration with t the Heart Failure Association (HFA) of the ESC . Eur Heart J . 2012 ; 33 : 1787 - 847 .
21. Richiardi L , Belloco R , Zugna D . Mediation analysis in epidemiology: methods, interpretation and bias . Int J Epidemiol . 2013 ; 42 : 1511 - 9 .
22. Musso CG . Magnesium metabolism in health and disease . Int Urol Nephrol . 2009 ; 41 : 357 - 62 .
23. Joosten MM , Gansevoort RT , Mukamal KJ , van der Harst P , Geleijnse JM , Feskens EJ , Navis G , Bakker SJ , PREVEND Study Group. Urinary and plasma magnesium and risk of ischemic heart disease . Am J Clin Nutr . 2013 ; 97 : 1299 - 306 .
24. Song Y , Li TY , van Dam RM , Manson JE , Hu FB . Magnesium intake and plasma concentrations of markers of systemic inflammation and endothelial dysfunction in women . Am J Clin Nutr . 2007 ; 85 : 1068 - 74 .
25. Dibaba DT , Xun P , He K. Dietary magnesium intake is inversely associated with serum C-reactive protein levels: meta-analysis and systematic review . Eur J Clin Nutr . 2014 ; 68 : 971 .
26. Nielsen FH . Magnesium deficiency and increased inflammation: current perspectives . J Inflamm Res . 2018 ; 11 : 25 - 34 .
27. Haas NA , Kemke J , Schulze-Neick I , Lange PE . Effect of increasing doses of magnesium in experimental pulmonary hypertension after acute pulmonary embolism . Intensive Care Med . 2004 ; 30 : 2102 - 9 .
28. Vonk-Noordegraaf A , Marcus JT , Holverda S , Roseboom B , Postmus PE . Early changes of cardiac structure and function in COPD patients with mild hypoxemia . Chest . 2005 ; 127 : 1898 - 903 .
29. Osawa K , Miyoshi T , Oe H , Sato S , Nakamura K , Kohno K , Morita H , Kanazawa S , Ito H . Association between coronary artery calcification and left ventricular diastolic dysfunction in elderly people . Heart Vessels . 2016 ; 31 : 499 - 507 .
30. Leening MJ , Elias-Smale SE , Kavousi M , Felix JF , Deckers JW , Vliegenthart R , Oudkerk M , Hofman A , Steyerberg EW , Stricker BH , Witteman JC . Coronary calcification and the risk of heart failure in the elderly: the Rotterdam Study . JACC Cardiovasc Imaging . 2012 ; 5 : 874 - 80 .
31. Sakuragi S , Ichikawa K , Yamada K , Tanimoto M , Miki T , Otsuka H , Yamamoto K , Kawamoto K , Katayama Y , Tanakaya M , Ito H. An increase in the coronary calcification score is associated with an increased risk of heart failure in patients without a history of coronary artery disease . J Cardiol . 2016 ; 67 ( 4 ): 358 - 64 .
32. Bai Y , Zhang J , Xu J , Cui L , Zhang H , Zhang S , Feng X . Magnesium prevents b-glycerophosphate-induced calcification in rat aortic vascular smooth muscle cells . Biomed Rep . 2015 ; 3 : 593 - 7 .
33. Louvet L , Bu¨chel J , Steppan S , Passlick-Deetjen J , Massy ZA . Magnesium prevents phosphate-induced calcification in human aortic vascular smooth muscle cells . Nephrol Dial Transplant . 2013 ; 28 ( 4 ): 869 - 78 .
34. Lee SY , Hyun YY , Lee KB , Kim H . Low serum magnesium is associated with coronary artery calcification in a Korean population at low risk for cardiovascular disease . Nutr Metab Cardiovasc Dis . 2015 ; 25 ( 11 ): 1056 - 61 .
35. Posadas-Sa´nchez R , Posadas-Romero C , Cardoso-Saldan˜ a G , Vargas-Alarco´n G , Villarreal-Molina MT , Pe´rez-Herna´ndez N, Rodr´ıguez-Pe´rez JM , Medina-Urrutia A , Jorge-Galarza E , Jua´rezRojas JG, Torres-Tamayo M . Serum magnesium is inversely associated with coronary artery calcification in the Genetics of Atherosclerotic Disease (GEA) study . Nutr J. 2016 ; 1 ( 15 ): 22 .
36. Olson F , Engborg J , Grønhøj MH , Sand NP , Lambrechtsen J , Steffensen FH , Nybo M , Gerke O , Mickley H , Diederichsen AC . Association between high-sensitive troponin I and coronary artery calcification in a Danish general population . Atherosclerosis . 2016 ; 245 : 88 - 93 .
37. Allison MA , Wright CM . Age and gender are the strongest clinical correlates of prevalent coronary calcification (R1) . Int J Cardiol . 2005 ; 98 ( 2 ): 325 - 30 .
38. Nicoll R , Henein M. Arterial calcification:a new perspective . Int J Cardiol . 2017 ; 228 : 11 - 2 .
39. Morais JBS , Severo JS , de Alencar GRR , de Oliveira ARS , Cruz KJC , Marreiro DDN , Freitas BJESA , de Carvalho CMR , Martins MDCCE , Frota KMG . Effect of magnesium supplementation on insulin resistance in humans: a systematic review . Nutrition . 2017 ; 38 : 54 - 60 .
40. Zhang X , Li Y , Del Gobbo LC , Rosanoff A , Wang J , Zhang W , Song Y. Effects of magnesium supplementation on blood pressure: a meta-analysis of randomized double-blind placebocontrolled trials . Hypertension . 2016 ; 68 : 324 - 33 .
41. Simental-Mend´ıa LE , Sahebkar A , Rodr´ ıguez-Mora´n M, Zambrano-Galva´n G , Guerrero-Romero F . Effect of magnesium supplementation on plasma C-reactive protein concentrations: a systematic review and meta-analysis of randomized controlled trials . Curr Pharm Des . 2017 ; 23 : 4678 - 86 .
42. Joris PJ , Plat J , Bakker SJ , Mensink RP . Long-term magnesium supplementation improves arterial stiffness in overweight and obese adults: results of a randomized, double-blind, placebocontrolled intervention trial . Am J Clin Nutr . 2016 ; 103 : 1260 - 6 .
43. Cunha AR , D'El-Rei J , Medeiros F , Umbelino B , Oigman W , Touyz RM . Neves MF Oral magnesium supplementation improves endothelial function and attenuates subclinical atherosclerosis in thiazide-treated hypertensive women . J Hypertens . 2017 ; 35 : 89 - 97 .
44. Bressendorff I , Hansen D , Schou M , Kragelund C , Brandi L. The effect of magnesium supplementation on vascular calcification in chronic kidney disease-a randomised clinical trial (MAGICALCKD): essential study design and rationale . BMJ Open . 2017 ; 7 : e016795 .
45. Taveira TH , Ouellette D , Gulum A , Choudhary G , Eaton CB , Liu S , Wu WC . Relation of magnesium intake with cardiac function and heart failure hospitalisations in black adults . The Jackson Heart Study. Circ Heart Fail . 2016 ; 9 : e002698 .