REALity March/April 2009 Volume XXVIII Issue No 2 THE TRAGEDY OF NO-FAULT DIVORCE By C. Gwendolyn Landolt, National Vice President, REAL Women of CanadaNo one seems prepared to discuss or come to grips with the fundamental flaw in Canadian society, created by the1986 Divorce Act, which provided for no-fault divorce. The problems this law is creating are overwhelming. Instead of dealing wit
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Am Heart J. Author manuscript; available in PMC 2011 September 1.
Am Heart J. 2010 September ; 160(3): 464–470. doi:10.1016/j.ahj.2010.06.012.
Serum Magnesium and Risk of Sudden Cardiac Death in the
Atherosclerosis Risk in Communities (ARIC) Study
James M. Peacock1, Tetsuya Ohira1, Wendy Post2,3, Nona Sotoodehnia4, Wayne
Rosamond5, and Aaron R. Folsom1
1 Division of Epidemiology & Community Health, School of Public Health, University of Minnesota,
2 Division of Cardiology, Department of Medicine, Johns Hopkins University School of Medicine,Baltimore, MD 3 Department of Epidemiology, Johns Hopkins University Bloomberg School of Public Health,Baltimore, MD 4 Cardiovascular Health Research Unit, Division of Cardiology, Department of Medicine, Universityof Washington, Seattle, WA 5 Department of Epidemiology, School of Public Health, University of North Carolina, Chapel Hill,NC Abstract
Background—We hypothesized that serum magnesium (Mg) is associated with increased risk of
sudden cardiac death (SCD).
Methods—The Atherosclerosis Risk in Communities (ARIC) Study assessed risk factors and levels
of serum Mg in a cohort of 45–64 year olds in 1987–1989 (n = 14,232). After an average of 12 years
of follow-up we observed 264 cases of SCD, as determined by physician review of all suspected
cases. We used proportional hazards regression to evaluate the association of serum Mg with risk of
Results—Individuals in the highest quartile of serum Mg were at significantly lower risk of SCD
in all models. This association persisted after adjustment for potential confounding variables, with
an almost 40% reduced risk of SCD (HR=0.62, 95% CI=0.42–0.93) in quartile 4 vs. 1 of serum Mgobserved in the fully-adjusted model.
Conclusions—This study suggests that low levels of serum Mg may be an important predictor of
SCD, and warrants further research into the effectiveness of Mg supplementation for those considered
to be at high risk for SCD.
sudden cardiac death; magnesium; cohort study Introduction
Sudden cardiac death (SCD) is a major public health problem comprising more than half of allcardiovascular disease (CVD) deaths in the USA. 1 Even with estimates of coronary heart Correspondence: Aaron R. Folsom, Division of Epidemiology & Community Health, School of Public Health, University of Minnesota,1300 South 2nd Street, Suite 300, Minneapolis, MN 55454. Phone: (612) 624-1818. [email protected]
disease (CHD) mortality declining by more than 50% from 1950 to 1999, the relative proportionof SCD of all CVD deaths in the USA simultaneously increased during this time. 1, 2 Secular trends in Olmsted County, Minnesota from 1979 to 2003 have shown much larger declines inin-hospital death rates, with declines in out-of-hospital death rates occurring much moreslowly. 3 Major risk factors for SCD include hypertension, diabetes, smoking, family historyof myocardial infarction, and obesity, but the majority of SCDs occur in those with no priorhistory of CVD.4 Magnesium (Mg), a micronutrient and common cation in the human body, is a natural calciumantagonist and modulates vasomotor tone, blood pressure, and peripheral blood flow. Thoughvirtually all Mg is stored in cells, low levels of serum Mg are usually predictive of low levelsof total body Mg as well.5 Previous epidemiological studies have reported that serum anddietary Mg are associated inversely with CVD risk factors such as hypertension,6,7 type 2diabetes mellitus, 8 the metabolic syndrome, 9 in addition to CHD.10,11 Additional evidencefrom ecologic, clinical, and autopsy studies has shown higher Mg to be potentially protectiveagainst SCD,12,13 but no prospective studies have reported the association of Mg levels withincidence of SCD in the general population. In addition to its role in the regulation of bloodpressure and maintenance of vascular smooth muscle tone, Mg deficiencies are known to causeventricular arrhythmias, the most common precursors to SCD. 12,14 Serum Mg levels aremodified by intake of dietary Mg, calcium (Ca) and potassium (K), in addition to alcohol intake Previous studies in the Atherosclerosis Risk in Communities (ARIC) cohort have shown thatserum Mg levels are associated inversely with incidence of hypertension, 9 CHD,10,11 anddiabetes. 8 In three of these studies,8–10 there were no associations between dietary Mg asmeasured from a food frequency questionnaire and these outcomes. The current study wasconducted to assess the relative contribution of serum Mg and dietary Mg intake to theincidence of SCD.
