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O R I GI N AL PA P ER

Serum Calcium Levels and Hypertension Among US AdultsCharumathi Sabanayagam, MD, PhD; Anoop Shankar, MD, PhD

From the Department of Community Medicine, West Virginia University School of Medicine, Morgantown, WV

Serum calcium levels have been shown to be associated withcardiovascular disease (CVD); however, it is not clear whetherserum calcium levels are related to hypertension, a risk factorfor CVD. The authors examined the association betweenserum calcium and hypertension in a representative sampleof US adults. A cross-sectional study of 12,405 third NationalHealth and Nutrition Examination Survey participants20 years and older was conducted. Serum total and ionizedcalcium levels were analyzed as quartiles. The main outcomeof interest was hypertension (n=3437), dened as self-reported use of antihypertensive medication and ⁄ or systolicblood pressure ! 140 mm Hg or diastolic blood pressure! 90 mm Hg. Elevated serum total calcium levels were posi-

tively associated with hypertension, independent of potentialconfounders including C-reactive protein, estimated glomer-ular ltration rate, serum albumin, 25(OH)D, and phospho-rous. Compared with the lowest quartile of serum totalcalcium (referent category), the multivariable odds ratio (95%condence interval) of hypertension was 1.49 (1.15–1.93) forthe highest quartile ( P =.005). This association persisted insubgroup analyses stratied by sex, age, and race-ethnicity.In contrast, serum ionized calcium levels were not associatedwith hypertension. Higher serum total calcium levels arepositively associated with hypertension in a representativesample of US adults. J Clin Hypertens (Greenwich).2011;13:716–721. Ó 2011 Wiley Periodicals, Inc.

Hypertension, a major modiable risk factor for car-diovascular disease, is estimated to affect nearly onethird of adults in the United States. 1 Serum calciumplays an important pathophysiologic role in cardiovas-cular 2 and kidney function. 3 However, the associationbetween serum calcium levels and hypertension is notclear. Previous studies that examined the associationbetween serum calcium and hypertension have shownmixed results. 4–11 While some studies reported a posi-tive association between serum calcium and hyper-tension, 6–9 others reported an inverse 4 or noassociation. 5,10,11 Further, the majority of the studiesthat examined the association between serum calciumand hypertension were either limited by small samplesize9 or by inadequate adjustment for confounders,including serum albumin, 5,6 glomerular ltration rate(GFR), and serum phosphorous. 6,8,9 In this context,we examined the association between serum ionizedcalcium, total calcium, and hypertension in a nation-ally representative sample of adults in the UnitedStates after adjusting for important confounders.

METHODSThe data for the current study are derived from the

third National Health and Nutrition ExaminationSurvey (NHANES III). Detailed description of the com-plex survey design and methods have been publishedelsewhere and are available online. 12 In brief, NHANESemployed a stratied, multistage, probability samplerepresentative of the civilian noninstitutionalized US

population with oversampling of non-Hispanic blacksand Mexican Americans to ensure adequate representa-tion of these groups. Eligible participants were requiredto sign an informed consent form and ethics approvalwas obtained from the Human Subjects Committee inthe US Department of Health and Human Service.

Of the 15,951 participants 20 years and older in thecurrent study, serum calcium levels were available in13,910 participants. After excluding those with missingvalues of blood pressure (BP) (n=24), those with self-reported cardiovascular disease (CVD) (n=1148), andthose with missing values for other covariates includedin the multivariable analysis including education, bodymass index (BMI), serum phosphorous, albumin, totaland high-density lipoprotein (HDL) cholesterol, plasmaglucose, and glycated hemoglobin (n=333), 12,405were available for the current analysis.

Assessment of outcomeThree sets of BP measurements were taken using amercury sphygmomanometer by a physician at theMedical Examination Center (MEC) according to thestandardized BP measurement protocols as recom-mended by the American Heart Association. The aver-age of the 3 measures was taken as the systolic anddiastolic BP of the participant for the current analysis.Patients were considered to have hypertension if theyreported using current BP-reducing medication and ⁄ orhad systolic BP ! 140 mm Hg and ⁄ or diastolic BP! 90 mm Hg.

