J Cardiol 2002 Mar; 39（3）: 151 – 157

Serum Calcium Concentration andCarotid Artery Plaque: A Population-Based Study
Nobukazu
Yuko

ISHIZAKA, MD
ISHIZAKA, MD＊1

Eiko TAKAHASHI, MD＊1
Ei-ichi TOODA, RMS＊1
Hideki HASHIMOTO, MD＊2
Ryozo

NAGAI, MD, FJCC

MinoruYAMAKADO, MD＊1

Abstract ─────────────────────────────────────────────────────────────────────────────────────────────────────────────────────────────────────────────────────────────────────
Objectives. Serum calcium level may be associated with the morbidity and mortality of cerebrovascularand cardiovascular diseases. However, only a few large-scale population studies have been performed toinvestigate the association between serum calcium and carotid plaque.
Methods. A retrospective cross-sectional study was performed on the subjects who underwent general
health screening tests including ultrasonographic evaluation of the carotid artery between 1994 and 2000 at
our institute. Before the statistical analysis, all serum calcium values were adjusted for the serum albumin
concentration.
Results. Of 5,732 subjects enrolled in the present study, 3,785 were male and 1,947 were female, and（23%）
subjects. Serum
were aged 22−88 years（median 57 years）. Carotid plaque was identified in 1,313
calcium concentration was slightly greater in the subjects with plaque than in those without（2.28 ± 0.8 vs2.27 ± 0.7 mmol/l, p ＜ 0.001 ; unpaired t-test）. Multivariate logistic regression analysis including confounding risk factors revealed that serum calcium is an independent positive predictor for carotid plaquewith an odds ratio of 1.70
［95% confidence interval（CI）: 1.50−1.92］for each increase of 1 mg/dl. Maleand female subjects in the highest quartiles of serum calcium concentrations had a greater risk of carotid
plaque with odds ratios of 1.52
（95% CI 1.35−1.71, p ＜ 0.01）and 1.57（95% CI 1.27−1.92, p ＜ 0.05）,
respectively, compared to the subjects in the lowest quartiles of calcium concentrations.
Conclusions. These findings indicate that serum calcium is an independent risk factor for carotid plaque.
─────────────────────────────────────────────────────────────────────────────────────────────────────────────────────J Cardiol 2002 Mar ; 39
（3）
: 151−157

Key Words
Carotid arteries
Risk factors

Atherosclerosis

INTRODUCTION
Several epidemiological studies have shown thathigher serum calcium concentration is associatedwith increased risk of cardiovascular and cere-

PlaqueCalcium

brovascular diseases1,2）. Serum calcium is an independent, prospective risk factor for myocardial
infarction in middle-aged men3）. The risk of premature death in men less than 50 years of age increases with rising serum calcium concentration, even──────────────────────────────────────────────
東京大学大学院医学系研究科 循環器内科 : 〒 113−8655 東京都文京区本郷 7−3−1 ; ＊ 1 三井記念病院 総合健診センター，東京 ; ＊ 2 帝京大学医学部 公衆衛生学，東京
Department of Cardiovascular Medicine, University of Tokyo, Graduate School of Medicine, Tokyo ; ＊ 1Center for Multiphasic Health
Testing and Services, Mitsui Memorial Hospital, Tokyo ; ＊ 2Department of Hygiene and Public Health, Teikyo University School of
Medicine, Tokyo
Address for correspondence : ISHIZAKA N, MD, Department of Cardiovascular Medicine, University of Tokyo, Graduate School of
Medicine, Hongo 7−3−1, Bunkyo-ku, Tokyo 113−8655
Manuscript received November 21, 2001 ; revised January 4, 2002 ; accepted January 4, 2002
RMS ＝ registered medical sonographer