Research Design and Methods
The ARIC Study 17 is a multicenter prospective cohort study investigating the etiology ofatherosclerotic disease in a middle-aged biracial population. One aspect of the study includesa 1987–89 baseline examination and follow-up of population-based cohorts of 45–64 year oldsfrom Forsyth County, NC; Jackson, MS (African-Americans only); the northwest suburbs ofMinneapolis, MN; and Washington County, MD.
The ARIC Study protocol was approved by the institutional review board of each participatinguniversity. After obtaining written informed consent, participants underwent a baseline clinicalexamination (visit 1). Approximately 46% of those eligible in Jackson and 65% in the otherthree communities completed visit 1, yielding a total of 15,792 participants. Participants werere-examined in 1990–92 (94% return rate), 1993–95 (86%), and 1996–98 (80%). Response toannual telephone interviews has been 93% of cohort survivors.
Risk Factor Measurements
Most SCD risk factors examined in this analysis were ascertained at the baseline examination.
Participants were asked to fast for twelve hours prior to the clinic exam. Blood was drawn froman antecubital vein of seated participants into vacuum tubes containingethylenediaminetetraacetic acid (for measurement of lipids) or a serum separator gel (Mg, K,and glucose). Aliquots were stored at −70°C and were shipped to central laboratories foranalyses. The measurement of serum Mg was performed at visits 1 and 2 and was based on the Am Heart J. Author manuscript; available in PMC 2011 September 1.
procedure of Gindler and Heth using the metallochromic dye, Calmagite (1-(1-hydroxy-4-methyl-2-phenylazo)-2-napthol-4sulfonic acid). Serum K was measured on a Coulter DACOS analyzer (Coulter Instruments, Hialeah, FL) using a direct ion-selective electrode. Thelaboratory coefficient of variation for Mg, based on split samples sent 1 week apart blindly tothe laboratory, was 3%, 17 and repeated testing of 40 individuals over several weeks yielded areliability coefficient of 0.69 for Mg and 0.66 for K. 18 The correlation coefficient of serumMg measured at visit 1 versus visit 2 was 0.46. Serum glucose was assayed by a hexokinase/glucose-6-phosphate dehydrogenase method. Prevalent diabetes mellitus was defined as afasting glucose ≥ 126 mg/dl, non-fasting glucose ≥ 200 mg/dl, a self-reported physiciandiagnosis, or current treatment for diabetes. Prevalent hypertension was defined as restingsystolic blood pressure ≥ 140 mm Hg, diastolic blood pressure ≥ 90 mm Hg, or currenthypertension treatment.
Questionnaires assessed education, smoking status, number of cigarettes smoked per day andduration of smoking (pack years computed), and usual alcohol consumption (grams per weekcomputed). Level of sports physical activity was assessed by the Baecke Questionnaire. 19Usual dietary intake over the last year was collected using an adapted version of Willett’s 61-item food frequency questionnaire. 20 Dietary Mg intake was computed by multiplying the Mgcontent of each food item by the frequency of its daily consumption and summing over allitems. All medications used in the two weeks before each clinic visit were recorded from bottles Participants underwent a standard supine digitally recorded 12-lead electrocardiogram at rest,≥1 hour after smoking or caffeine ingestion. Computer analysis at the ARIC ECG ReadingCenter included measurement of the voltage and duration of the ECG waves and ECGclassification according to the Minnesota Code. 21,22 In those free of Minnesota codes forconduction defects (right or left bundle branch block, or intraventricular conduction defect),the QT interval duration was computed and corrected by Bazett’s formula 23,24: QTcorrected= QT/√ (heart rate standard/heart rate). The standard heart rate used was 60 beats/min.
