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Serum magnesium and the prevalence of peripheral artery disease: The Atherosclerosis Risk in Communities (ARIC) study

  • Author Footnotes
    1 These authors contribute equally to this work.
    Xiuting Sun
    Footnotes
    1 These authors contribute equally to this work.
    Affiliations
    Department of Cardiology, First Affiliated Hospital of Sun Yat-Sen University, Guangzhou, China

    Key Laboratory on Assisted Circulation, Ministry of Health, Guangzhou, China
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  • Author Footnotes
    1 These authors contribute equally to this work.
    Xiaodong Zhuang
    Footnotes
    1 These authors contribute equally to this work.
    Affiliations
    Department of Cardiology, First Affiliated Hospital of Sun Yat-Sen University, Guangzhou, China

    Key Laboratory on Assisted Circulation, Ministry of Health, Guangzhou, China
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  • Mengjuan Huo
    Affiliations
    Department of Radiology, Second Affiliated Hospital of Guangzhou University of Traditional Chinese Medicine, Guangzhou, China
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  • Pinning Feng
    Affiliations
    Laboratory Medicine Department, First Affiliated Hospital of Sun Yat-Sen University, Guangzhou, China
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  • Shaozhao Zhang
    Affiliations
    Department of Cardiology, First Affiliated Hospital of Sun Yat-Sen University, Guangzhou, China

    Key Laboratory on Assisted Circulation, Ministry of Health, Guangzhou, China
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  • Xiangbin Zhong
    Affiliations
    Department of Cardiology, First Affiliated Hospital of Sun Yat-Sen University, Guangzhou, China

    Key Laboratory on Assisted Circulation, Ministry of Health, Guangzhou, China
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  • Huimin Zhou
    Affiliations
    Department of Cardiology, First Affiliated Hospital of Sun Yat-Sen University, Guangzhou, China

    Key Laboratory on Assisted Circulation, Ministry of Health, Guangzhou, China
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  • Yue Guo
    Affiliations
    Department of Cardiology, First Affiliated Hospital of Sun Yat-Sen University, Guangzhou, China

    Key Laboratory on Assisted Circulation, Ministry of Health, Guangzhou, China
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  • Xun Hu
    Affiliations
    Department of Cardiology, First Affiliated Hospital of Sun Yat-Sen University, Guangzhou, China

    Key Laboratory on Assisted Circulation, Ministry of Health, Guangzhou, China
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  • Zhimin Du
    Affiliations
    Department of Cardiology, First Affiliated Hospital of Sun Yat-Sen University, Guangzhou, China

    Key Laboratory on Assisted Circulation, Ministry of Health, Guangzhou, China
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  • Meifen Zhang
    Correspondence
    Corresponding author. School of Nursing, Sun Yat-Sen University, No.74 zhongshan 2nd road, Guangzhou, 510080, China.
    Affiliations
    School of Nursing, Sun Yat-Sen University, Guangzhou, China
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  • Xinxue Liao
    Correspondence
    Corresponding author. Department of Cardiology, first affiliated hospital of Sun Yat-Sen University, No.58 zhongshan 2nd road, Guangzhou, 510080, China.
    Affiliations
    Department of Cardiology, First Affiliated Hospital of Sun Yat-Sen University, Guangzhou, China

    Key Laboratory on Assisted Circulation, Ministry of Health, Guangzhou, China
    Search for articles by this author
  • Author Footnotes
    1 These authors contribute equally to this work.
Open AccessPublished:December 19, 2018DOI:https://doi.org/10.1016/j.atherosclerosis.2018.12.004

      Highlights

      • Serum magnesium (Mg) was inversely and independently associated with the risk of peripheral arterial disease (PAD).
      • The relation between serum magnesium and peripheral arterial disease was non-linear.
      • Serum Mg may become a new biomarker for PAD risk prediction.

      Abstract

      Background and aims

      Peripheral arterial disease (PAD) is a clinical manifestation of extracoronary atherosclerosis. Many risk factors are involved in the process of PAD, but the association between serum magnesium (Mg) and PAD is not clear. Our study aimed to investigate whether serum Mg is associated with PAD incidence.

      Methods

      A total of 13,826 participants (aged 40–64 years) in the Atherosclerosis Risk in Communities (ARIC) study (1987–1989) without prior PAD were included in the final analysis. Serum Mg levels were measured at visits 1 and 2. PAD was defined as an ankle brachial index less than 0.9, or hospitalization with a PAD diagnosis. Cox regression was used to calculate hazard ratios (HRs) for incidence of PAD and serum Mg.

      Results

      During a median follow-up of 24.4 years, 1364 (48.4% female) PAD events were observed. After multiple adjustment, participants in the lowest (≤1.4 mEq/L) category of serum Mg compared with the highest (≥1.8 mEq/L) ones were at higher PAD risk (HR: 1.3; 95% confidence interval (CI): 1.06–1.58) (p value = 0.004). The HRs for PAD in 1.5, 1.6 and 1.7 mEq/L of serum Mg were 1.29 (95% CI: 1.08–1.54), 1.05 (95% CI: 0.89–1.24), and 1.0 (95% CI: 0.85–1.18), respectively.

