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Keywords:

  • atherosclerosis;
  • cadmium;
  • cardiovascular risk factors;
  • carotid artery;
  • smoking

Abstract

  1. Top of page
  2. Abstract
  3. Introduction
  4. Material and methods
  5. Results
  6. Discussion
  7. Acknowledgements
  8. Conflict of interest statement
  9. References
  10. Supporting Information

Objectives

There is currently widespread exposure to the toxic metal cadmium through the diet as well as through smoking, and it has been suggested that cadmium exposure may increase the risk of cardiovascular disease. Here we examined whether cadmium exposure is associated with prevalence and growth of atherosclerotic plaques in the carotid arteries.

Design and subjects

The analyses were performed in a screening-based cohort of 64-year-old Caucasian women with stratified, random selection to groups with normal glucose tolerance, impaired glucose tolerance and diabetes (= 599). We measured cadmium concentrations in blood and urine at baseline. In addition, we performed ultrasound examination to determine the prevalence and area of atherosclerotic plaques in the carotid arteries and assessed smoking history and other cardiovascular risk factors at baseline and at a follow-up examination after a mean of 5.4 years.

Results

At baseline, blood cadmium levels were associated with increased risk of plaque and a large plaque area after adjustment for confounders. In women who had never smoked, blood cadmium levels correlated positively with plaque area at baseline. The occurrence of large plaques and the change in plaque area at follow-up were associated with blood and creatinine-corrected urinary cadmium concentrations at baseline after adjustment for confounders. Blood and urine cadmium levels added information to established cardiovascular risk factors in predicting progress of atherosclerosis.

Conclusions

We have shown that cadmium levels in blood and urine are independent factors associated with the development of atherosclerotic plaques at baseline as well as prospectively. This novel observation emphasizes the need to consider cadmium as a pro-atherogenic pollutant.


Introduction

  1. Top of page
  2. Abstract
  3. Introduction
  4. Material and methods
  5. Results
  6. Discussion
  7. Acknowledgements
  8. Conflict of interest statement
  9. References
  10. Supporting Information

Cadmium is a nonessential, toxic metal that is widely distributed in the environment [1, 2]. Major sources of cadmium exposure include the diet and smoking; cadmium in tobacco smoke is effectively absorbed into the lungs [1]. Levels of cadmium, which has a long biological half-life, are higher in women than men, mainly because of increased intestinal absorption of dietary cadmium in the presence of low iron stores owing to menstruation and pregnancy [1, 2]. Cadmium concentrations in the blood and urine are valid biomarkers of exposure, irrespective of source [1, 2].

Experimental studies have shown that cadmium causes endothelial dysfunction in vitro and promotes the formation of atherosclerotic plaques in vivo [2-6]. Results from cross-sectional and prospective studies have indicated an association between cadmium exposure and cardiovascular disease [2, 7-9]. However, these data are not consistent and results differ between countries [10] and between men and women [9]. A cross-sectional study, based on data from the National Health and Nutrition Examination Survey, showed that cadmium exposure was associated with self-reported stroke [8]. Using ultrasound, cadmium concentrations were found to be associated with carotid intima-media thickness (IMT) above the 90th percentile in 20-year-old women [5]. However, IMT is not a direct measure of atherosclerosis [11] and is less precise than the area of atherosclerotic plaques as a predictor of stroke [12].

Here, we tested the hypothesis that cadmium exposure is associated with the prevalence and growth of atherosclerotic plaques in the carotid arteries of 64-year-old women at increased risk of cardiovascular disease.

Material and methods

  1. Top of page
  2. Abstract
  3. Introduction
  4. Material and methods
  5. Results
  6. Discussion
  7. Acknowledgements
  8. Conflict of interest statement
  9. References
  10. Supporting Information

Study design

We conducted an observational study with a cross-sectional analysis at baseline followed by an analysis of prospective data obtained during re-examination performed after 5.1–6.7 (median 5.4) years. The study was approved by the regional ethics committee, and all participating subjects provided written informed consent (T 094-10, Ad 282-07).