Follow-up and Sudden Cardiac Death Definition
All participants were contacted annually by phone and all hospitalizations and deaths in theprevious year were identified. Hospitalizations related to potential myocardial infarctions (MI)or coronary deaths were abstracted by trained nurses. For deaths, we obtained death certificates.
If the death occurred out-of-hospital, we also sought next of kin interviews and physician,coroner, and autopsy information about the death. Events were classified as definite, probable,possible, or no MI, and if fatal, as definite fatal MI, definite fatal CHD, possible fatal CHD, ornon-CHD death. Incident CHD was defined for analysis as definite or probable MI or definite To classify sudden cardiac death (SCD), all events classified as having fatal CHD (definitefatal MI, definite fatal CHD, or possible fatal CHD, in- and out-of-hospital) were reviewedagain and adjudicated by a committee of physicians, funded through the Johns HopkinsUniversity Donald W. Reynolds Cardiovascular Research Center. SCD was defined as a suddenpulseless condition from a cardiac origin in a previously stable individual. After review of dataavailable, cases were classified as either definite sudden arrhythmic death, possible suddenarrhythmic death, not sudden arrhythmic death, or unclassifiable. For this analysis, SCD wasdefined as the first two categories above. Reviewers were blinded to serum Mg status.
Data Analysis and Statistical Methods
We hypothesized that serum Mg is inversely associated with incidence of SCD. From theoriginal ARIC cohort (n = 15,792), we excluded participants in very small minority groups Am Heart J. Author manuscript; available in PMC 2011 September 1.
(n = 103), those missing baseline serum Mg measurements (n = 149), those not fasting at least8 hours for the baseline examination (n = 550), and those missing covariates (n = 758). This Analyses were conducted using SAS software (v. 9.1; SAS Institute, Inc., Cary, NC). Toexplore possible confounding factors of associations between Mg and SCD, means orprevalences of risk factors were computed by quartile of serum Mg using ANOVA. Anindividual’s quartile rank was based on up to two serum Mg measurements (visits 1 and 2).
Those individuals who were censored before or did not attend visit 2 were ranked using theirsingle visit 1 serum Mg measurement. Those individuals who attended visit 2 and werecensored after that visit were ranked using the mean value of their two measurements.
Person-years at risk were calculated from the date of baseline clinical examination until thedate of sudden cardiac death, other death, loss to follow-up, or 31 May 2001, whicheveroccurred first. Crude SCD rates (per 1000 person-years) were calculated for quartiles of serumMg. Adjusted hazard ratios (HRs) for the association of serum Mg with SCD were calculatedby using Cox proportional hazards regression. Model 1 included adjustment for baseline age,sex, race and ARIC field center. Adjustment for continuous measures of HDL-c, LDL-c,triglycerides, serum K, heart rate-adjusted QT-interval, physical activity score, weekly alcoholintake, and pack years of smoking in addition to baseline smoking status (yes, no), andeducation level (< high school, ≥high school) were added to Model 2. The final model included adjustment for diabetes, hypertension, and use of diuretics (yes, no), modeled as time-varyingcovariates with the status at the last visit before death or censoring compared to that of all otherparticipants still at risk. The test for linear trend in HRs modeled each quartile group as equally-spaced categories. The proportional hazards assumption of the Cox model was found not to beviolated by testing an interaction between quartiles of serum Mg and time.
We also analyzed the association of SCD with dietary Mg. All diet models were adjusted fortotal energy intake, and the final model included dietary covariates highly correlated with Mg:K, Ca, dietary fiber, protein, caffeine (all measured continuously), and polyunsaturated tosaturated fat ratio.