Measurement of Exposure VariablesInformation on participant’s demographic characteris-tics, educational attainment, cigarette smoking, alcoholconsumption, physical activity, history of diabetes,hypertension, and medication use was assessed using astandardized questionnaire. 12 Detailed description

Address for correspondence: Anoop Shankar, MD, PhD, Departmentof Community Medicine, West Virginia University School of Medicine,Morgantown, WV 26506-9190E-mail: [email protected]

Manuscript received: February 15, 2011; Revised: April 27, 2011; Accepted: May 13, 2011DOI: 10.1111/j.1751-7176.2011.00503.x

716 The Journal of Clinical Hypertension Vol 13 | No 10 | October 2011 Ofcial Journal of the American Society of Hypertension, Inc.

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about the blood collection, processing, and quality-control checks are provided in the LaboratoryProcedures Manual. 13 Laboratory tests relevant to thisanalysis included serum total and ionized calcium,phosphorous, albumin, 25(OH) D, total and HDLcholesterol, glucose, glycated hemoglobin, creatinine,

and C-reactive protein, and measurement of laboratoryvariables has been published before. 14 Serum total cal-cium, phosphorous, and albumin were measured usinga Hitachi 737 Analyzer (Boehringer Mannheim Diag-nostics, Indianapolis, IN). Serum ionized calcium wasmeasured using a NOVA 7+7 Electrolyte Analyzer(Nova Biomedical; Waltham, MA) adjusting the mea-sured value for pH. Serum 25(OH) D was measuredusing a radioimmunoassay kit (Diasorin, Stillwater,MN) at the National Center for EnvironmentalHealth, CDC, Atlanta, GA. Diabetes was dened as aserum glucose ! 126 mg ⁄ dL after fasting for a mini-mum of 8 hours, a serum glucose ! 200 mg ⁄ dL for

patients who fasted<

8 hours before their NHANESvisit, or self-reported current use of oral hypoglycemicmedication or insulin. Serum creatinine was measuredusing a modied kinetic Jaffe reaction and GFR wasestimated from serum creatinine using the Modica-tion of Diet in Renal Disease equation. 15

Statistical AnalysisSerum total calcium levels were categorized into quar-tiles (< 2.25, 2.25–2.30, 2.31–2.37, > 2.37 mmol ⁄ L).We compared selected baseline characteristics of thestudy population by quartiles of total calcium usingchi-square or analysis of variance as appropriate forthe variable. We examined the association betweenquartiles of total calcium and hypertension in 3 multi-variable-adjusted logistic regression models: model 1adjusted for age (years) and sex (women, men); model2 additionally adjusted for race-ethnicity (non-His-panic whites, non-Hispanic blacks, Mexican Ameri-cans, others), smoking (never, former, currentsmoker), current alcohol intake (absent, present), BMI(kg ⁄ m2 ), physical inactivity (absent, present), diabetesmellitus (absent, present), serum total cholesterol(mg ⁄ dL), and HDL cholesterol (mg ⁄ dL); model 3adjusted for variables in model 2 plus C-reactiveprotein (CRP) (mg ⁄ dL), estimated GFR (mL ⁄

min ⁄ 1.73 m 2 ), serum albumin (g ⁄ L), serum phospho-rous (mg ⁄ dL), and serum 25(OH)D (ng ⁄ mL). We per-formed tests for linear trend by modeling total calciumquartiles as an ordinal variable in the correspondingmultivariable logistic regression models. We also ana-lyzed total calcium as a continuous variable (per stan-dard deviation [SD] change). We then repeated theabove analyses using serum ionized calcium quartiles(< 1.21, 1.21–1.23, 1.24–1.26, > 1.26 mmol ⁄ L). Sincethere was no signicant association between serum ion-ized calcium levels and hypertension, we focused oursubsequent analyses on total calcium levels. To examinethe consistency of the association between total calciumand hypertension, we performed subgroup analyses

stratied by age, sex, and race-ethnicity. Interactionswere formally evaluated by including cross-productinteraction terms in the corresponding multivariablemodels. All analyses were conducted by includingsampling weights 13 to account for unequal probabilitiesof selection, oversampling, and non-response using