Study population

A cohort of 64-year-old Caucasian women (= 2595) from Gothenburg, Sweden, participated in a population-based screening examination in 2001–2003 including oral glucose tolerance tests, as previously described in detail [13]. Criteria of the World Health Organization were used for the definitions of diabetes mellitus, and impaired (IGT) and normal glucose tolerance (NGT) [14]. Women with diabetes, IGT and NGT were selected and invited to participate in a prospective study. The baseline examination included 599 women (diabetes, = 218; IGT, = 198; NGT, = 183). The re-examination during 2007–2009 included 465 women; the reasons for loss of follow-up data were death (= 19), relocation to another place of residence or no contact (= 21), refusal to participate (= 84) or technical problem with ultrasound measurements (= 10).

Examinations

For both baseline and follow-up examinations, questionnaires were used to obtain information on previous and present disease, current medication and smoking history [13]. Smoking was evaluated in terms of pack-years, calculated by multiplying the number of packs of cigarettes smoked per day by the number of years the person had smoked. Body mass index (BMI), waist circumference and blood pressure were assessed [13]. Blood was drawn after an overnight fast, and cardiovascular risk factors were assessed [13]. Whole blood, plasma and serum were stored at −80 °C within 4 h of collection/preparation. For the baseline examination only, participants collected their urine for 12 h overnight, and a 20-mL sample was stored at −80 °C. Urine samples were available in 569 women.

Biochemical analyses

Concentrations of cadmium in the blood and urine were determined by inductively coupled plasma-mass spectrometry (ICP-MS; Thermo X7, Thermo Elemental, Winsford, UK) at the Department of Occupational and Environmental Medicine, Lund University, Sweden. The detection limits for blood and urinary cadmium were 0.05 and 0.03 μg L−1, respectively. Imprecision as calculated from duplicate analyses was 4% [coefficient of variation (CV)] for both blood and urine cadmium concentrations. Analysis of external quality control samples for blood and urine showed results within recommended levels. Five different quality control samples were used from two providers (Trace Elements Whole Blood, Seronorm AS, Billingstad, Norway and Human Blood Reference Material, Le Centre de Toxicologie du Quebec, International Comparison Program, Canada). The results versus recommended values were as follows: (i) 0.26 ± 0.02 μg L−1 versus 0.26–0.36 μg L−1; (ii) 1.0 ± 0.03 μg L−1 versus 1.0 ± 0.13 μg L−1; (iii) 0.95 ± 0.03 μg L−1 versus 1.01 ± 0.09 μg L−1; (iv) 5.0 ± 0.11 μg L−1 versus 5.1 ± 0.26 μg L−1; and (v) 5.1 ± 0.14 μg L−1 versus 5.3 ± 0.13 μg L−1 (n = 22–24 for all).

The cadmium concentration in urine was expressed in μg g−1 creatinine. Urinary creatinine was measured using the alkaline picrate rate method. High-sensitivity enzyme-linked immunosorbent assay kits were used to measure intercellular adhesion molecule 1 (ICAM-1; R&D System Europe Ltd, Abingdon, UK). Intra- and interassay CVs for ICAM-1 were 3.3% and 6.0%, respectively. All other analyses were performed with well-documented routine methods as previously described [13].

Ultrasound imaging

Ultrasound examinations of the carotid arteries were performed at baseline with an ultrasound scanner equipped with a linear 8L5-MHz transducer (Sequoia 512; Siemens, Mountain View, CA, USA) and at follow-up with an ultrasound scanner with a VF10-5 MHz transducer (Antares Sonoline; Siemens). The same scanning method was used for both baseline and follow-up examinations. The occurrence and area of carotid plaques in the near and far wall were assessed in accordance with previously published semi-automated methods and definitions (see Data S1 for further details) [15-17].

For technical reasons, complete measurements of the plaque area from both carotid arteries were not possible in 40 subjects at baseline and 17 subjects at follow-up.

Statistical analysis

Results are presented as mean (standard deviation) for continuous variables and as percentage for categorical variables. Skewed variables are presented as median (5th–25th percentile) or as geometric mean (standard error) in the figures. Differences between groups were analysed using the t-test and trend test after log transformation of skewed variables. Differences in proportions were analysed with chi-square test.