The ARIC Study is supported by National Heart, Lung, and Blood Institute contracts N01-HC-55015, N01-HC-55016, N01-HC-55018, N01-HC-55019, N01-HC-55020, N01-HC-55021, and N01-HC-55022, and the Johns Hopkins University Donald W. ReynoldsCardiovascular Research Center. The authors are solely responsible for the design and conductof this study, all study analyses, the drafting and editing of the article, and its final contents.
The cohort at risk for SCD included 7,887 women and 6,345 men aged 45–64 years at baseline.
Serum Mg levels measured at visits 1 and 2 ranged from 0.4 to 3.1 mEq/L and appeared to benormally distributed, with 98% of individuals from 1.2 to 2.0 mEq/L. As table 1 shows, LDL-c and HDL-c, heart rate-adjusted QT interval, serum K, physical activity, education, and dietaryMg intake were all associated positively with levels of serum Mg. Fasting triglycerides, pack-years of smoking, systolic blood pressure, hypertension, diabetes, use of diuretics, female sex,being African-American, and education were associated inversely with serum Mg. There wereno differences in the percentage of current or former smokers, mean weekly alcohol intake, ordaily total energy intake by quartile of serum Mg.
Through May 31, 2001, 264 individuals were classified as having died from either definite(n=217) or possible (n=47) SCD. There were 46 events in Forsyth County, 93 in Jackson, 48in Minneapolis, and 77 in Washington County. Table 2 shows that the age-, race-, sex-, andfield center-adjusted risk of SCD was inversely associated with serum Mg (p for linear trend Am Heart J. Author manuscript; available in PMC 2011 September 1.
<0.0001). Compared to the lowest quartile of Mg, the risk of SCD was 55% lower (HR=0.45,95% C.I., 0.31–0.67) in the highest Mg quartile and 47% lower in the second highest quartile (HR=0.53, 95% C.I., 0.38–0.74). This strong association persisted after adjustment forpotentially confounding variables, including baseline measures of fasting lipids, heart rateadjusted-QT interval, serum K, physical activity score, smoking status and pack years, regularalcohol intake, and education level (Model 2) (p for linear trend = 0.0006), but point estimatesof the association were attenuated modestly (HR = 0.55 for quartile 4 vs. 1, 95% C.I. = 0.37–0.83; and HR = 0.62 for quartile 3 vs. 1, 95% C.I. = 0.44–0.88). Apart from lower Mg, onlygreater age, male sex, being African-American, not being at the Forsyth County field center,lower HDL, higher LDL, greater pack-years of smoking, and less education were associatedwith greater risk of SCD in Model 2.
After further adjustment for prevalent diabetes, prevalent hypertension, and use of diuretics(Model 3), each associated with greater risk of SCD, the serum Mg association was attenuatedslightly (p for linear trend = 0.006), with both quartiles 4 (HR = 0.62, 95% C.I. = 0.42–0.93)and 3 (HR = 0.70, 95% C.I. = 0.49–0.99) at significantly reduced risk of SCD when comparedto the lowest quartile of serum Mg. Restriction of this analysis to only definite cases of SCD(n=217) attenuated these results, with quartile 4 (HR = 0.72, 95% C.I. = 0.46–1.11) no longerassociated with a reduced risk of SCD (data not shown).
In order to assess the specificity of this association, we restricted the definition of SCD in three ways: cases that were 1) unwitnessed, 2) determined to have taken place outside of the hospital,or 3) determined to not be associated with MI by the physician reviewers (Table 2 bottom).
The risk of unwitnessed SCD in the fully-adjusted model was marginally lower than for allSCD cases for quartile 4 compared to quartile 1 (HR = 0.49, 95% C.I. = 0.25–0.99), but thelinear trend was no longer significant (p = 0.07). Restricting the SCD cases to out-of-hospitalevents did not change the overall association. The serum Mg association with SCD wassomewhat stronger for cases not associated with MI, with quartile 4 (HR = 0.51, 95% C.I. =0.32–0.83) at one-half the risk of death as the lowest quartile, greatly excluding the null.