151

152

Ishizaka, Ishizaka, Takahashi et alwithin the normal range, and this increase seems to
be largely due to the increased mortality from cardiovascular diseases1）. As serum calcium is associated with several conventional risk factors for atherosclerosis, such as blood pressure, total cholesterol, and triglycerides2）, increases in serum calcium concentration may be related to a metabolic
syndrome that promotes atherogenesis, and may
subsequently increase cardiovascular morbidity andmortality.
The correlation between serum calcium concentration and carotid atherosclerosis has beenassessed in patients with hyperparathyroidism anddialysis patients4,5）. However, little information isavailable about the relationship between carotid
plaque and serum levels of calcium corrected foralbumin, or ionized calcium. The present study
investigated whether there is any association
between serum levels of albumin-corrected calcium
and carotid plaque by analyzing data from subjects
who had undergone general health-screening tests
at our institute.
METHODS
Study subjects
Between August 1994 and December 2000,
5,732 subjects underwent general health screening
tests including high resolution B-mode carotid
ultrasonography and serum calcium test at theCenter for Multiphasic Health Testing and Services,
Mitsui Memorial Hospital. Clinical information
was obtained by physical examination and chart
review of each patient s history, including sex, age,and smoking habits.
Carotid ultrasoundThe ultrasound protocol involved the scanning of
the internal（bulbous and distal segments）and common carotid arteries bilaterally using high-resolution B-mode carotid ultrasound（ Sonolayer
SSA270A, Toshiba）equipped with a 7.5-MHztransducer（ PLF-703ST, Toshiba）. The intimamedia thickness was measured with computerassisted methods by experienced sonographers who
were unaware of the subjects clinical and laboratory characteristics. Plaque was defined as a clearly
identified focal thickening of the intima-media
layer with a thickness of ＞
− 1.3 mm at the common
or internal carotid arteries or the carotid bulb6）.

Clinical characteristics and laboratory tests
Body mass index was calculated as［weight（kg）］/
2［height（m）］. Blood samples of the subjects wereobtained after an overnight fast. Total cholesterol（TC）, high-density lipoprotein cholesterol（HDLC）, and triglyceride levels were determined enzymatically, and hemoglobin A1C was determined bylatex agglutination immunoassay. The serum calcium concentrations used for the statistical assessment in the present study were all adjusted for theserum albumin concentration. Based on the same
study population, the following formula was empirically obtained using a linear regression model withordinary least square estimation by the remodelingof the correction formula of Payne et al. 7）: Calcium（adjusted）＝［calcium（analyzed）−（albumin × 0.5387）＋ 2.2684 − 1.9190］, where
0.5387 was the determination coefficient of theregression, 2.2684 was the mean analyzed calcium
concentration in the population, and 1.9190 was they intercept. Pearson s correlation coefficients forthe relationships between serum calcium and serum
albumin before and after the correction were 0.418
and 0.00, respectively.
Statistical analysis
Statistical analysis was performed using computer software, Statistica ver. 5J（StatSoft Inc.）. Sex
and smoking status were included as categoricalvariables. Other variables were included as continuous variables.
RESULTS
Baseline characteristics of the study population
Baseline clinical characteristics and laboratory
data for the study population are illustrated inTable 1. In 5,732 subjects enrolled in the present
study, 3,785（66%）
were male subjects, 1,947 werefemale subjects, and the age range was 22−88
years（median 57 years）. Serum calcium concentrations were 1.95−2.72 mmol/l（7.81−10.90 mg/dl）
with a median of 2.26 mmol/l（9.06 mg/dl）. Serum
calcium concentration was slightly greater in thesubjects with carotid plaque（mean ± SE : 2.28 ±0.08 mmol/l）than those without（ 2.27 ± 0.07
mmol/l）, and the difference was statistically significant by unpaired t-test（p ＜ 0.001）.
Relationship between serum calcium and risk
factors for atherosclerosis
At first, we investigated whether there was a sigJ Cardiol 2002 Mar; 39（3）: 151 – 157

Serum Calcium Concentration and Carotid Artery Plaque153

Table 1 Clinical characteristics and laboratory data of the study population
Variable
Age（yr）