In the cross-sectional analyses at baseline, multiple logistic regression and multiple linear regression were used to examine the odds ratios for plaque occurrence by quartiles of blood and urine cadmium levels and associations between levels of cadmium and carotid plaque area, respectively. In the prospective analyses, multiple logistic and linear regressions were used to examine whether baseline levels of cadmium in blood and urine were associated with the occurrence of large plaques and plaque growth during follow-up. To adjust for the influence of potential confounders, we used two models in the multivariate analyses. Model 1 included the variables that correlated significantly with cadmium as well as the dependent variable. These covariates were pack-years of smoking, diastolic blood pressure (systolic blood pressure for prospective analyses), glycated haemoglobin (HbA1c) and serum ICAM-1 as potential confounders. Model 2 additionally included factors with known relevance for atherosclerosis: use of statins, BMI, apolipoprotein B/apolipoprotein A-I ratio and high-sensitivity C-reactive protein (hsCRP). The part correlation coefficient was also calculated, and the square of this coefficient (part r2) was interpreted as the contribution of the variance in the dependent variable that is associated uniquely with the given independent variable. Part r2 was compared with R2 to estimate the contribution of cadmium to the total variability in carotid plaque area, taking all potential confounders into account. A two-tailed P-value of <0.05 was considered statistically significant.

Results

  1. Top of page
  2. Abstract
  3. Introduction
  4. Material and methods
  5. Results
  6. Discussion
  7. Acknowledgements
  8. Conflict of interest statement
  9. References
  10. Supporting Information

Association between cadmium levels and atherosclerosis at baseline

The baseline characteristics of the cohort of 64-year-old women are presented in Table 1. Quartiles of both blood- and creatinine-corrected urine cadmium concentrations were associated with the prevalence of plaque and with the total plaque area (Fig. 1).

image

Figure 1. Prevalence of carotid plaques (a) and total plaque area (b) at baseline by quartiles of blood cadmium concentration in 64-year-old women. Corresponding data are presented for quartiles of creatinine-corrected urinary cadmium concentration (c, d). Distribution of cadmium in each quartile is presented as the median (5th–95th percentile) and plaque area as the geometric mean (standard error).

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Table 1. Characteristics of the study cohort of 64-year-old women at baselinea
VariableBaseline (= 599)
  1. a

    Values are presented as median (5th–95th percentile) unless otherwise indicated.

  2. b

    Complete examinations of subjects with plaques.

BMI, kg m−2 mean (SD)27.8 (4.7)
Waist circumference, cm92.0 (75.0–116.0)
Smoking status, n (%)
Never267 (44.6)
Previous209 (34.9)
Current123 (20.5)
Pack-years in smokers (previous/current), mean (SD)19 (16)
Previous myocardial infarction, n (%)14 (2.3)
Previous stroke, n (%)11 (1.8)
Known hypertension, n (%)168 (28.1)
Diabetes mellitus, n (%)218 (36.4)
Statin treatment, n (%)72 (12.0)
Blood pressure, mmHg, mean (SD)
Systolic145 (18)
Diastolic81 (8)
Serum apolipoprotein B/apolipoprotein A-I ratio, mean (SD)0.75 (0.22)
HbA1c, mmol mol−138 (32–66)
hsC-reactive protein, mg mL−11.47 (0.24–11.17)
Serum ICAM-1, ng mL−1253 (178–405)
Blood cadmium, μg L−10.34 (0.14–1.69)
Urine cadmium, μg g−1 creatinine (= 569)0.35 (0.14–1.01)
Plaque in carotid artery, n (%)262 (43.7)
Carotid plaque area, mm2 (= 222)b20.7 (7.3–83.5)

The prevalence of carotid plaques was associated with smoking, the number of pack-years of smoking, hypertension, diastolic blood pressure, diabetes, HbA1c, ICAM-1 and statin treatment, whereas plaque area was correlated with pack-years of smoking, systolic blood pressure and HbA1c (all associations were statistically significant; see Tables S1 and S2). Blood cadmium levels were correlated with pack-years of smoking, diastolic blood pressure, serum ICAM-1, HbA1c and BMI, and cadmium level in the urine was associated with smoking, serum ICAM-1 levels and BMI (all associations were statistically significant; see Table S2). Neither blood nor urine cadmium levels differed between women with and without diabetes [median 0.34 (5th–95th percentile 0.13–2.03) μg L−1 vs. 0.34 (0.15–1.52) μg L−1 and 0.35 μg g−1 creatinine (0.14–1.13) vs. 0.35 (0.14–0.95) μg g−1 creatinine, respectively].