To explore potential effect modification by prevalent CHD, we redid the analysis severaldifferent ways. Additional analyses which excluded prevalent CHD cases at baseline andcensored individuals at the time of an incident non-fatal event (definite or possible MI, ECG-detected silent MI between examinations, coronary revascularization), reducing the number ofcases by about half, showed similar, albeit weaker, results with wide confidence intervalsincluding the null. Alternatively, adjusting for incident CHD occurrence before SCD bymodeling it as a time-dependent covariate attenuated the association, with quartile 4 (HR =0.69, 95% C.I. = 0.46–1.04), no longer significantly associated with a reduced risk of SCD.
There was no evidence of effect modification by prevalent or incident CHD on the associationof serum Mg with SCD. None of the two-way interactions of sex, race, heart rate-adjusted QTinterval, serum K, and diuretic use with serum Mg was statistically significant at p<0.05.
Figure 1 illustrates the pattern of risk in those individuals who had serum Mg measured at bothclinic examinations (n=13,010 at risk, 194 cases). For this figure, the cohort was dichotomizedat the median value of both measurements of serum Mg, thereby comparing the upper twoquartiles vs. lower two. Compared to those with Mg < median at both visits, individuals withserum Mg above the median at only one visit were not at a different risk of SCD. However,the risk of SCD was 42% lower in those individuals with serum Mg above the median at bothvisits (HR = 0.58, 95% C.I. = 0.37–0.89).
We also compared this association to that of serum Mg with CHD deaths not classified asdefinite or possible SCD. Over the same time period, 868 individuals were classified as havingdied from CHD, but not SCD. In all three models, the association was present, but attenuated Am Heart J. Author manuscript; available in PMC 2011 September 1.
compared with the association of Mg level with SCD (Model 3 HR = 0.69, 95% C.I. = 0.56–0.84). Similar analyses were performed with dietary Mg as the exposure of interest. There was no evidence of an association between dietary Mg intake and risk of SCD in any of the modelsdescribed above (data not shown).
The main finding from this analysis was a significantly reduced risk of SCD in the highestquartile compared to the lowest quartile of serum Mg in a prospective cohort with over 173,000person years of follow-up. This association persisted after adjustment for the major predictorsof SCD and potential confounders (or mediators) of the Mg – SCD relationship, includinghypertension, diabetes, serum K, heart-rate adjusted QT interval, and use of diuretics. Theassociation was monotonic with a declining risk of SCD with each quartile of higher serumMg. This association did not differ by race, sex, prevalent CHD, use of diuretics, serum Klevel, or heart-rate adjusted QT interval. Despite these strong findings for serum Mg, weobserved no association between dietary Mg and risk of SCD. This is not surprising givenprevious reports from this cohort showing no association of dietary Mg with either incidenthypertension or CHD, despite associations of these outcomes with serum Mg. 9,10 The reliability coefficient for serum Mg was moderate at 0.69, 18 but we were still able to detecta strong association between low serum Mg and risk of SCD. Individuals who maintained serum Mg levels above the median value at two visits 3 years apart had the lowest risk of SCD.
Nevertheless, a limitation of our study was an inability to assess levels of serum Mg just priorto an event. It could be that a sudden drop in Mg is important. However, measurement justbefore SCD is not possible in a prospective study. Serial measurements of serum Mg overmany years would improve our ability to understand the impact of short-term transient changesin serum Mg on the risk of SCD.
The final model included adjustment for important predictors of SCD that may or may not beon the causal pathway of the Mg/SCD association. Hypertension is a known risk factor forSCD, 4,25,26 and a previous analysis in this population showed a modest association of lowserum Mg with incident hypertension.7 It is unclear to what degree depleted Mg affects riskof SCD through its influence on blood pressure and risk of hypertension, but it seems unlikelythat this is a major pathway given that adjustment had little impact on risk estimates.
Prescription of diuretics for hypertension presents an unusual circumstance whereby themedication use clearly reduces blood pressure at the same time it leads to excessive Mg lossthrough urinary excretion. 12,27 Previous case-control studies have shown an increased oddsof SCD in patients taking non-potassium-sparing diuretics. 28,29 Recent large clinical trials have not clearly shown diuretics to affect risk of death and cardiovascular events differentlyfrom beta blockers and ACE inhibitors. 30,31 Low serum Mg is often observed in conjunction with low serum K, and low levels of bothmicronutrients have been implicated in ECG changes, including a shortening of the QT interval.
