Cadmium exposure and incident peripheral arterial disease.

NIH Public Access Author Manuscript Circ Cardiovasc Qual Outcomes. Author manuscript; available in PMC 2014 October 08.

NIH-PA Author Manuscript

Published in final edited form as: Circ Cardiovasc Qual Outcomes. 2013 November ; 6(6): 626–633. doi:10.1161/CIRCOUTCOMES. 112.000134.

Cadmium Exposure and Incident Peripheral Arterial Disease Maria Tellez-Plaza1,2,3,4, Eliseo Guallar2,4,5, Richard R. Fabsitz6, Barbara V. Howard7, Jason G. Umans7, Kevin A. Francesconi8, Walter Goessler8, Richard B. Devereux9, and Ana Navas-Acien1,4 1Department

of Environmental Health Sciences, Johns Hopkins University Bloomberg School of Public Health, Baltimore, MD

2Area

of Epidemiology and Population Genetics, National Center for Cardiovascular Research (CNIC), Madrid, Spain

3Fundacion

de Investigacion del Hospital Clinico de Valencia-INCLIVA, Valencia, Spain


4Department

of Epidemiology and Welch Center for Prevention, Epidemiology and Clinical Research, Johns Hopkins University Bloomberg School of Public Health, Baltimore, MD

5Department

of Medicine, Johns Hopkins Medical Institutions, Baltimore, MD

6Epidemiology 7MedStar 8Institute 9Weill

Branch, National Heart, Lung, and Blood Institute, Bethesda, MD

Health Research Institute and Georgetown University, US of Chemistry – Analytical Chemistry, Karl-Franzens University Graz, Austria

Cornell Medical College, New York, NY

Abstract Background—Cadmium has been associated with peripheral arterial disease in cross-sectional studies but prospective evidence is lacking. Our goal was to evaluate the association of urine cadmium concentrations with incident peripheral arterial disease in a large population-based cohort.


Methods and Results—A prospective cohort study was performed with 2,864 adult American Indians 45-74 years old from Arizona, Oklahoma and North and South Dakota who participated in the Strong Heart Study in 1989-91 and were followed through two follow-up examination visits in 1993-1995 and 1997-1999. Participants were free of peripheral arterial disease, defined as an ankle brachial index 1.4, at baseline and had complete baseline information on urine cadmium, potential confounders and ankle brachial index determinations in the follow-up examinations. Urine cadmium was measured using inductively coupled plasma mass spectrometry (ICPMS) and corrected for urinary dilution by normalization to urine creatinine.. Multivariable-

Address correspondence to: Maria Tellez-Plaza, MD, PhD, Departments of Environmental Health Sciences and Epidemiology, Johns Hopkins Bloomberg School of Public Health, 615 N Wolfe Street, Room W7513D, Baltimore, MD 21205, US, Phone: (410) 502-4267; Fax: (410) 955-1811, [email protected]. Disclosures: No conflict of interest to declare. Disclaimer: The opinions expressed in this paper are those of the author(s) and do not necessarily reflect the views of the Indian Health Service.

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adjusted hazard ratios (HR) were computed using Cox-proportional hazards models for intervalcensored data. A total of 470 cases of incident peripheral arterial disease, defined as an ankle brachial index 1.4, were identified. After adjustment for cardiovascular disease risk factors including smoking status and pack-years, the hazard ratio comparing the 80th to the 20th percentile of urine cadmium concentrations was 1.41 (1.05, 1.81). The hazard ratio comparing the highest to the lowest tertile was 1.96 (1.32, 2.81). The associations persisted after excluding participants with ankle brachial index > 1.4 only as well as in subgroups defined by sex and smoking status. Conclusions—Urine cadmium, a biomarker of long-term cadmium exposure, was independently associated with incident peripheral arterial disease, providing further support for cadmium as a cardiovascular disease risk factor. Keywords Cadmium; peripheral arterial disease; prospective cohort study; Strong Heart Study


Cadmium is a toxic metal1, 2 with widespread population exposure through smoking, diet and ambient air.1-3 Experimental models support that cadmium can induce atherosclerosis and vascular dysfunction in animal models.4-6 Proposed mechanisms include upregulation of cytokines and cell adhesion molecules and increase of endothelial cell permeability and death.7 Promotion of oxidative stress and hypertension-related mechanisms could also be involved.8-11 Cadmium has been associated with increased cardiovascular disease mortality and incidence.12-16 In cross-sectional studies, cadmium has been also associated with carotid atherosclerosis,6, 17 electro-cardiogram diagnosed myocardial infarction, 18 self-reported ischemic heart disease,19 stroke and heart failure,20 and peripheral arterial disease (PAD).21-23 Prospective evidence evaluating the association of cadmium exposure with incident PAD is lacking. Our a priori hypothesis was that increasing long-term cadmium exposure would be associated with increased incidence of peripheral artery disease.