All subjects（n＝5,732）

No plaque（n＝4,419）

Plaque（n＝1,313）

57±10

55±10

64±9†

Male（%）

66

63

77

Height（m）

1.63±0.09

1.63±0.09

1.63±0.08

Weight（kg）

62.1±11.2

61.9±11.5

63.1±10.3†

23±3

23±3

24±3†

Systolic

128.2±20.6

126.2±19.9

135±21.6†

Diastolic78.9±12.578.2±12.3

81.2±13.0†

Current smoker（%）

31

30

33

Ex-smoker（%）

18

17

22

Carotid plaque（%）

23

−

−

Corrected calcium（mmol/l）2.27±0.07

2.27±0.07

2.28±0.08†

Phosphorus（mmol/l）

1.06±0.15

1.06±0.15

1.04±0.15†

TC（mmol/l）5.38±0.87

5.36±0.86

5.44±0.90

Triglycerides（mmol/l）

1.46±1.09

1.44±1.09

1.52±1.10＊

HDL-C（mmol/l）1.52±0.45

1.54±0.45

1.46±0.42†

Glucose（mmol/l）

5.32±1.10

5.28±1.08

5.46±1.18†

Hemoglobin A1C（%）

5.30±0.71

5.26±0.69

5.46±0.78†

Body mass index（kg/m2）
Blood pressure（mmHg）

Smoking status

Continuous values are mean±SD. ＊p＜0.05,†p＜0.001 vs no plaque group.
TC＝total cholesterol ; HDL-C＝high-density lipoprotein cholesterol.

nificant association between serum calcium concentration and other variables. Pearson s correlation
coefficients for the relationships between serum
calcium and the variables were as follows : age,
0.045 ; body mass index, 0.01 ; systolic blood pressure, 0.072 ; diastolic blood pressure, 0.058 ; serum
phosphorus, 0.149 ; TC, 0.18 ; triglycerides, 0.033 ;HDL-C, 0.109 ; hemoglobin A 1C, 0.082 ; serum
glucose, 0.007. p values for all these correlations
were ＜ 0.001 except body mass index（NS）, serum
glucose（NS）and triglyceride（p ＜ 0.05 ; Fig. 1）.
Although there was a significant association
between serum calcium and several conventionalrisk factors, correlation coefficients were less than
0.2 and therefore the relationship did not seem to
be strong（Fig. 1）. Serum calcium level in the nonsmokers was 2.27 ± 0.07 mmol/l, which was not
significantly different from that in the current
smokers（2.27 ± 0.07 mmol/l）, but was significantly greater than that in the ex-smokers（ 2.26 ±0.07 mmol/l, p ＜ 0.001）.
Serum calcium and carotid plaqueWe examined whether higher serum calcium
J Cardiol 2002 Mar; 39（3）: 151 – 157

concentration is an independent risk for carotid
plaque. Multivariate logistic regression analysis
including other confounding risk factors for atherosclerosis demonstrated that serum calcium concentration is an independent risk factor for carotid
plaque with an odds ratio of 8.32
［95% confidence
interval（CI）5.06−13.56］per 1 mmol/l increase, or
1.70（95% CI 1.50−1.92）per 1 mg/dl increase（Table 2）. Serum phosphorus was also positively
associated with carotid plaque after the adjustmentof risk factors for atherosclerosis and serum calcium concentration. The odds ratio of serum phosphorus for carotid plaque was 1.59（95% CI 1.21−
2.09）per 1 mmol/l increase（Table 2）, or 1.16（95%
CI 1.06−1.27）
per 1 mg/dl increase.
Odds ratios were then calculated against the lowest（i.e., the first）quartile after adjustment for confounding risk factors and serum phosphorus concentration. Mean calcium concentrations in thefirst, second, third, and fourth quartiles are 2.18,
2.24, 2.29, and 2.36 mmol/l, respectively. Subjects
in the highest and the second highest quartiles ofserum calcium concentrations had a significantly
greater risk for carotid plaque with the odds ratios

154

Ishizaka, Ishizaka, Takahashi et al

Fig. 1 Relationships between serum calcium and conventional risk factors for atherosclerosis
Relationship between serum calcium and systolic blood pressure（A）, total cholesterol（B）, high-density（F）. Correlation colipoprotein cholesterol（C）, triglyceride（D）, serum glucose（E）, and hemoglobin A1C
efficient is given in each graph. All these correlations were statistically significant except for that between
serum calcium and serum glucose.
BP ＝ blood pressure ; Ca ＝ calcium ; TG ＝ triglyceride. Other abbreviations as in Table 1.