32,33 In addition, serum Mg deficiency has been shown to lead to ventricular arrhythmias, themost common precursor to SCD. 12 In the multivariable-adjusted models, there was noassociation of serum K or heart rate-adjusted QT interval with SCD. At least one study hasshown that Mg may serve to block the short-term increase in intracellular calcium duringmyocardial ischemia, another precursor to arrhythmia. 15,34 The addition of these variables tothe models had little influence on the HRs of SCD by quartile of serum Mg, suggesting anindependent pathway whereby Mg influences risk of SCD.
Several studies have shown that serum Mg deficiency is frequently detected in patients whohave survived an MI. 13 Mg therapy during and after an MI has been shown to reduce the Am Heart J. Author manuscript; available in PMC 2011 September 1.
occurrence of ventricular arrhythmias, 13,14 and improve survival, in some, but not all studies.
14,15,36–39 In addition, autopsy studies have shown Mg in myocardial tissue of SCD cases is lower than in those dying of other causes. 13 Whether these lower levels of Mg are a cause orresult of SCD remain unknown. Low levels of serum Mg in the normal range, such as in thisstudy, may predispose individuals to serum Mg deficiency that could be detected with serialmeasurements. Additional prospective studies with more frequent measurements of serum Mgwould help address this question. Despite the positive results on the prevention of secondaryevents with Mg therapy, no clinical trials on the efficacy of Mg supplementation on the primaryprevention of SCD have been conducted.
In summary, this analysis is the first to demonstrate a significantly higher risk of SCD inindividuals in the lowest quartile of the normal physiologic range of serum Mg compared tothose in the highest quartile. This association is independent of other risk factors for SCD withonly marginal attenuation of the association after full adjustment for all known potentialpredictors. There is a similar, albeit weaker, increased risk of non-sudden CHD death inindividuals with low levels of serum Mg. The association reported here is moderately strong,and potentially modifiable. It becomes stronger in SCD cases that are unrelated to MI. A betterunderstanding of the causal mechanism will require more detailed studies of temporal changesin serum Mg levels just before SCD and related events. Replication of these findings in otherpopulations and additional research into the causal mechanism is warranted. If the association is consistent and replicated across other studies, it may warrant the initiation of clinical trialsto evaluate the impact of targeted Mg supplementation in individuals at higher risk for SCD.
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Figure 1. Adjusted* hazard ratios (95% CI) of definite or possible Sudden Cardiac Death by
categories of serum Magnesium at two ARIC visits
* Adjusted for age, race, sex, field center, HDL, LDL, TG, BMI, serum K, heart rate-adjusted
QT interval, physical activity, current smoking, pack years, ETOH intake, education, prevalent
diabetes, hypertension, and diuretics use Am Heart J. Author manuscript; available in PMC 2011 September 1.
p-value for difference
Serum Magnesium (meq/L)
Age-, race-, sex-, and field center-adjusted means or percentages of potential Sudden Cardiac Death risk factors by serum Magnesium quartiles Am Heart J. Author manuscript; available in PMC 2011 September 1.
p for linear trend
Serum Magnesium (meq/L)
(adjusted for age, race, sex, field center) (also adjusted for HDL, LDL, TG, serum K, heart rate-adjusted QT interval, physical activity, current (also adjusted for prevalent diabetes, hypertension, diuretics use) Crude Incidence Rate (per 1000 Person Yrs) smoking, pack years, ETOH intake, education) Crude incidence rate and adjusted hazard ratios (95% CI) of definite or possible Sudden Cardiac Death by baseline serum Magnesium quartiles in the ARIC Am Heart J. Author manuscript; available in PMC 2011 September 1.
In any given area the water quality is determined by local conditions. Pure rain water starts to absorb pol utants even as it fal s through the atmosphere. As it permeates through the soil and lies as ground water, its chemical composition is affected by the nature of the earth’s strata in the locality and the level of contaminants these contain. The various treatments that are used to produc