In this study, our goal was to evaluate the prospective association between cumulative cadmium exposure and PAD incidence defined as an ankle brachial blood pressure index (ABI) 1.4 in at least one leg in PAD-free adults who participated in the Strong Heart Study (SHS) in 1989-91 and were followed through two examination visits in 1993-1995 and 1997-1999. Traditionally an ABI 1.4 has been related to non-compressible vessels due to calcification of the arterial wall.24 A recent AHA statement concluded that ABI >1.4 can also be related to occlusive disease.24 It is unknown, however, if this also applies to populations with a large burden of diabetes such as the Strong Heart Study. Nonetheless, individuals with either ABI 1.40 can be considered at increased risk of incident cardiovascular events and mortality independently of the presence of symptoms of PAD and other cardiovascular risk factors.24 As a consequence, we will also study ABI 1.4 in at least one leg only as secondary outcomes. Cumulative cadmium exposure was evaluated measuring cadmium in urine, a biomarker of long term exposure with a half-life of decades.3 Because a cross-sectional study from a US population exposed to very low levels of cadmium suggested interactions by sex and smoking,25 we also evaluated the associations in subgroups defined by sex and smoking status. Circ Cardiovasc Qual Outcomes. Author manuscript; available in PMC 2014 October 08.

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METHODS NIH-PA Author Manuscript

Study Population


The SHS is a large population-based prospective cohort study of cardiovascular disease in American Indian communities in Arizona, Oklahoma and the Dakotas.26, 27 Conducted in a population with high rates of cardiovascular disease, the SHS is one of the major cardiovascular cohorts funded by the National Heart, Lung, and Blood Institute in the United States and has served as a model for evaluation of physiologic and environmental risk factors in populations with a high burden of cardiovascular disease. From 1989 to 1991, men and women 45-75 years of age from 13 American Indian communities from Arizona, Oklahoma and North and South Dakota were invited to participate in the SHS. In Arizona and Oklahoma every eligible person was invited; in North and South Dakota a cluster sampling technique was used.26, 28 The overall participation rate was 62%.26 3,974 individuals from the original cohort had frozen urine specimens available for metal determinations. At baseline, the number of individuals with prevalent primary endpoint (ABI 1.40 in at least one leg), and secondary endpoints (ABI 1.40 in at least one leg only) was 415, 182 and 234, respectively. One individual at baseline showed 1 leg with ABI1.4. For this study, we used data from 3,559 SHS participants with urine samples available for metal determinations who were free of PAD at baseline (defined as ABI 1.40). We further excluded 396 participants missing follow-up ABI determinations, 2 participants missing urine cadmium determinations due to insufficient sample, 129 participants missing smoking information and 168 participants missing other variables of interest, leaving 2,864 participants for the primary analysis. Included participants were similar to excluded participants in age and body mass index but were less likely to be men, and have selfreported diabetes and hypertension (data not shown). In secondary analyses, alternative PAD definitions included ABI 1.40 only (N=2,950 and N= 2,937 participants, respectively, after excluding prevalent PAD cases with those definitions and participants with missing in the corresponding follow-up variables and baseline data). The 13 participating tribes, the Indian Health Service (IHS) Institutional Review Board (IRB) and the IRBs of the participating institutions approved the SHS and SHFS protocol and consent forms. Informed consent was obtained from all the participants.


Baseline data collection Sociodemographic data (age, sex, geographical location, education), post-menopausal status, smoking history (smoking status and pack-years), and history of diabetes and medication use were obtained from the baseline SHS questionnaire administered by trained and certified staff.26 Body mass index was calculated as measured weight in kilograms divided by measured height in meters squared. Three consecutive blood pressure determinations were taken from the right arm in the sitting position after 5 minutes of rest using a Baum mercury sphigmomanometer26 and the last two determinations were averaged. Hypertension was defined as a mean systolic blood pressure ≤140 mm Hg, a mean diastolic blood pressure ≤90 mm Hg, or antihypertensive medication use.