of 1.51（ 95% CI 1.37−1.67, p ＜ 0.01）and 1.19
（95% CI 1.08−1.32, p ＜ 0.05）, respectively. The
male and the female subjects in the highest quartiles of serum calcium levels were at a significantly
greater risk for carotid plaque with odds ratios of1.52（95% CI 1.35−1.71, p ＜ 0.01）, 1.57
（95% CI, respectively（Fig. 2）.
1.27−1.92, p ＜ 0.05）
DISCUSSION
The present study showed that serum calcium
was a predictor of carotid plaque, which was independent of other confounding risk factors. Maleand female subjects in the highest quartile of serum
calcium had a greater risk of carotid plaque, withodds ratios of 1.52 and 1.57, respectively, thanthose in the lowest quartiles of serum calcium.
An association between serum calcium and someof the cardiovascular risk factors has been demonstrated in several previous studies2,8）. Althoughserum calcium had not been corrected for serum
albumin concentration, an association was foundbetween serum calcium and blood pressure,
TC/HDL-C, and, in men only, triglycerides2）. Thisfinding is consistent with the idea that serum calci-

Table 2 Multivariate logistic regression analysis
Variable

Odds ratio（95% CI）

Age（per yr）†
1.11（1.11−1.12）

Male†
2.12（1.93−2.33）

Blood pressure（per 10 mmHg）†
1.12（1.10−1.14）

Current smoker†
1.39（1.29−1.50）

Ex-smoker＊
1.10（1.00−1.20）

Calcium
Per 1 mmol/l†
8.32（5.06−13.69）

Per 1 mg/dl†
1.70（1.50−1.92）

Phosphorus
Per 1 mmol/l＊
1.59（1.21−2.09）

Per 1 mg/dl＊
1.16（1.06−1.27）

TC（per 1 mmol/l）†
1.17（1.12−1.22）

Triglycerides（per 1 mmol/l）1.00（0.97−1.03）

HDL-C（per 1 mmol/l）†
0.73（0.65−0.80）

Hemoglobin A1C（per 1%）＊
1.12（1.07−1.18）

All listed variables were considered as co-variables in themultivariate logistic regression analysis.
＊p＜0.05, †p＜0.001.
CI＝confidence interval.

J Cardiol 2002 Mar; 39（3）: 151 – 157

Serum Calcium Concentration and Carotid Artery Plaque155

Fig. 2 Odds ratios for carotid plaque according to the serum calcium concentrations
Subjects were divided into four subgroups according to their serum calcium concentrations.
＊p ＜ 0.05 and † p ＜ 0.01 compared with the subjects in the first（i.e., lowest）quartile of serum calcium
concentration.
Abbreviation as in Table 2.

um is related to a metabolic syndrome that may be
involved in atherogenesis. It is possible thatchanges in membrane Ca 2 ＋ binding andtransport 9,10）that are observed in patients withhypertension may be involved in abnormal calcium
handling in some metabolic disorders. Indeed, thepresent study also found significant and positive
correlations between serum calcium and several
conventional risk factors for atherosclerosis,
including age, blood pressure, TC, triglycerides,
HDL-C, and hemoglobin A1C. However, correlation
coefficients between serum calcium and these risk
factors were rather small（＜ 0.2）
in our study population.
Multivariate logistic regression analysis indicated that serum calcium is independently associatedwith carotid plaque. The reason for this association
was not evident in the present study, though there
are some possible mechanisms. Parathyroid hormone may be important in cardiovascular complications 11）, and progression of aortosclerosis is
reduced in parathyroidectomized patients 12）. In
addition, animal studies have suggested thatparathyroid hormone is involved in the hypertrophyof the vascular wall13）. Therefore, parathyroid hormone, which will modify the calcium homeostasis,
may have a role in the development of vascularlesions. This possibility should be investigated bymeasuring parathyroid hormone levels in futurestudies.
Multivariate analysis of our data suggested a
possible link between serum phosphorus andcarotid plaque. Only a little information about the