SUDAAN (version 8.0; Research Triangle Institute,Research Triangle Park, NC) and SAS (version 9.2; SASInstitute, Cary, NC) software. SEs were estimated usingthe Taylor series linearization method.

RESULTSTable I shows the baseline characteristics of the studypopulation. Compared with those in the lowest quar-tile of total calcium, those in the highest quartile weremore likely to be younger, had higher levels of systolicand diastolic BP, total and HDL cholesterol, serumphosphorous, albumin, and 25(OH)D levels; were lesslikely to be female and non-Hispanic white; and had

lower levels of BMI and CRP.Table II shows the association between serum totalcalcium, ionized calcium levels, and hypertension.Increasing categories of total calcium were positivelyassociated with hypertension in all 3 regression models(P< .01). The positive association between total cal-cium and hypertension persisted when total calciumwas analyzed as a continuous variable (per SDincrease). In contrast, no statistically signicant associ-ation was observed between serum ionized calciumand hypertension in any model.

In subgroup analyses, the positive associationbetween total calcium and hypertension was consis-tently present in men and women (Table III), those 60years and older, and those younger than 60 years(Table IV). When stratied by race-ethnicity (Table V),the association was stronger in non-Hispanic whitesand non-Hispanic blacks but not signicant amongother race-ethnicities. There was no interaction by sex(P=.55), age (P=.43), or race-ethnicity ( P=0.26) in theassociation between total calcium and hypertension.

DISCUSSIONHigher serum total calcium levels were found to bepositively associated with hypertension in a representa-tive sample of US adults without CVD. This associa-tion was independent of age, sex, race-ethnicity,smoking, alcohol intake, BMI, physical activity, diabe-tes mellitus, total cholesterol, HDL cholesterol, CRP,estimated GFR, serum albumin, serum vitamin D, andserum phosphorous. Further, the positive associationbetween serum total calcium and hypertension wasconsistently present in subgroups of sex, age, and race-ethnicity and was persistent when serum calcium wasanalyzed as a continuous variable. In contrast, serumionized calcium was not signicantly associated withhypertension.

Serum total calcium is the total sum of 3 forms,ionized or free, protein-bound and soluble formcomplexed with anions such as bicarbonate and

Ofcial Journa l o f the American Soc ie ty o f Hyper tension, Inc . The Journal of Cl in ical Hypertens ion Vol 13 | No 10 | October 2011 717

Serum Calcium and Hypertension | Sabanayagam and Shankar

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phosphate. Around 50% of total serum calcium is inthe ionized form, 40% in the bound form mainly toalbumin, and 10% bound to anions. 16 Ionized cal-cium, the physiologically active form in the blood, isan accurate indicator of calcium homeostasis. 17 How-ever, ionized calcium measurement is more expensiveand is affected by a number of factors includingmethod of collection, choice of anticoagulant, pHchanges, and variability of reference range used bydifferent laboratories using different analyzers. 18 Totalcalcium measurement is least affected by thesechanges, correlates well with ionized calcium measure-ment, and is routinely used in clinical practice toassess calcium status in health and disease. Our studywas unique in that we examined the associationbetween both serum total and ionized calcium andhypertension separately.

In the current study, we found that serum total cal-cium levels were positively associated with hyperten-sion, whereas ionized calcium levels were not. Themagnitude of association between serum total calciumand hypertension, its persistence after multivariate

adjustment for potential confounders, and the consis-tency of the association in subgroups of sex, age, andrace-ethnicity render support to the validity of ourstudy ndings. The nding of a null associationbetween serum ionized calcium and hypertension wasalso similarly robust.