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Total cholesterol, plasma glucose and plasma creatinine were measured in fasting serum samples using enzymatic methods (reagent kits from Boehringer Mannheim Diagnostics, Indianapolis, IN). LDL-cholesterol was estimated by the Friedewald equation.29 High cholesterol was defined as estimated LDL-cholesterol ≤130 mg/dL. HbA1c was measured by high-performance liquid chromatography.30 Diabetes was defined as a fasting glucose ≤126 mg/dL, a non-fasting glucose ≤200 mg/dL, an HbA1c ≤6.5%, or the use of insulin or oral hypoglycemic agents. Estimated GFR was calculated from calibrated creatinine, age and sex using the Modification of Diet in Renal Disease Study formula.31 The MDRD equation factor for ethnicity was dropped for all participants. Urine cadmium determinations

NIH-PA Author Manuscript NIH-PA Author Manuscript

Spot urine samples were collected in polypropylene tubes, frozen within 1 to 2 hours of collection, shipped on dry ice and stored at −70°C in the Penn Medical Laboratory, MedStar Research Institute (Washington, DC). In 2009 up to 1.0 mL of urine from each participant was transported on dry ice to the Trace Element Laboratory of the Institute of ChemistryAnalytical Chemistry, Graz University, Austria. We measured cadmium using inductively coupled plasma mass spectrometry (ICPMS) (Agilent 7700× ICPMS, Agilent Technologies, Waldbronn, Germany), a multi-element technique that also provided information on other metals including As, Mo, Pb, Sb, Se, W, and Zn. In this paper, we focused on cadmium as we have strong experimental and epidemiological evidence supporting the study hypothesis. For other metals, except arsenic, limited evidence is available supporting a possible role in cardiovascular disease development. The analytical methods used in these analyses and the associated quality control criteria have been described in detail.32 The limit of detection for urine cadmium was 0.015 μg/L. Only one participant had urine cadmium concentrations below the limit of detection. The cadmium concentration in this participant was imputed as the limit of detection divided by the square root of two. The “Seronorm™ Trace elements Urine blank” (SERO As, Billingstad, Norway) with a recommended cadmium concentration of 0.35 μg/l was used for quality control. We found a mean of 0.38 (standard deviation 0.07) μg/l (n=66). Additionally, the cadmium concentration in the Certified Reference Material NIST 1643e “Trace elements in water” (NIST, Gaithersburg, USA) was determined in each run. We obtained a mean of 6.42 (standard deviation 0.38) μg/l (n=79), while the certified concentration mean was 6.57 (standard deviation 0.07) μg/l. Following the methods by Jarret and co-workers,33 urine cadmium concentrations were corrected for molybdenum oxide interference using the formula [Cd]corr = [Cd]-0.0016*[Mo]. To account for urine dilution, urine cadmium concentrations were expressed in μg per g of urine creatinine. Urine creatinine was measured at the Laboratory of the National Institute of Diabetes and Digestive and Kidney Disease, Epidemiology and Clinical Research Branch (Phoenix, AZ) by an alkaline picrate methodology conducted in a rapid flow analyzer.26 Incident PAD follow-up Right arm blood pressure and bilateral ankle blood pressure for ankle brachial index (ABI) determinations were measured twice, with the subject in supine position, using a handheld Doppler device (Imex medical Systems, Golden, Colorado). ABI for each leg was computed as the mean systolic blood pressure in the ankle (posterior tibial artery) divided by the mean


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systolic blood pressure in the right arm (brachial artery). In the main analysis, incident cases of PAD were defined as a newly diagnosed ABI 1.40 in at least one leg in at least one of the two follow-up clinic visits conducted in 1993–1995 and 1997–1999. Stenotic peripheral arterial disease and vascular calcification are generally long-term progressive processes.24, 34 Consequently, participants missing ABI determinations in the 1993-1995 visit, but free of PAD in 1997-1999 (N=161), were imputed as not having PAD at the 1993-1995 visit. Participants missing ABI determinations in the baseline visit but free of PAD in the 1993-1995 visit (N=30) were imputed as not having PAD in the baseline visit. Time to event was calculated from the date of baseline examination in 1989-91 to the date of the follow-up examination with newly diagnosed PAD for participants with incident PAD and to the date of the last examination available or the date of death, whichever occurred first, for participants without incident PAD. The mean follow-up time among participants who did and did not develop PAD (primary outcome) was 4.3 and 6.9 years, respectively. Statistical methods


Urine cadmium levels were markedly right-skewed and log-transformed for statistical analyses. The prospective association of urine cadmium concentrations with cardiovascular disease incidence was evaluated using Cox-proportional hazard models for interval-censored data using the R-package “intcox”35 using years since the baseline examination as the time scale. The assumption of hazards proportionality was visually assessed based on the smoothed association between time and the log(−log(S(t))), with S(t) being the survival at time “t”, by urine cadmium categories, with no major departures from proportionality.