J Cardiol 2002 Mar; 39（3）: 151 – 157

association between serum phosphorus and the atherosclerotic diseases is available. A retrospective
study analyzing patients who had undergone routine coronary angiography showed that serum phosphorus concentration was associated with theangiographic severity of coronary artery disease
and was independent of other coronary risk factors 14）. Serum phosphorus levels are associatedwith the intima-media thickness of the carotid
artery in patients with uremia after adjustment for
confounding risk factors15）. As serum phosphorus
level is regulated by mechanisms that may also
affect serum calcium level, we have to be careful ininterpreting the data.
The present study showed a significant relationship between serum calcium and carotid plaque.
However, it should be kept in mind that only ionized calcium is physiologically active and underhomeostatic control. Reported correction formulae
may not agree well with the ionized calcium levelin some cases16）. However, measurement of ionized
calcium is relatively difficult and is not available instandard laboratories, such as ours. To demonstrate
an independent correlation between serum calcium
and carotid plaque more definitively, ionized calcium should be measured in future studies.
CONCLUSIONS
Serum calcium, which has been adjusted forserum albumin level, is associated with formationof carotid plaque, which is independent of confounding risk factors for atherosclerosis. The pathophysiologic mechanisms involved in this relationship should be assessed in future studies.

156

Ishizaka, Ishizaka, Takahashi et al

要約

血清カルシウム値と頸動脈プラークの関連: 健診データに基づいた検討
石坂

目

信和

石坂

裕子

高橋

英孝

遠田

橋本

英樹

永井

良三

山 門

実

栄一

的 : 血清 Ca 値は高いほど，心血管系の罹病率や，死亡率を上昇させると考えられている．

これは，血清 Ca 値が，血圧や血清コレステロール値など，動脈硬化の危険因子と正相関を有する
ことに関係している可能性がある．今回我々は，健診受診者のデータを分析し，アルブミン値で補正した血清 Ca 値が，頸動脈硬化の危険因子となっているか否かについて検討した．
方法 : 症例は 1994−2000 年に三井記念病院総合健診センターに健康評価のために訪れた症例のうち，血中の Ca，アルブミン値を含む採血を受け，かつ頸動脈心エコー図法を施行されている症例を対象とした．統計学的検討は，すべてアルブミンで補正した Ca 値を用いた．
結果 : エントリーされた 5,732 症例のうち，3,785 例が男性，1,947 例が女性で，年齢範囲は 22−

88 歳（中央値 57 歳）であった．血清 Ca 値は 7.8−10.9 mg/dl（1.95−2.72 mmol/l）で，中央値が 9.1 mg/dl（2.26 mmol/l）であった．頸動脈プラークは 1,313 例（23%）に認められた．Ca 値はプラーク群，非プ
ラーク群でそれぞれ 2.28，2.27 mmol/l と，若干プラーク群で高かった（p ＜ 0.001，t 検定）．多変量のロジスティック回帰分析では，血清 Ca 値は独立した，有意なプラークの危険因子であることがわかった（1 mg/dl の上昇につきオッズ比 1.70，95% 信頼区間 1.50−1.92）．また，症例を血清 Ca 値により，4 分割して同様の多変量解析を行った場合，最も Ca 値の低い第 1 の 4 分位数と比較して，最も高い第 4 の 4 分位数でのオッズ比は，男性で 1.52（ 95% 信頼区間 1.35−1.71，p ＜ 0.01），女性で1.57（95% 信頼区間 1.27−1.92，p ＜ 0.05）と，有意にプラークのリスクが高かった．
結論 : 健診受診症例における検討で，血清 Ca 値は頸動脈プラークの独立した危険因子である