An association between serum total calcium andhypertension is plausible, including a direct effect on vas-culature by enhanced vascular resistance, 19 alteration inextracellular binding of calcium, 20 interaction betweenserum calcium, and other cations such as sodium, potas-sium and magnesium, 21 renal vasoconstriction causingkidney dysfunction, 22 and hyperactivity of renin-angio-tensin system from hyperparathyroidism. 23 Animalstudies have demonstrated elevated total calcium con-centrations but normal ionized calcium levels in sponta-neously hypertensive rats. 24 Treatment of hypertensivepatients with calcium channel blockers lower BP byinhibiting transmembrane transport of calcium throughmembrane channels. 25

Our nding of a positive association between ele-vated serum total calcium levels and hypertension is

TABLE I. Baseline Characteristics of the Study Population by Quartiles of Total Calcium

CharacteristicsQuartile 1(n=3167)

Quartile 2(n=2816)

Quartile 3(n=3306)

Quartile 4(n=3116) P Value a

Unweighted sample size Age, y 45.12Æ0.64 44.71 Æ0.49 42.39 Æ0.57 42.18 Æ0.52 < .0001

Female, % 58.22 Æ1.51 57.26 Æ1.50 49.00 Æ1.63 47.12 Æ1.38 < .0001Smoking categories, % .1985

Never smoker 47.41 Æ1.41 46.36 Æ1.41 49.69 Æ1.44 48.12 Æ1.15Former smoker 22.58 Æ1.10 24.38 Æ0.99 23.65 Æ1.08 24.77 Æ1.24Current smoker 30.01 Æ1.25 29.26 Æ1.35 26.66 Æ1.40 27.11 Æ1.22

Current drinker, % 53.68 Æ1.96 53.24 Æ1.81 56.70 Æ1.72 55.53 Æ1.74 .2121Race-ethnicity, % .0001

Non-Hispanic whites 77.36 Æ1.26 78.94 Æ1.46 77.38 Æ1.71 73.87 Æ1.76Non-Hispanic blacks 8.98 Æ0.59 9.70 Æ0.80 9.85 Æ0.68 13.10 Æ1.01Mexican Americans 5.47 Æ0.50 5.47 Æ0.63 4.92 Æ0.44 4.69 Æ0.45Others 8.19 Æ1.18 5.90 Æ0.82 7.84 Æ1.17 8.34 Æ1.19

Diabetes mellitus, % 5.48 Æ0.63 6.01 Æ0.64 5.37 Æ0.57 5.98 Æ0.57 .7784Physical inactivity, % 49.13 Æ1.46 46.66 Æ1.64 46.65 Æ1.59 49.47 Æ1.75 .3435Body mass index, kg ⁄ m 2 26.53 Æ0.15 26.44 Æ0.19 26.61 Æ0.19 26.34 Æ0.15 .0293

Systolic blood pressure,mm Hg

120.98 Æ0.68 120.88 Æ0.63 121.66 Æ0.51 122.71 Æ0.58 .0008

Diastolic blood pressure,mm Hg

73.18 Æ0.31 73.95 Æ0.29 74.62 Æ0.30 75.07 Æ0.34 < .0001

Total cholesterol, mg ⁄ dL 197.83 Æ1.17 201.82 Æ1.33 203.46 Æ1.30 209.13 Æ1.16 < .0001HDL cholesterol, mg ⁄ dL 50.64 Æ0.47 50.81 Æ0.54 50.82 Æ0.57 51.06 Æ0.45 .0003Serum phosphorous, mg ⁄ dL 3.39 Æ0.01 3.41 Æ0.02 3.46 Æ0.02 3.51 Æ0.02 < .0001Serum albumin, g ⁄ L 4.02 Æ0.03 4.12 Æ0.02 4.25 Æ0.02 4.34 Æ0.02 < .0001Serum C-reactive protein,