      Conclusions

      Low serum Mg was independently associated with an increased prevalence of PAD in the large population-based study; further studies are needed to confirm our findings.

      Graphical abstract

      Keywords

      1. Introduction

      Peripheral artery disease (PAD) has become a severe public health problem, affecting almost 202 million people worldwide by 2010 [
      • Fowkes F.G.R.
      • Rudan D.
      • Rudan I.
      • Aboyans V.
      • Denenberg J.O.
      • et al.
      Comparison of global estimates of prevalence and risk factors for peripheral artery disease in 2000 and 2010: a systematic review and analysis.
      ]. PAD is one of the leading causes of morbidity and mortality for atherosclerotic cardiovascular disease (ASCVD) [
      • Heald C.L.
      • Fowkes F.G.R.
      • Murray G.D.
      • Price J.F.
      Risk of mortality and cardiovascular disease associated with the ankle-brachial index: systematic review.
      ,
      • Joosten M.M.
      • Pai J.K.
      • Bertoia M.L.
      • Rimm E.B.
      • Spiegelman D.
      • et al.
      Associations between conventional cardiovascular risk factors and risk of peripheral artery disease in men.
      ,
      • Fowkes F.G.R.
      • Murray G.D.
      • Butcher I.
      • Heald C.L.
      • Lee R.J.
      • et al.
      Ankle brachial index combined with framingham risk Score to predict cardiovascular events and mortality: a meta-analysis.
      ]. PAD is a strong and independent predictor of CVD and cerebrovascular disease as well [
      • Golomb B.A.
      • Dang T.T.
      • Criqui M.H.
      Peripheral arterial disease: morbidity and mortality implications.
      ]. Many previous studies have shown that diabetes, hypertension, dyslipidemia, smoking, as well as inflammation, urinary albumin, C-reactive protein (CRP), could accelerate the process of PAD [
      • Pande R.L.
      • Perlstein T.S.
      • Beckman J.A.
      • Creager M.A.
      Association of insulin resistance and inflammation with peripheral arterial disease: the National health and Nutrition examination survey, 1999 to 2004.
      ,
      • Navas-Acien A.
      • Selvin E.
      • Sharrett A.R.
      • Calderon-Aranda E.
      • Silbergeld E.
      • et al.
      Lead, cadmium, smoking, and increased risk of peripheral arterial disease.
      ,
      • Zhuang X.
      • Ni A.
      • Liao L.
      • Guo Y.
      • Dai W.
      • et al.
      Environment-wide association study to identify novel factors associated with peripheral arterial disease: evidence from the National Health and Nutrition Examination Survey (1999-2004).
      ,
      • Eraso L.H.
      • Fukaya E.
      • Mohler E.R.
      • Xie D.
      • Sha D.
      • et al.
      Peripheral arterial disease, prevalence and cumulative risk factor profile analysis.
      ,
      • Emdin C.A.
      • Anderson S.G.
      • Callender T.
      • Conrad N.
      • Salimi-Khorshidi G.
      • et al.
      Usual blood pressure, peripheral arterial disease, and vascular risk: cohort study of 4.2 million adults.
      ]. Identifying new potential biomarkers may help clinicians to diagnose PAD and give intervention at an early stage.
      Magnesium (Mg) is one of the most important minerals in the human body, involved in many key metabolic reactions such as energy production, glycolysis and electrolyte balance [
      • Costello R.
      • Wallace T.C.
      • Rosanoff A.
      Magnesium.
      ]. Serum Mg plays an important role in protection against stress, vasodilation of the coronary and peripheral arteries, and reduction of platelet aggregation [
      • Gröber U.
      • Schmidt J.
      • Kisters K.
      Magnesium in prevention and therapy.
      ]. Earlier studies demonstrated low serum Mg levels is associated with a greater risk of coronary heart disease (CHD), hypertension, sudden cardiac death (SCD) and heart failure (HF) [
      • Peacock J.M.
      • Ohira T.
      • Post W.
      • Sotoodehnia N.
      • Rosamond W.
      • et al.
      Serum magnesium and risk of sudden cardiac death in the Atherosclerosis Risk in Communities (ARIC) Study.
      ,
      • Lutsey P.L.
      • Alonso A.
      • Michos E.D.
      • Loehr L.R.
      • Astor B.C.
      • et al.
      Serum magnesium, phosphorus, and calcium are associated with risk of incident heart failure: the Atherosclerosis Risk in Communities (ARIC) Study.
      ,
      • Ma J.
      • Folsom A.R.
      • Melnick S.L.
      • Eckfeldt J.H.
      • Sharrett A.R.
      • et al.
      Associations of serum and dietary magnesium with cardiovascular disease, hypertension, diabetes, insulin, and carotid arterial wall thickness: the ARIC study. Atherosclerosis Risk in Communities Study.
      ]. Dietary Mg intake is not related to hypertension and CHD, but there is an inverse association with diabetes and ischemic stroke [
      • Ma J.
      • Folsom A.R.
      • Melnick S.L.
      • Eckfeldt J.H.
      • Sharrett A.R.
      • et al.
      Associations of serum and dietary magnesium with cardiovascular disease, hypertension, diabetes, insulin, and carotid arterial wall thickness: the ARIC study. Atherosclerosis Risk in Communities Study.
      ,
      • Liao F.
      • Folsom A.R.
      • Brancati F.L.
      Is low magnesium concentration a risk factor for coronary heart disease? The Atherosclerosis Risk in Communities (ARIC) Study.
      ,
      • Larsson S.C.
      • Orsini N.
      • Wolk A.
      Dietary magnesium intake and risk of stroke: a meta-analysis of prospective studies.
      ]. However, studies on the association of serum or dietary Mg with PAD are still limited.
      We hypothesized that low serum Mg is involved in the process of arteriosclerosis (AS). In this study, we aimed to investigate the relation of baseline serum Mg levels with the incidence of PAD using data from the community-based Atherosclerosis Risk in Communities (ARIC) study.