Comparing quartile 4 with quartile 1 of blood cadmium concentration, the odds ratios for the prevalence of plaques in the carotid arteries were 2.6 (95% CI 1.4–4.7) for model 1 (including potential confounders, see 'Material and methods') and 2.5 (95% CI 1.3–4.6) for model 2 (including additional risk factors, see 'Material and methods'), as shown in Fig. 2 (see also Table S3). Similar results were obtained in stratified analyses of the subgroups with and without diabetes (data not shown). Urinary cadmium levels did not remain significantly associated with plaque prevalence at baseline in multivariate analyses (Fig. 2).

image

Figure 2. Odds ratios (95% CI) for prevalence of atherosclerotic plaques in the carotid arteries at baseline by quartiles of blood (a) (n = 599) and urine cadmium concentrations (b) (n = 569) in 64-year-old women. White bars, unadjusted analysis; grey bars, model 1 with adjustment for pack-years of smoking, log HbA1c, diastolic blood pressure and log ICAM-1; striped bars, model 2 adjusted for variables in model 1 and additionally for statin treatment, BMI, apolipoprotein B/apolipoprotein A-I ratio and log hsCRP. †P < 0.01, ‡P < 0.001.

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In a stepwise multiple regression analysis, log blood cadmium levels (but not log urine cadmium levels, data not shown) were associated with log carotid plaque area at baseline after adjustment for the variables in model 1 (= 0.003) and model 2 (= 0.001; part r2 = 0.051, accounting for the major part of R2 = 0.089).

Association between cadmium levels and atherosclerosis at baseline according to smoking history at baseline

In the subgroup of women who had never smoked (= 267), more than two-thirds had blood cadmium levels corresponding to cadmium quartiles 1 and 2 and only seven subjects (2.6%) had levels as high as quartile 4 (Fig. 3). By contrast, in the subgroup of current smokers (= 123), almost 90% had blood cadmium concentrations corresponding to quartile 4. Previous smokers (= 209) had a more even distribution of blood cadmium concentrations across the four quartiles. Women who had never smoked but had been exposed to passive smoking did not have higher cadmium concentrations in blood or urine compared with those without such exposure (data not shown). Amongst women with carotid plaques who had never smoked (= 82), log carotid plaque area at baseline correlated with log blood cadmium concentrations (r = 0.24, = 0.029) but not with any of the potential confounders (data not shown).

image

Figure 3. Distribution of blood cadmium concentrations by quartiles in 64-year-old women who had never smoked (n = 267), had previously smoked (n = 209) or were current smokers (n = 123) at baseline.

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In women who were previous smokers, blood cadmium concentrations were higher in those with (= 95) than without (= 114) plaques in the carotid arteries [median 0.41 (5th–95th percentiles 0.17–0.93) vs. 0.31 (5th–95th percentiles 0.15–0.71) μg L−1, = 0.001]. Time since smoking cessation in previous smokers ranged from <1 year to 51 years with a median of 16 years; 80% had stopped smoking for more than 5 years. The unadjusted odds ratio for prevalence of plaques in the carotid arteries was 6.1 (95% CI 2.2–16.4) when quartile 4 was compared with quartile 1 of blood cadmium concentration. After adjustment for time since smoking cessation and the variables included in model 2, the corresponding odds ratio was 4.8 (95% CI 1.3–17.7).

Association between cadmium levels at baseline and atherosclerosis at follow-up

The characteristics at baseline and follow-up of the women who participated in the follow-up re-examination are presented in Table 2. With the exception of fewer current smokers and a nonsignificant change in apolipoprotein B/apolipoprotein A-I ratio, all changes at follow-up compared with baseline increased the risk of cardiovascular disease (i.e. increased BMI, waist circumference, blood pressure, HBA1c and hsCRP, and an increased proportion of women with hypertension or diabetes) and more women were treated with statins. We observed increases in the prevalence of carotid plaques and in carotid plaque area at follow-up compared with baseline (Table 2).

Table 2. Comparisons between baseline and follow-up characteristics of the subgroup of 64-year-old women at baseline who also participated in the re-examination (= 465)a
VariableBaselineFollow-up P
  1. a

    Values are presented as median (5th–95th percentile) unless otherwise indicated.

  2. b

    Inclusion of all subjects with carotid plaques at both or either of the baseline and follow-up visits, and with available plaque area measurements.