mg ⁄ dL0.46 Æ0.02 0.40 Æ0.01 0.37 Æ0.01 0.36 Æ0.02 < .0001

Estimated GFR,mL ⁄ min ⁄ 1.73m 2

97.38 Æ0.92 93.80 Æ0.77 93.56 Æ0.63 94.73 Æ0.82 .08

Serum 25(OH) D, ng ⁄ mL 28.32 Æ0.38 29.38 Æ0.51 30.20 Æ0.51 30.17 Æ0.45 < .0001

Abbreviations: HDL, high-density lipoprotein; GFR, glomerular ltration rate.a

P value represents differences in means (SD) or proportions, usinganalysis of variance or chi-square test.



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consistent with several previous studies. 1,6–926 Jordeand colleagues, in a large cross-sectional study of 12,865 men and 14,293 women in Norway, reportedthat serum total calcium was positively associated withhypertension in both men and women after adjustingfor age, BMI, heart rate, and cholesterol. 6 Kestelootand associates, in a cross-sectional study of 4167 menand 3891 women in Belgium, documented that higherserum total calcium was positively associated withhypertension in both men and women after adjustingfor serum creatinine and other confounders. 7 Philipsand colleagues, 8 in a cross-sectional study involving

7735 healthy middle-aged British men, reported thathigher serum total calcium was associated with hyper-tension even after adjusting for serum albumin. Rinnerand coworkers, 9 in a small sample of 182 Dutchadults, reported that higher serum total calcium waspositively associated with hypertension after adjustingfor age, BMI, and albumin and in the subgroup analy-sis stratied by sex, the association was found to bestronger in women than in men. In our study, consis-tent with the majority of literature in this eld, 6,7,26

we found that higher serum total calcium levels werepositively associated with hypertension in both men

TABLE II. Association Between Serum Total and Ionized Calcium Levels and Hypertension

Cases, No. Age- and Sex-Adjusted

OR (95% CI)Multivariate Model 1

OR (95% CI) a

Multivariate Model 2OR (95% CI) b

Ionized calcium, mmol ⁄ LQuartile 1 ( < 1.21 mmol ⁄ L) 2845 (836) 1.00 (Referent) 1.00 (Referent) 1.00 (Referent)

Quartile 2 (1.21–1.23 mmol ⁄ L) 3170 (856) 0.87 (0.69–1.08) 0.87 (0.69–1.09) 0.88 (0.70–1.10)Quartile 3 (1.24–1.26 mmol ⁄ L) 3360 (855) 0.96 (0.79–1.17) 0.92 (0.76–1.13) 0.93 (0.75–1.14)Quartile 4 ( > 1.26 mmol ⁄ L) 3030 (890) 1.02 (0.80–1.32) 0.98 (0.75–1.28) 0.97 (0.74–1.27)P (trend) .66 .99 .90

Per SD increase in ionized calcium 12,405 (3437) 1.02 (0.93–1.10) 1.00 (0.92–1.09) 0.99 (0.91–1.08)Total calcium, mmol ⁄ L

Quartile 1 ( < 2.25 mmol ⁄ L) 3167 (866) 1.00 (Referent) 1.00 (Referent) 1.00 (Referent)Quartile 2 (2.25–2.30 mmol ⁄ L) 2816 (766) 1.20 (0.95–1.51) 1.13 (0.90–1.42) 1.13 (0.90–1.41)Quartile 3 (2.31–2.37 mmol ⁄ L) 3306 (861) 1.30 (1.06–1.59) 1.17 (0.97–1.42) 1.15 (0.95–1.40)Quartile 4 ( > 2.37 mmol ⁄ L) 3116 (944) 1.69 (1.33–2.13) 1.52 (1.19–1.94) 1.49 (1.15–1.93)P (trend) < .0001 .002 .005