      2. Materials and methods

      2.1 Study population

      The ARIC study is a prospective epidemiologic study conducted in four U.S. communities (Forsyth County, NC; Jackson, MS (African Americans only); the northwest suburbs of Minneapolis, MN; and Washington County, MD). The study began in 1987, a total of 15,792 individuals (aged 45–64 years old) received an extensive examination, including medical, social and demographic data. Participants were reexamined every three years after the first screening (baseline, visit 1) occurring in 1987–1989, the second (visit 2) in 1990–1992, the third (visit 3) in 1993–1995, and the fourth (visit 4) in 1996–98, and the last exam (visit 5) was in 2011–2013.
      We excluded participants with prior PAD (n = 1023) or missing covariates (n = 794), as well as those without serum Mg measurement at visit 1 (n = 149), leaving 13,826 participants in the final analysis.

      2.2 Serum Mg measurement

      Participants were asked to fast for 12 h before blood sample collection. Blood was drawn from an antecubital vein of participants into vacuum tubes containing ethylenediaminetetraacetic acid (for measurement of lipids) or a serum separator gel (Mg, potassium, creatinine and glucose). Aliquots were stored at −70 °C for further analyses. Serum Mg levels were measured using the metallochromic dye calmagite at visits 1 and 2, following the Gindler and Heth's procedure [
      • Investigators T.A.
      The atherosclerosis risk in communities (ARIC) study: design and objectives.
      ].

      2.3 Peripheral artery disease definition

      Follow-up for events started from the first visit and continued when PAD occurred or until 31 December, 2012, whichever happened first. PAD was defined as an ankle brachial index (ABI) less than 0.9 at ARIC visits 3, 4 or 5, or a hospital discharge diagnosis of PAD, peripheral artery revascularization procedure, or peripheral artery intervention therapy during follow-up [
      • Fowkes F.G.R.
      • Murray G.D.
      • Butcher I.
      • Heald C.L.
      • Lee R.J.
      • et al.
      Ankle brachial index combined with framingham risk Score to predict cardiovascular events and mortality: a meta-analysis.
      ]. ABI was defined as the ratio of the ankle systolic blood pressure (SBP) to the brachial SBP.
      ABI was measured in almost all subjects at visit 1(96.4%), only a random sample at visits 3 (n = 4325), 4 (n = 6107) and 5 (n = 5194) [
      • Wattanakit K.
      • Folsom A.R.
      • Selvin E.
      • Coresh J.
      • Hirsch A.T.
      • et al.
      Kidney function and risk of peripheral arterial disease: results from the Atherosclerosis Risk in Communities (ARIC) Study.
      ]. ABI was not measured at visit 2. Dinamap 1846 automated oscillometric device (Criticon, Tampa, FL) was used by well-trained staff to measure ankle SBP at the posterior tibial artery with the participant prone, and brachial SBP in the right arm with the participant supine [
      • Weatherley B.D.
      • Chambless L.E.
      • Heiss G.
      • Catellier D.J.
      • Ellison C.R.
      The reliability of the ankle-brachial index in the atherosclerosis risk in communities (ARIC) study and the NHLBI family heart study (FHS).
      ]. Ankle and brachial SBPs in a randomly selected leg and the right arm were measured twice at visits 1 and 5. At visits 3 and 4, one ankle SBP and one brachial SBP of participants were measured. We also used the following ICD codes to define PAD: 39.25 (aorto-iliac-femoral bypass), 39.29 (leg bypass surgery), 84.11 (toe amputation), 84.12 (foot amputation), 84.15 (below-knee amputation), 84.17 (above-knee amputation), 38.18 (leg endarterectomy), 443.9 (claudication, peripheral arterial disease not otherwise specified, peripheral angiopathy not otherwise specified, spasm of artery).