BMI, kg m−2, mean (SD)27.7 (4.4)27.9 (4.8)0.040
Waist circumference, cm91.5 (74.5–113.0)95.0 (78.3–117.0)<0.001
Smoking status, n (%)
Never214 (46.0)213 (45.9)<0.001
Previous167 (35.9)190 (40.9)
Current84 (18.1)61 (13.1)
Previous myocardial infarction, n (%)7 (1.5)20 (4.3)0.001
Previous stroke, n (%)10 (2.2)10 (2.2)>0.05
Known hypertension, n (%)121 (26.0)165 (35.5)<0.001
Diabetes mellitus, n (%)141 (30.3)200 (43.0)<0.001
Statin treatment, n (%)53 (11.4)141 (30.6)<0.001
Blood pressure, mmHg, mean (SD)
Systolic148 (18)155 (18)<0.001
Diastolic80 (9)87 (8)<0.001
Serum apolipoprotein B/apolipoprotein A-I ratio, mean (SD)0.75 (0.21)0.86 (3.26)>0.05
HbA1c, mmol mol−1 38 (32–58)40 (33–63)<0.001
hsCRP, mg mL−1 1.41 (0.22–10.19)1.96 (0.42–15.56)<0.001
Plaque in carotid artery, n (%)202 (43.4)339 (72.9)<0.001
Carotid plaque area, mm2 (= 292)b 7.7 (0–58.4)28.7 (6.7–122.6)<0.001

The prevalence of plaques and the size of the carotid plaque area at follow-up were associated with similar baseline variables compared with the cross-sectional analysis; the only differences were that a positive association with systolic pressure instead of a negative association with diastolic blood pressure was observed, and the association with statin treatment was no longer significant (Tables S1 and S2).

At the follow-up of subjects without plaques at baseline, 144 women had developed new plaques, whereas 119 remained plaque free. Amongst both these groups (i.e. women with and without new plaques), the odds ratio for occurrence of new plaques was 1.8 (95% CI 0.9–4.0) when quartile 4 was compared with quartile 1 of blood cadmium concentration at baseline. The corresponding odds ratio for urinary cadmium level was 1.6 (95% CI 0.8–3.6).

Quartiles of both blood- and creatinine-corrected urine cadmium concentrations at baseline were associated with the prevalence of large plaques at follow-up (tertile 3 of the total plaque area) (Tables 3 and 4). These differences remained after adjustment that also included occurrence or not of plaques at baseline (Tables 3 and 4).

Table 3. Odds ratios for prevalence of large atherosclerotic plaquesa in the carotid arteries at follow-up by quartiles of blood cadmium concentration at baseline in 64-year-old women
Model (n in each quartile)Odds ratios (95% CI) by quartiles of blood cadmium concentrationP for quartile 4 versus quartile 1
1234
  1. a

    Subjects in tertile 3 of total plaque area at follow-up.

  2. b

    In model 1, adjustments were made for pack-years of smoking, log HbA1c, systolic blood pressure and log ICAM-1. Plaque status at baseline: 1 = presence of plaque, 0 = no plaque.

  3. c

    Model 2 also included adjustments for statin treatment, BMI, apolipoprotein B/apolipoprotein A-I ratio and log hsCRP.

No adjustment (= 109/124/116/99)1.02.7 (1.2–6.0)4.6 (2.1–10.2)7.9 (3.6–17.3)<0.005
Model 1 and plaque status at baselineb (= 105/121/113/91)1.02.5 (1.0–6.3)3.7 (1.5–9.1)4.5 (1.6–12.3)0.004
Model 2 and plaque status at baselinec (= 104/120/108/91)1.02.6 (1.1–6.5)3.9 (1.6–9.7)4.6 (1.7–12.9)0.003
Table 4. Odds ratios for prevalence of large atherosclerotic plaquesa in the carotid arteries at follow-up by quartiles of creatinine-corrected urinary cadmium concentration at baseline in 64-year-old women
Model (n in each quartile)Odds ratios (95% CI) by quartiles of creatinine-corrected urinary cadmium concentrationP for quartile 4 versus quartile 1
1234
  1. a

    Subjects in tertile 3 of total plaque area at follow-up.

  2. b

    In model 1, adjustments were made for pack-years of smoking, HbA1c, systolic blood pressure and ICAM-1. Plaque status at baseline: 1 = presence of plaque, 0 = no plaque.