ことが示唆された．

J Cardiol 2002 Mar; 39（3）: 151−157

References
1）Leifsson BG, Ahren B : Serum calcium and survival in alarge health screening program. J Clin Endocrinol Metab
1996 ; 81 : 2149−2153
2）Jorde R, Sundsfjord J, Fitzgerald P, Bonaa KH : Serum calcium and cardiovascular risk factors and diseases : The
Tromso study. Hypertension 1999 ; 34 : 484−490
3）Lind L, Skarfors E, Berglund L, Lithell H, Ljunghall S :Serum calcium : A new, independent, prospective risk factor for myocardial infarction in middle-aged men followed
for 18 years. J Clin Epidemiol 1997 ; 50 : 967−973
4）Malatino LS, Benedetto FA, Mallamaci F, Tripepi G,
Zoccali C, Parlongo S, Cutrupi S, Marino C, Panuccio V,
Garozzo M, Candela V, Bellanuova I, Cataliotti A,
Rapisarda F, Fatuzzo P, Bonanno G, Seminara G,
Stancanelli B, Tassone F, Labate C, for the CREED
Investigators : Smoking, blood pressure and serum albumin
are major determinants of carotid atherosclerosis in dialysis
patients : Cardiovascular Risk Extended Evaluation in
Dialysis patients. J Nephrol 1999 ; 12 : 256−260
5）Kosch M, Hausberg M, Vormbrock K, Kisters K, Rahn
KH, Barenbrock M : Studies on flow-mediated vasodilationand intima-media thickness of the brachial artery in patientswith primary hyperparathyroidism. Am J Hypertens 2000 ;

13 : 759−7646）Ishizaka N, Ishizaka Y, Takahashi E, Yamakado M,
Hashimoto H : High serum bilirubin level is inversely associated with the presence of carotid plaque. Stroke 2001 ;32: 580−583
7）Payne RB, Little AJ, Williams RB, Milner JR : Interpretation of serum calcium in patients with abnormal serum
proteins. Br Med J 1973 ; 4 : 643−6468）Lind L, Jakobsson S, Lithell H, Wengle B, Ljunghall S :Relation of serum calcium concentration to metabolic risk
factors for cardiovascular disease. BMJ 1988 ; 297 : 960−
9639）Vincenzi FF, Morris CD, Kinsel LB, Kenny M, McCarron
DA : Decreased calcium pump adenosine triphosphatase in
red blood cells of hypertensive subjects. Hypertension
1986 ; 8 : 1058−1066
10）Hvarfner A, Larsson R, Morlin C, Rastad J, Wide L,
Akerstrom G, Ljunghall S : Cytosolic free calcium inplatelets : Relationships to blood pressure and indices ofsystemic calcium metabolism. J Hypertens 1988 ; 6 : 71−
7711）Tsuchihashi K, Takizawa H, Torii T, Ikeda R, Nakahara N,
Yuda S, Kobayashi N, Nakata T, Ura N, Shimamoto K :Hypoparathyroidism potentiates cardiovascular complications through disturbed calcium metabolism : Possible risk

J Cardiol 2002 Mar; 39（3）: 151 – 157

Serum Calcium Concentration and Carotid Artery Plaqueof vitamin D（3）analog administration in dialysis patientswith end-stage renal disease. Nephron 2000 ; 84 : 13−20
12）Bommer J, Strohbeck E, Goerich J, Bahner M, Zuna I :Arteriosclerosis in dialysis patients. Int J Artif Organs
1996 ; 19 : 638−64413）Amann K, Tornig J, Flechtenmacher C, Nabokov A, MallG, Ritz E : Blood-pressure-independent wall thickening of
intramyocardial arterioles in experimental uraemia :Evidence for a permissive action of PTH. Nephrol Dial
Transplant 1995 ; 10 : 2043−204814）Narang R, Ridout D, Nonis C, Kooner JS : Serum calcium,

J Cardiol 2002 Mar; 39（3）: 151 – 157

157

phosphorus and albumin levels in relation to the angiographic severity of coronary artery disease. Int J Cardiol
1997 ; 60 : 73−79
15）Kawagishi T, Nishizawa Y, Konishi T, Kawasaki K, Emoto
M, Shoji T, Tabata T, Inoue T, Morii H : High-resolution
B-mode ultrasonography in evaluation of atherosclerosis inuremia. Kidney Int 1995 ; 48 : 820−82616）Clase CM, Norman GL, Beecroft ML, Churchill DN :Albumin-corrected calcium and ionized calcium in stablehaemodialysis patients. Nephrol Dial Transplant 2000 ; 15:
1841−1846