      2.4 Other variables of interests

      Information about age, race, sex, smoking and drinking status, history of stroke and medication use was self-reported. Body mass index (BMI) was calculated by dividing weight in kilograms by height in meters squared. Hypertension (HT) was defined as a SBP ≥ 140 mmHg or diastolic blood pressure (DBP) ≥ 90 mmHg or use of antihypertensive medication, or a self-reported physician diagnosis. Prevalent diabetes mellitus (DM) was defined as fasting plasma glucose (FPG) level ≥ 126 mg/dL (≥7 mmoL/L), nonfasting glucose level ≥ 200 mg/dL (≥11.1 mmoL/L), or medication use, or self-reported physician diagnosis. Prevalent CHD was acquired by self-reported history of myocardial infarction, heart surgery, coronary bypass or balloon angioplasty, or current medication use. And Gothenburg Score or current medication use for HF were used to identify prevalent HF.
      Serum potassium (K), and sodium (Na) were assessed with a Coulter DACOS analyzer (Coulter Instruments, Hialeah, FL) using a direct ion-selective electrode. Serum calcium (Ca) was measured using θ-cresolphthalein complexone. Serum creatinine was measured using a modified kinetic Jaffe method and uric acid (UA) using urease method. An estimated glomerular filtration rate (eGFR) was calculated using the four-variable Modification of Diet in Renal Disease equation [
      • Levey A.S.
      • Bosch J.P.
      • Lewis J.B.
      • Greene T.
      • Rogers N.
      • et al.
      A more accurate method to estimate glomerular filtration rate from serum creatinine: a new prediction equation.
      ]. Enzymatic method was used to measure high-density lipoprotein cholesterol (HDL-C), total cholesterol (TC), triglycerides (TG) and Friedewald equation was used to calculate low-density lipoprotein cholesterol (LDL-C) [
      • Investigators T.A.
      The atherosclerosis risk in communities (ARIC) study: design and objectives.
      ].

      2.5 Statistical analysis

      Baseline characteristics of participants were described by means and proportions. ANOVA was used to compare baseline categories of serum Mg for continuous variables and chi-square tests for categorical variables. The statistical significance level was set at α = 0.05 (two-sided). A p-value of <0.05 was considered statistically significance.
      We used Cox proportional hazards regression to calculate hazard ratios (HRs) and 95% confidence intervals (CI) between serum Mg categories and time to incident PAD, according to baseline serum Mg levels. Three multivariate models with progressive degrees of adjustment were used to adjust for potential confounders. The first model included adjustment for baseline age, sex, race, smoking and drinking status. Model 2 was Model 1 plus continuous measures of BMI, SBP, DBP, TC, TG, HDL-C, LDL-C, FPG, eGFR, serum K, Na and Ca, UA. And adjustment for dietary Mg intake, prevalent CHD, HF, DM, history of stroke and use anti-HT medication were added to Model 3. In the spline models, as serum Mg values were reported to one decimal point; therefore, we categorized serum magnesium in a manner into five groups that approximated quintiles.
      We performed subgroup analyses stratifying by key demographic and clinical subgroups of age (45–50, 51–57 vs. 58–65 years), gender (female vs. male), race (white vs. black), smoking status (current vs. former), kidney function (eGFR < 60 vs. ≥ 60 mL/min/1.73 m2), serum K (<4.5 vs. ≥ 4.5 mmoL/l) and abnormal ABI vs. actual PAD clinical events. We used missing data from cardiovascular disease (prevalent of coronary heart disease, heart failure or history of stroke) to conduct the sensitivity analysis. The likelihood ratio test was used to test potential effect modification comparing models with and without interaction terms of interest. The proportional hazards assumption for all variables was confirmed. All analyses were done using SPSS 22.0 and R 3.3.0 (http://www.R-project.org).