Per SD increase in total calcium 12,405 (3437) 1.20 (1.10–1.32) 1.16 (1.07–1.27) 1.15 (1.05–1.26)

Abbreviations: CI, condence interval; OR, odds ratio; SD, standard deviation. a Adjusted for age (years), sex (men, women), race-ethnicity(non-Hispanic whites, non-Hispanic blacks, Mexican Americans, others), smoking categories (never, former, current), current drinker (absent, pres-ent), body mass index categories ( < 25, 25–29, ! 30 kg ⁄ m 2 ), physical inactivity (absent, present), diabetes (absent, present), total cholesterol (mg ⁄ dL),and high-density lipoprotein cholesterol (mg ⁄ dL). b Adjusted for all variables in model 2, plus C-reactive protein (mg ⁄ dL), estimated GFR(mL ⁄ min ⁄ 1.73 m 2 ), serum albumin (g ⁄ L), serum phosphorous (mg ⁄ dL), serum 25(OH)D (ng ⁄ mL).

TABLE III. Association Between Total Calcium Levels and Hypertension by Sex

Total Calcium, mmol ⁄ L Cases, No. Age- and Sex-Adjusted


OR (95% CI) a


MenQuartile 1 ( < 2.25 mmol ⁄ L) 1334 (442) 1.00 (Referent) 1.00 (Referent) 1.00 (Referent)Quartile 2 (2.25–2.30 mmol ⁄ L) 1235 (383) 1.21 (0.82–1.79) 1.12 (0.75–1.68) 1.11 (0.75–1.65)Quartile 3 (2.31–2.37 mmol ⁄ L) 1582 (414) 1.22 (0.85–1.76) 1.08 (0.75–1.55) 1.06 (0.74–1.52)

Quartile 4 ( > 2.37 mmol ⁄ L) 1563 (388) 1.53 (1.08–2.18) 1.39 (0.95–2.04) 1.36 (0.93–2.00)P (trend) .02 .12 .16

WomenQuartile 1 ( < 2.25 mmol ⁄ L) 1833 (424) 1.00 (Referent) 1.00 (Referent) 1.00 (Referent)Quartile 2 (2.25–2.30 mmol ⁄ L) 1581 (383) 1.15 (0.85–1.56) 1.11 (0.80–1.52) 1.13 (0.83–1.54)Quartile 3 (2.31–2.37 mmol ⁄ L) 1724 (447) 1.26 (0.92–1.75) 1.18 (0.87–1.61) 1.21 (0.90–1.62)Quartile 4 ( > 2.37 mmol ⁄ L) 1553 (556) 1.64 (1.23–2.18) 1.48 (1.10–1.98) 1.50 (1.10–2.04)P (trend) .001 .009 .01

Abbreviations: CI, condence interval; OR, odds ratio. a Adjusted for age (years), race-ethnicity (non-Hispanic whites, non-Hispanic blacks, Mexican Americans, others), smoking categories (never, former, current), current drinker (absent, present), body mass index categories ( < 25, 25–29,! 30 kg ⁄ m 2 ), physical inactivity (absent, present), diabetes (absent, present), total cholesterol (mg ⁄ dL), and high-density lipoprotein cholesterol(mg ⁄ dL). b Adjusted for all variables in model 2, plus C-reactive protein (mg ⁄ dL), estimated glomerular ltration rate (mL ⁄ min ⁄ 1.73 m 2 ), serumalbumin (g ⁄ L), serum phosphorous (mg ⁄ dL), serum 25(OH)D (ng ⁄ mL); P interaction (total calcium quartiles Â female)=0.55.