  3. c

    Model 2 also included adjustments for statin treatment, BMI, apolipoprotein B/apolipoprotein A-I and hsCRP.

No adjustment (= 107/115/108/98)1.01.3 (0.6–2.6)2.0 (1.0–3.9)4.1 (2.1–8.0)<0.005
Model 1 and plaque status at baselineb (= 102/112/102/94)1.01.2 (0.6–2.4)1.8 (0.8–3.7)2.6 (1.2–5.7)0.021
Model 2 and plaque status at baselinec (= 102/111/101/92)1.01.2 (0.6–2.5)1.8 (0.9–3.9)2.7 (1.2–6.1)0.018

Change in the size of the plaque area from baseline to follow-up increased in parallel with increasing blood and urine cadmium levels at baseline (Fig. 4). Stepwise multiple regression analyses were performed with change in plaque area during follow-up as the dependent variable and the variables in model 1 with the addition of plaque area at baseline as independent variables. Only log blood cadmium and log urine cadmium levels were independently associated with change in plaque area (= 0.001, R2 = 0.066, and = 0.025, R2 = 0.025, respectively). Adjustment according to model 2 did not affect the results (data not shown).

image

Figure 4. Results from prospective analyses showing that the change in total plaque area during follow-up was positively associated with quartiles of blood- (a) and creatinine-adjusted urinary cadmium concentration (b) at baseline. Data are presented as geometric mean (standard error).

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Association between cadmium levels at baseline and atherosclerosis at follow-up according to smoking history at baseline

In previous smokers, a multiple regression analysis showed that log blood cadmium concentration at baseline was higher amongst women who had large plaques compared with those with no plaque at follow-up (= 0.036), after adjustment for variables included in model 1 and plaque prevalence at baseline (data not shown). Furthermore, in previous smokers, only log blood cadmium concentrations at baseline and neither variables in the revised model 2 nor plaque at baseline predicted the change in plaque area from baseline to follow-up (= 0.002, R2 = 0.09, = 101).

In women who had never smoked, there were no statistically significant associations between cadmium concentrations in blood or urine at baseline and atherosclerosis at follow-up.

Subjects lost to follow-up

The characteristics at baseline of women who did (= 465) and did not participate (= 134) in the follow-up examination did not differ in terms of cadmium exposure, but the group of nonparticipants had a higher cardiovascular disease risk with more smokers, a higher prevalence of diabetes and hypertension, larger waist circumference and elevated serum ICAM-1 levels (Table S4). This increased risk of cardiovascular disease was accompanied by larger carotid plaque area and higher prevalence of previous myocardial infarction.

Discussion

  1. Top of page
  2. Abstract
  3. Introduction
  4. Material and methods
  5. Results
  6. Discussion
  7. Acknowledgements
  8. Conflict of interest statement
  9. References
  10. Supporting Information

The novel finding of the present cross-sectional and prospective study was that cadmium concentrations in blood and urine as measures of cadmium exposure predicted the prevalence and growth of atherosclerotic plaques in the carotid arteries in a cohort of 64-year-old women who were re-examined after 5 years. Blood and urinary cadmium levels provided additional information to that of well-known cardiovascular risk factors in predicting future progress of atherosclerosis.

We identified smoking, diabetes, blood pressure and ICAM-1 as potential confounding factors. As expected, women who smoked at the time of examination had the highest blood concentration of cadmium. As smoking is a well-known cardiovascular risk factor, it may confound any pro-atherogenic effects of cadmium [18-21]. However, high cadmium exposure might be one of many mechanisms by which tobacco smoking causes atherosclerosis. This is supported by the fact that smoking status correlates with cadmium concentrations in the arterial wall, which are many fold higher than the concentrations in serum [22].

We examined the association between cadmium and atherosclerosis taking the confounding effects of smoking into account in two ways. First, we performed a multivariate analysis that included pack-years of smoking as a measure of total cigarette consumption. Blood and urine cadmium levels were overall the most powerful predictors in these analyses and remained associated with plaque prevalence and plaque area after adjustment for pack-years of smoking and other covariates. Secondly, we stratified the analyses for smoking history (never/previous smokers). In women who never smoked, blood cadmium concentration was the only variable that was statistically significantly correlated to carotid plaque area at baseline, despite the fact that most women had cadmium concentrations below the median of the cohort. The group of previous smokers had a wide range of blood cadmium levels. The median time since smoking cessation was 16 years, and 80% of women had stopped more than 5 years before the baseline measurements. As the increased risks of cardiovascular disease and occurrence of atherosclerotic plaques level off 5–10 years after smoking cessation [18-21], we assumed that our group of previous smokers constituted a subgroup with high cadmium exposure but without the pro-atherogenic effects of on-going smoking. Levels of cadmium in blood and urine were associated with plaque prevalence and growth of plaques in previous smokers.