      3. Results

      3.1 Baseline characteristics through distributions of serum Mg level

      Among 13,826 participants, 54.1% were female, 42% were black, and the mean ± SD age was 54.2 ± 5.7 years. The baseline characteristics of the ARIC study population by serum Mg level are shown in Table 1. Compared with the higher serum Mg groups, participants in the lower groups were mainly female or black, with higher BMI, SBP, TC, TG, LDL-C, FPG, UA, but lower eGFR, serum K and Na. Furthermore, participants with low serum Mg levels were more likely to suffer from CHD, HF and DM at baseline. However, there were no obvious differences among DBP, HDL-C, history of stroke and medication use. No obvious difference of daily dietary Mg intake was observed between these five groups either.
      Table 1Baseline characteristics of participants according to serum Mg levels.
      Category
      CharacteristicsGroup 1Group 2Group 3Group 4Group 5p value
      Mg level, (mEq/L)<1.51.51.61.7≥1.8
      N15672234355134782996
      Age, years54.31 ± 5.8753.94 ± 5.8254.06 ± 5.7654.17 ± 5.7154.33 ± 5.620.084
      Sex<0.0001
       Female905 (57.8%)1284 (57.5%)1901 (53.5%)1828(52.6%)1560 (52.1%)
       Male622 (42.2%)950 (42.5%)1650 (46.5%)1650 (47.4%)1436 (47.9%)
      Race<0.0001
       White833 (53.2%)1542 (68.2%)2678 (75.4%)2836 (81.5%)2501 (83.5%)
       Black734 (43.8%)710 (31.8%)873 (24.6%)642 (18.5%)495 (16.5%)
      Smoking status
       Current440 (28.1%)549 (22.8%)925 (26.1%)893 (25.7%)718 (24.0%)0.025
       Former488 (31.2%)713 (32.2%)1143 (32 2%)1155 (33.2%)1027 (34.3%)0.132
       Ever928 (59.3%)1262(56.9%)2069 (58.3%)2048 (58.9%)1746 (58.3%)0.638
      Drinking status<0.0001
       Current737 (47.3%)1148 (51.8%)1995 (56.4%)2105 (60.5%)1833 (61.4%)
       Former360 (23.1%)440 (19.8%)683 (19.3%)596 (17.1%)509 (17.1%)
       Ever1095 (70.3%)1588 (71.6%)2678 (75.6%)2701 (77.7%)2345 (78.6%)
      BMI, kg/m229.22 ± 6.1428.34 ± 5.5527.58 ± 5.1827.17 ± 4.9226.92 ± 4.74<0.0001
      SBP, mmHg125.98 ± 20.55123.32 ± 18.93120.72 ± 18.67121.03 ± 18.85121.49 ± 18.92<0.0001
      DBP, mmHg75.85 ± 11.9174.70 ± 11.5973.43 ± 11.3573.58 ± 11.2373.69 ± 11.550.23
      FPG, mg/dl133.36 ± 70.97112.66 ± 46.78106.46 ± 35.33103.15 ± 24.56101.44 ± 19.45<0.0001
      Potassium, mmol/l4.18 ± 0.514.32 ± 0.474.42 ± 0.454.48 ± 0.464.56 ± 0.48<0.0001
      Sodium, mmol/l140.23 ± 2.67140.71 ± 2.42140.87 ± 2.40141.17 ± 2.29141.38 ± 2.33<0.0001
      Calcium, mg/dl9.78 ± 0.469.76 ± 0.459.76 ± 0.429.79 ± 0.419.81 ± 0.42<0.0001
      Creatinine, mg/dl1.09 ± 0.391.09 ± 0.221.09 ± 0.481.11 ± 0.231.14 ± 0.58<0.0001
      eGFR, mL/min/1.73 m285.61 ± 24.6782.33 ± 21.3379.99 ± 20.3378.44 ± 18.8476.71 ± 18.89<0.0001
      Albumin, mg/dl3.77 ± 0.303.83 ± 0.273.87 ± 0.253.90 ± 0.253.93 ± 0.26<0.0001
      Uric acid, mg/dl6.46 ± 1.746.14 ± 1.616.00 ± 1.555.93 ± 1.475.93 ± 1.45<0.0001
      TC, mmol/l5.49 ± 1.135.51 ± 1.085.52 ± 1.175.55 ± 1.045.61 ± 1.050.002
      LDL-C, moll/l3.39 ± 1.053.5 ± 1.013.54 ± 1.013.59 ± 0.993.65 ± 1.000.001
      HDL-C, mol/l1.34 ± 0.481.33 ± 0.441.34 ± 0.451.34 ± 0.431.34 ± 0.420.291
      TG, mmol/l1.80 ± 1.441.54 ± 1.051.46 ± 0.941.41 ± 0.881.37 ± 0.77<0.0001
      Dietary Mg, mg/day250.96 ± 95.74252.92 ± 96.54253.80 ± 96.15254.94 ± 95.41255.63 ± 94.310.814
      Use of anti-HT medicine381 (24.4%)584 (26.3%)919 (26.0%)879 (25.4%)765 (25.7%)0.731
      Prevalent CHD106 (6.8%)108 (4.8%)162 (4.6%)154 (4.4%)128 (4.3%)0.02
      Prevalent HF131 (8.4%)109 (4.9%)165 (4.9%)121 (3.5%)93 (3.1%)<0.0001
      Prevalent DM405 (25.9%)293 (13.1%)301 (8.5%)200 (5.8%)115 (3.8%)<0.0001
      History of stroke36 (2.3%)42 (1.9%)56 (1.6%)67 (1.9%)47 (1.6%)0.342
      Values are mean ± SD or number (%).
      Mg: magnesium; BMI: body mass index; SBP: systolic blood pressure; DBP: diastolic blood pressure; FPG: fasting plasma glucose; eGFR: estimated glomerular filtration rate; HDL-C: high-density lipoprotein cholesterol; TC: total cholesterol; TG: triglycerides; LDL-C: low-density lipoprotein cholesterol; CHD: coronary heart disease; HF: heart failure; DM: diabetes mellitus.