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and women. In contrast to serum calcium, dietary cal-cium has been shown to be inversely associated withhypertension. 27–30

In the current study, we found no associationbetween serum ionized calcium and hypertension. Thisis in keeping with 3 previous reports that suggested asimilar null association between serum ionized calciumlevels and hypertension, including the study by Buck-

ley and colleagues 31 in 325 male industrial workers;the study by Andersen and associates in 70 men andwomen from Denmark 32 ; and the study by Resnik andcolleagues 33 in a clinical sample of 200 normotensiveand hypertensive patients. However, in contrast to ourndings, some previous studies have reported aninverse association between serum ionized calcium andhypertension. Folsom and coworkers 4 reported an

TABLE V. Association Between Total Calcium Levels and Hypertension by Race-Ethnicity

Total Calcium, mmol ⁄ L Cases, No. Age- and Sex- Adjusted


OR (95% CI) a


Non-Hispanic whitesQuartile 1 ( < 2.25 mmol ⁄ L) 1323 (420) 1.00 (Referent) 1.00 (Referent) 1.00 (Referent)Quartile 2 (2.25–2.30 mmol ⁄ L) 1188 (376) 1.28 (0.94–1.75) 1.20 (0.89–1.62) 1.19 (0.88–1.60)Quartile 3 (2.31–2.37 mmol ⁄ L) 1370 (423) 1.43 (1.11–1.84) 1.27 (1.00–1.59) 1.23 (0.97–1.55)Quartile 4 ( > 2.37 mmol ⁄ L) 1163 (418) 1.79 (1.31–2.45) 1.59 (1.16–2.18) 1.51 (1.09–2.09)

P (trend) .0001 .004 .02Non-Hispanic blacks

Quartile 1 ( < 2.25 mmol ⁄ L) 743 (228) 1.00 (Referent) 1.00 (Referent) 1.00 (Referent)Quartile 2 (2.25–2.30 mmol ⁄ L) 713 (216) 1.24 (0.95–1.63) 1.22 (0.92–1.63) 1.21 (0.91–1.60)Quartile 3 (2.31–2.37 mmol ⁄ L) 910 (264) 1.07 (0.80–1.43) 1.03 (0.75–1.41) 1.00 (0.76–1.32)Quartile 4 ( > 2.37 mmol ⁄ L) 1071 (342) 1.46 (1.15–1.87) 1.37 (1.07–1.75) 1.32 (1.03–1.70)P (trend) .02 .08 .12

Other race-ethnicityQuartile 1 ( < 2.25 mmol ⁄ L) 1101 (218) 1.00 (Referent) 1.00 (Referent) 1.00 (Referent)Quartile 2 (2.25–2.30 mmol ⁄ L) 915 (174) 0.66 (0.39–1.12) 0.60 (0.35–1.02) 0.57 (0.33–0.98)Quartile 3 (2.31–2.37 mmol ⁄ L) 1026 (174) 0.73 (0.43–1.24) 0.70 (0.41–1.20) 0.63 (0.36–1.09)Quartile 4 ( > 2.37 mmol ⁄ L) 882 (184) 1.04 (0.60–1.81) 1.00 (0.57–1.76) 0.85 (0.47–1.54)P (trend) .91 .99 .57

Abbreviations: CI, condence interval; OR, odds ratio; a Adjusted for age (years), sex (men, women), smoking categories (never, former, current),current drinker (absent, present), body mass index categories ( < 25, 25–29, ! 30 kg ⁄ m 2 ), physical inactivity (absent, present), diabetes (absent,present), total cholesterol (mg ⁄ dL), and high-density lipoprotein cholesterol (mg ⁄ dL). b Adjusted for all variables in model 2, plus C-reactive protein(mg ⁄ dL), estimated glomerular ltration rate (mL ⁄ min ⁄ 1.73 m 2 ), serum albumin (g ⁄ L), serum phosphorous (mg ⁄ dL), serum 25(OH)D (ng ⁄ mL);P interaction (serum calcium quartiles Â race-ethnicity categories)=0.26.