Additional potential confounding factors include IGT and type 2 diabetes, which are known to increase the risk of atherosclerotic disease [23, 24]. Cross-sectional data have indicated that cadmium exposure may be associated with an increased risk of type 2 diabetes [25]. In the present study, circulating HbA1c concentration correlated both with ultrasound measures of atherosclerosis and cadmium levels in blood and urine. However, blood and urine cadmium levels were not elevated in women with diabetes compared with those without. Furthermore, the results of multivariate analyses were not affected by addition of HbA1c. Hypertension and systolic blood pressure were related to atherosclerosis in the present study, but adjustment for blood pressure did not affect the results. Previous studies have not shown any consistent relationship between cadmium exposure and blood pressure [10].

We found that ICAM-1 levels were associated with both degree of cadmium exposure and ultrasound-assessed atherosclerosis at baseline and at follow-up. ICAM-1 is expressed by the endothelium and is believed to be an important component in the atherosclerotic process [26]. In endothelial cells from mice, cadmium has been reported to stimulate the expression of ICAM-1 [27], but there is still a lack of precise information on uptake of cadmium in human vascular cells [28].

A limitation of the present study is that the results cannot be extended to men or to all age groups. On the other hand, variability was minimized by limiting the analysis to women of the same age. In addition, of interest, postmenopausal women have a higher mean cadmium exposure than men and younger women, while at the same time there is a considerably increased incidence of atherosclerotic diseases, such as myocardial infarction and stroke, in women of this age with diabetes [24, 29].

In conclusion, we have shown that cadmium exposure is an independent factor related to the development of atherosclerotic plaques both at baseline and at follow-up in a cohort of 64-year-old women with varying degrees of glucose tolerance. From a public health perspective, it is important to determine the role of cadmium exposure as a causal factor in cardiovascular disease. Furthermore, whether cadmium also contributes to the pro-atherogenic effects of smoking should be investigated.

Acknowledgements

  1. Top of page
  2. Abstract
  3. Introduction
  4. Material and methods
  5. Results
  6. Discussion
  7. Acknowledgements
  8. Conflict of interest statement
  9. References
  10. Supporting Information

We are grateful to Marie-Louise Ekholm, Birgitta Jannemark, Caroline Schmidt and Ulrica Prahl for technical assistance, Rosie Perkins for editing the manuscript and Thomas Lundh for skilful analyses of blood and urinary cadmium levels. This study was supported by the Swedish Research Council, the Swedish Heart-Lung Foundation, the Swedish Foundation for Strategic Research and AstraZeneca R&D Mölndal, Sweden.

References

  1. Top of page
  2. Abstract
  3. Introduction
  4. Material and methods
  5. Results
  6. Discussion
  7. Acknowledgements
  8. Conflict of interest statement
  9. References
  10. Supporting Information
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Supporting Information

  1. Top of page
  2. Abstract
  3. Introduction
  4. Material and methods
  5. Results
  6. Discussion
  7. Acknowledgements
  8. Conflict of interest statement
  9. References
  10. Supporting Information
FilenameFormatSizeDescription
joim2578-sup-0001-DataS1-TableS1-S4.docWord document96KData S1. Methods. Table S1. Comparison of factors related to atherosclerosis in 64-year-old women with or without plaques in the carotid arteries at baseline and follow-up. Table S2. Correlations between blood and creatinine-corrected urine cadmium levels, as well as other known or potential risk factors for atherosclerosis at baseline, and carotid plaque area at baseline and follow-up in women who were 64 years old at study entry. Table S3. Odds ratios for occurrence of atherosclerotic plaques in the carotid arteries at baseline by quartiles of blood cadmium concentration in 64-year-old women (= 599). Table S4. Comparison of the baseline characteristics of women who did not or did participate in the follow-up examination.

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