      3.2 Serum Mg and PAD

      After the median follow-up of 24.4 years, a total of 1364 (9.9%) participants developed incident PAD, with 48.5% (n = 661) females, and 23.7% (n = 323) African-American. Serum Mg levels measured at visit 1 ranged from 0.5 to 3.1 mEq/L, The distribution of baseline serum Mg is shown in Fig. 1.
      Fig. 1
      Fig. 1Hazard ratios for peripheral arterial disease by levels of serum magnesium.
      The curves represent adjusted hazard ratios (solid line) and their 95% confidence intervals (dashed lines) by categories of serum magnesium.
      As shown in Table 2, after adjustment for age, sex, race, the incidence of PAD was inversely associated with circulating Mg (p value < 0.0001). Compared to the highest group (group 5) of Mg, the risk of PAD was increased (HR = 1.81, 95% CI: 1.49–2.19) in the lowest group (group 1). The strong relation still persisted after adjustment for potentially risk factors, including smoking status, lipids, BMI, SBP, DBP, FPG, serum K, serum Na and so on (Model 2) (HR = 1.34 for group 1 vs. group 5, 95% CI: 1.10–1.63; and HR = 1.29 for group 2 vs. group 5, 95% CI: (1.09–1.54)) (p value = 0.004).
      Table 2Hazard ratio (95% Cis) for peripheral arterial disease by serum Mg.
      CategoriesEvents/Total (N)Model 1Model 2Model 3
      1364/13,826HR(95% CI)p valueHR(95% CI)p valueHR(95% CI)p value
      Group 1187/15671.81 (1.49–2.19)<0.00011.34 (1.10–1.63)0.0041.30 (1.06–1.58)0.004
      Group 2252/22341.51 (1.27–1.80)<0.00011.29 (1.09–1.54)0.0041.29 (1.08–1.54)0.01
      Group 3342/35511.20 (1.02–1.40)0.0291.08 (0.92–1.27)0.3421.05 (0.89–1.24)0.533
      Group 4317/34781.06 (0.90–1.25)0.4531.01 (0.85–1.18)0.9781.00 (0.85–1.18)0.990
      Group 5 (reference)266/2996111
      HR: hazard ratio; CI: confidence interval; BMI: body mass index; SBP: systolic blood pressure; DBP: blood pressure; TC: total cholesterol; TG: triglycerides; HDL-C: high-density lipoprotein cholesterol; LDL-C: low-density lipoprotein cholesterol; eGFR: estimated glomerular filtration rate; CHD: coronary heart disease; HF: heart failure.
      Model 1 was adjusted for age, sex, race.
      Model 2, further adjusted for smoking and drinking status, BMI, glucose, SBP, DBP, TC, TG, HDL, LDL, eGFR, potassium, sodium, calcium, albumin, uric acid.
      Model 3, further adjusted for dietary Mg, prevalent CHD, DM and HF, history of stroke and use of medication.
      After further adjustment for dietary Mg, prevalent CHD, DM and HF, history of stroke and use of medication (Model 3), participants in the lowest category of serum Mg compared with the highest ones were at higher PAD risk (HR = 1.38, 95% CI: 1.12–1.71) (p value = 0.002). The HRs for PAD in groups 2, 3 and 4 were 1.29 (95% CI: 1.08–1.54), 1.05 (95% CI: 0.89–1.24), and 1.0 (95% CI: 0.85–1.18), respectively (Table 2 and Fig. 2). Spline regression analysis confirmed that serum Mg level was inversely associated with risk of PAD, with a non-linear relationship (Fig. 1). The incidence of PAD was higher in participants with serum Mg less than or equal to 1.5 mEq/L, no significant differences in participants with serum Mg higher than 1.5 mEq/L were found.
      Fig. 2
      Fig. 2Kaplan-Meier curve of peripheral arterial disease by levels of serum magnesium.
      Cox proportional hazards model adjusted for age, sex, race, smoking and drinking status, body mass index, glucose, high density lipoprotein cholesterol, low density lipoprotein cholesterol, triglycerides, serum potassium, serum sodium, uric acid, estimated glomerular filtration rate, systolic and diastolic blood pressure, diabetes, use of medication, dietary Mg intake and prevalent coronary heart disease, heart failure, diabetes and history of stroke. The reference group is the fifth serum magnesium group.
      Results of subgroup analyses and sensitivity analyses are summarized in Supplementary Fig. 1. The subgroup analyses showed that in participants with abnormal ABI or incident PAD, higher serum Mg was associated with decreased PAD (p for interaction > 0.05). The results did not differ significantly in subgroup analyses stratified by age, race, gender, eGFR (p for interaction > 0.05). In sensitivity analyses, results for the lower serum Mg groups were still consistent.