TABLE IV. Association Between Total Calcium Levels and Hypertension by Age Groups

Total Calcium, mmol ⁄ L Cases, No. Age- and Sex-Adjusted


OR (95% CI) a


Age ! 60 yQuartile 1 ( < 2.25 mmol ⁄ L) 1000 (557) 1.00 (Referent) 1.00 (Referent) 1.00 (Referent)

Quartile 2 (2.25–2.30 mmol ⁄ L) 793 (470) 1.21 (0.89–1.64) 1.14 (0.82–1.58) 1.13 (0.82–1.56)Quartile 3 (2.31–2.37 mmol ⁄ L) 809 (489) 1.23 (0.95–1.61) 1.18 (0.91–1.54) 1.15 (0.89–1.48)Quartile 4 ( > 2.37 mmol ⁄ L) 812 (555) 1.88 (1.49–2.38) 1.73 (1.34–2.22) 1.65 (1.27–2.14)P (trend) < .0001 < .0001 .0007

Age < 60 yQuartile 1 ( < 2.25 mmol ⁄ L) 2167 (309) 1.00 (Referent) 1.00 (Referent) 1.00 (Referent)Quartile 2 (2.25–2.30 mmol ⁄ L) 2023 (296) 1.16 (0.82–1.62) 1.11 (0.80–1.55) 1.10 (0.79–1.52)Quartile 3 (2.31–2.37 mmol ⁄ L) 2497 (372) 1.24 (0.94–1.64) 1.09 (0.83–1.43) 1.09 (0.84–1.41)Quartile 4 ( > 2.37 mmol ⁄ L) 2304 (389) 1.49 (1.04–2.12) 1.36 (0.95–1.95) 1.34 (0.93–1.94)P (trend) .03 .12 .16

Abbreviations: CI, condence interval; OR, odds ratio. a Adjusted for sex (women, men), race-ethnicity (non-Hispanic whites, non-Hispanic blacks,Mexican Americans, others), smoking categories (never, former, current), current drinker (absent, present), body mass index categories ( < 25, 25–29,! 30 kg ⁄ m 2 ), physical inactivity (absent, present), diabetes (absent, present), total cholesterol (mg ⁄ dL), and high-density lipoprotein cholesterol(mg ⁄ dL). b Adjusted for all variables in model 2, plus C-reactive protein (mg ⁄ dL), estimated glomerular ltration rate (mL ⁄ min ⁄ 1.73 m 2 ), serum albu-

min (g ⁄

L), serum phosphorous (mg ⁄

dL), serum 25(OH)D (ng ⁄

mL); P interaction (serum calcium quartilesÂ

age)=0.43.



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inverse association between serum ionized calcium andhypertension in a small sample of 56 patients in Min-nesota. Vargas and coworkers, 11 in a previous studyusing NHANES III data, reported an inverse associa-tion between serum ionized calcium and hypertensionin the subgroup of younger Mexican-American men

only in the dataset. Finally, there is some evidence tosuggest that the association between ionized calciumand hypertension may vary by plasma renin levels.Hunt and colleagues, 34 in a study involving 875 nor-motensive patients observed a positive associationbetween ionized calcium and BP among the high reningroup and an inverse association between ionized cal-cium and BP among the low renin group. This differ-ential relationship of ionized calcium with BP acrosscategories of plasma renin activity suggests that theassociation between ionized calcium and hypertensionis modied by plasma renin and that ionized calciumin isolation may not be independently related to

BP.30,34

In the current study, we did not have mea-surements of plasma renin levels to validate or dis-prove this hypothesis.

LIMITATIONSThe major advantages of our study include the largesample size, vigorous methodology, and availability of both ionized and total calcium measurements. Thecross-sectional nature of the study limits making cau-sal inferences. Further, bias due to unmeasured con-founding, for example, plasma renin activity, couldnot be excluded.

CONCLUSIONSElevated total calcium levels were found to be posi-tively associated with hypertension in a nationally rep-resentative sample of US adults.

Acknowledgments and disclosures: This study was partially funded by an American Heart Association National Clinical Research Program grant (AS) and NIH/NIEHS grant 1R03ES018888-02(AS). There are no conicts of interest related to this manuscript.

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