      4. Discussion

      The main finding of our study is that serum Mg is inversely and non-linear associated with risk of PAD in the community-based prospective cohort prospective cohort (ARIC) study. Participants in the low quintile (≤1.4 mEq/L) of serum Mg had nearly a 38% higher risk of PAD compared to those in the high quintile (≥1.8 mEq/L). The association between serum Mg and PAD was still present after adjusting for traditional PAD risk factors, indicating that serum Mg is independently related with PAD. Additionally, this novel association was similar among males and females. Our findings imply that low circulating Mg may be a risk marker of PAD.
      The observed relations in our study are consistent with previous studies suggesting low serum Mg played an important role in the process of AS. Low serum Mg is linked to a number of chronic diseases, such as CHD, HF, hypertension, diabetes, and could increase total mortality [
      • Qu X.
      • Jin F.
      • Hao Y.
      • Li H.
      • Tang T.
      • et al.
      Magnesium and the risk of cardiovascular events: a meta-analysis of prospective cohort studies.
      ,
      • Del Gobbo L.C.
      • Imamura F.
      • Wu J.H.
      • de Oliveira Otto M.C.
      • Chiuve S.E.
      • et al.
      Circulating and dietary magnesium and risk of cardiovascular disease: a systematic review and meta-analysis of prospective studies.
      ,
      • Misialek J.R.
      • Lopez F.L.
      • Lutsey P.L.
      • Huxley R.R.
      • Peacock J.M.
      • et al.
      Serum and dietary magnesium and incidence of atrial fibrillation in whites and in African Americans--Atherosclerosis Risk in Communities (ARIC) study.
      ]. Gobbo et al. analyzed 313,041 participants in 16 studies, and found that circulating Mg (per 0.2-mmol/L increment) is associated with a nearly 30% lower risk of CVD [
      • Del Gobbo L.C.
      • Imamura F.
      • Wu J.H.
      • de Oliveira Otto M.C.
      • Chiuve S.E.
      • et al.
      Circulating and dietary magnesium and risk of cardiovascular disease: a systematic review and meta-analysis of prospective studies.
      ]. Moreover, several earlier studies have shown that low serum Mg was related to the increased prevalence of SCD, HF and atrial fibrillation using data from ARIC [
      • Peacock J.M.
      • Ohira T.
      • Post W.
      • Sotoodehnia N.
      • Rosamond W.
      • et al.
      Serum magnesium and risk of sudden cardiac death in the Atherosclerosis Risk in Communities (ARIC) Study.
      ,
      • Misialek J.R.
      • Lopez F.L.
      • Lutsey P.L.
      • Huxley R.R.
      • Peacock J.M.
      • et al.
      Serum and dietary magnesium and incidence of atrial fibrillation in whites and in African Americans--Atherosclerosis Risk in Communities (ARIC) study.
      ,
      • Lutsey P.L.
      • Alonso A.
      • Michos E.D.
      • Loehr L.R.
      • Astor B.C.
      • et al.
      Serum magnesium, phosphorus, and calcium are associated with risk of incident heart failure: the Atherosclerosis Risk in Communities (ARIC) Study 1- 3.
      ]. Furthermore, lower intake of Mg is associated with higher levels of total and subclinical CVD events, coronary artery calcification, overall burden of AS [
      • Hruby A.
      • O'Donnell C.J.
      • Jacques P.F.
      • Meigs J.B.
      • Hoffmann U.
      • et al.
      Magnesium intake is inversely associated with coronary artery calcification.
      ,
      • Chiuve S.E.
      • Sun Q.
      • Curhan G.C.
      • Taylor E.N.
      • Spiegelman D.
      • et al.
      Dietary and plasma magnesium and risk of coronary heart disease among women.
      ]. Nevertheless, the relation of serum Mg and PAD has not been confirmed. Rusu et al. showed that low serum concentrations ae associated with approximately 20% higher incidence of PAD in 114 type 2 DM patients [
      • Rusu M.
      • Cristea V.
      • Frentiu T.
      • Marutoiu C.
      • Rusu L.D.
      Magnesium and selenium in diabetics with peripheral artery disease of the lower limbs.
      ], but the correlations of circulating Mg and PAD have not been well established in this small sample, cross-sectional study. Our study further illustrated the relation of serum Mg to incidence of PAD in the general population. Clinical attention should be paid to early-stage periphery atherosclerosis in patients with low serum Mg.
      Previous randomized trials have shown that Mg supplementation could improve endothelial function, lower BP and reduce AS [
      • Dibaba D.T.
      • Xun P.
      • Song Y.
      • Rosanoff A.
      • Shechter M.
      • et al.
      The effect of magnesium supplementation on blood pressure in individuals with insulin resistance, prediabetes, or noncommunicable chronic diseases: a meta-analysis of randomized controlled trials.
      ]. A meta-analysis, which included more than 1 million participants from forty prospective cohort studies, showed that a 100 mg/day increment in magnesium intake was associated with a 22% reduction in the risk of HF, a 7% reduction of stroke and a 10% reduction of all-cause mortality [
      • Fang X.
      • Wang K.
      • Han D.
      • He X.
      • Wei J.
      • et al.
      Dietary magnesium intake and the risk of cardiovascular disease, type 2 diabetes, and all-cause mortality: a dose–response meta-analysis of prospective cohort studies.
      ]. As both serum and dietary Mg levels are inversely related to AS, more attention should be paid to the use of pharmacologic drugs and food intake that may decrease magnesium levels. Few prospective clinical trials on the efficacy of Mg supplementation to prevent PAD have been conducted yet, and the precise mechanism between serum Mg and PAD has not been clearly illustrated. Several factors may contribute to the relation of serum Mg to PAD. Firstly, serum Mg plays an important role in the process of anti-atherosclerosis [
      • Maier J.A.M.
      Endothelial cells and magnesium: implications in atherosclerosis.
      ]. Low circulating Mg can cause endothelial cell dysfunction, which may partly explain the independent relations between serum Mg and PAD [
      • Chacko S.A.
      • Song Y.
      • Nathan L.
      • Tinker L.
      • de Boer I.H.
      • et al.
      Relations of dietary magnesium intake to biomarkers of inflammation and endothelial dysfunction in an ethnically diverse cohort of postmenopausal women.
      ]. In addition, Mg is an important cofactor for multiple enzymes involved in glucose metabolism. Deficiency of serum Mg is linked to metabolic syndrome, which could increase the prevalence of PAD [
      • Ju S.Y.
      • Choi W.S.
      • Ock S.M.
      • Kim C.M.
      • Kim D.-H.
      Dietary magnesium intake and metabolic syndrome in the adult population: dose-response meta-analysis and meta-regression.
      ]. Lastly, Mg has been shown to inhibit osteogenic differentiation of vascular smooth muscle cells. Low serum Mg may increase vascular calcification [
      • Hruby A.
      • O'Donnell C.J.
      • Jacques P.F.
      • Meigs J.B.
      • Hoffmann U.
      • et al.
      Magnesium intake is inversely associated with coronary artery calcification.
      ,
      • Salem S.
      • Bruck H.
      • Bahlmann F.H.
      • Peter M.
      • Passlick-Deetjen J.
      • et al.
      Relationship between magnesium and clinical biomarkers on inhibition of vascular calcification.
      ,
      • Montezano A.C.
      • Zimmerman D.
      • Yusuf H.
      • Burger D.
      • Chignalia A.Z.
      • et al.
      Vascular smooth muscle cell differentiation to an osteogenic phenotype involves TRPM7 modulation by magnesium.
      ].
      Our study has several important strengths. First of all, as far as we know, this is the first study to investigate the prospective relationship of serum Mg levels to PAD in the general population. Our results indicated that serum Mg is inversely associated with PAD independently of traditional risk factors, and provided new evidence regarding the link between serum Mg and PAD. Secondly, the results of our study came from a large sample size of a prospective cohort study which was well-characterized, bi-racial, and included a long follow-up period for PAD events. Thus, these results are representative of the US general population. Although the 2017 ESC Guidelines on the Diagnosis and Treatment of PAD recognized several new non-traditional predictors of PAD, our results suggest the need to pay attention to serum Mg levels in the future [
      • Aboyans V.
      • Ricco J.B.
      • Bartelink M.E.L.
      • Bjorck M.
      • Brodmann M.
      • et al.
      2017 ESC Guidelines on the diagnosis and treatment of peripheral arterial diseases, in collaboration with the european society for vascular surgery (ESVS).
      ].
      A few limitations should be considered as well. First, serum Mg levels were measured only at visits 1 and 2. Thus, variability or change of serum Mg over time may affect the results of our study. Secondly, ABI was not measured at visit 2, PAD was identified according to hospitalizations at visit 2. In addition, ABI was assessed in only a randomly sample of participants at visits 3, 4 and 5. ABI was measured in only one leg at visits 3 and 4. Measurement of ABI in only one leg may not be able to fully diagnose PAD. Fourth, the ARIC study enrolled participants aged 45–64 years, therefore, the generalizability of our findings to younger populations remains to be investigated. Lastly, this is an observational study, although several other major risk factors were adjusted, we cannot eliminate the possibility of residual confounding.

      4.1. Conclusions

      In conclusion, lower levels of serum Mg are strongly associated with an increased incidence of PAD, beyond traditional risk factors in the community-based prospective study. Our findings suggest that low serum Mg may be a new risk factor of PAD. Further prospectively planned clinical trials to confirm our findings and to elucidate possible mechanisms are needed.

      Conflicts of interest

      The authors declared they do not have anything to disclose regarding conflict of interest with respect to this manuscript.

      Financial support

      This study was supported by the National Natural Science Foundation of China (Grant NO: 81870195 ) to Xinxue Liao, and the National Natural Science Foundation of China (Grant NO: 81600206 ) to Xiaodong Zhuang.

      Author contributions

      Research idea and study design: XD Z, XT S, XX L and MF Z; data acquisition: X H, YG; data analysis/interpretation: MJ H, PN F; statistical analysis: XD Z, XT S, SZ Z. Manuscript drafting: SZ Z, HM Z, XB Z; Each author contributed important intellectual content during manuscript writing or revision, and all authors read and approved the final manuscript.

      Acknowledgements

      The authors thank the staff and participants of the ARIC study for their important contributions.

      Appendix A. Supplementary data

      Figure S1
      Figure S1Figure S1 Hazard ratio of peripheral artery disease and serum Mg in demographic and clinical subgroups
      HR: hazard ratio; CI: confidence interval; eGFR: estimated glomerular filtration rate; INC PAD: incident peripheral artery disease; CHD: coronary heart disease; HF: heart failure

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          We read with great interest the work by Sun et al., who observed a strong relationship between peripheral artery disease (PAD) and low serum levels of magnesium (Mg2+) [1]. Just as interesting is the commentary by Morello et al., who stressed that patients developing PAD were more frequently of Afro-American descent [2]. Moreover, they noted that both in Europe and in the United States, magnesium intake is below the recommended minimum dose [2]. In addition to the lack of dietary intake, we wish to highlight the well-known effect exerted by proton pump inhibitor (PPI) therapies, consisting in reducing the systemic levels of Mg2+ [3–5].
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