We used three statistical models with progressive adjustment. In model 1 we adjusted for sex, age at baseline (continuous as restricted cubic splines with knots at 50 and 60 years), education (≤12 years education completed, 1.4 from 60% to 80%.24 Importantly, cadmium was associated with incident PAD in smoking-adjusted models and separately in smokers and in never smokers, suggesting that cadmium is an important cardiovascular disease risk factor independent of the source of exposure.


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Cadmium is a by-product from mining, smelting and refining zinc, lead and copper ores. Over the last decades, its use and production in consumer products, particularly in nickelcadmium batteries, has increased substantially.37 Cadmium has also become an important soil contaminant from industrial releases, from fuel combustion and from cadmiumcontaining fertilizers.2, 3, 37, 38 Exposure to cadmium in the population occurs through tobacco smoke, food and ambient air, particularly near hazardous waste sites, and industrial and occupational settings.2, 39, 40 We do not have information on specific sources of cadmium exposure in our study population. Nonetheless, urine cadmium concentrations in the Strong Heart Study participants were higher than in the general US population.41 While the prevalence of smoking is higher in American Indians than in other US ethnic groups,42-44 their intensity of smoking is markedly lower43 and sources of exposure other than smoking, such as occupational and environmental exposures,40, 45-47 may be involved in the increased urine cadmium concentrations in our study population.


Our prospective analysis evaluated the association between cadmium and incident PAD. The findings were consistent with the limited number of cross-sectional studies evaluating the association between cadmium exposure and prevalent PAD.21-23 In the 1999-2000 National Health and Nutrition Examination Survey (NHANES), the odds ratio for PAD comparing the 75th to the 25th percentiles of urine cadmium distribution was 3.05 (0.97–9.58).22 In the same study population the odds ratio for PAD comparing the highest to the lowest quartiles of blood cadmium was 2.42 (1.13–5.15).21 In a subsample of 428 participants from the Flemish Study on Environment, Genes and Health Outcomes (FLEMENGHO), blood cadmium was also associated with PAD, and the points estimates were similar to the ones reported in NHANES 1999-2000.23 In the FLEMENGHO subsample, however, the association between PAD and 24hour urine cadmium concentrations was not statistically significant, but the point estimates were not reported and we cannot evaluate the power of the study to detect an association. Studies with other end-points, including increased carotid atherosclerosis,6, 17, 48 prevalent cardiovascular disease,19, 20 incident cardiovascular morbidity,16 and mortality12-15 all support a role for cadmium exposure in atherosclerosis development in humans.


Some,12, 14, 18-20, 25 but not all,13, 15, 16, 20, 49, 50 epidemiologic studies have found differences in cadmium-related cardiovascular outcomes by sex. In NHANES 1999-2004, the prevalence of PAD increased progressively throughout the whole range of cadmium concentrations among men but showed a U-shaped relation in women. The non-linear component in women mostly reflected the association in never smokers. 25 In the present study, the associations were similar for men and women, and the interaction by sex was not statistically significant. It is possible that the sex differences respond to random sampling variability, but it will be necessary to reproduce the findings in other prospective studies in general population samples exposed to relatively low levels of exposure. Residual confounding by smoking is a concern in epidemiologic studies of cadmium because smoking is a well-known and strong risk factor for PAD 51 and a major determinant of cadmium exposure.3 To address confounding by smoking, we performed separate analyses by smoking status. In our study, the association for never smokers was weaker than for smokers and non-statistically significant. While the p-value for the interaction of


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smoking status and cadmium was not statistically significant, the power of this test may be limited. Positive residual confounding by intensity or duration of smoking is possible for both never and ever smokers because smoking status and pack-years were defined by selfreport. Among never smokers, the association of cadmium with peripheral arterial disease is also subject to positive confounding due to potential exposure to second-hand smoke. In NHANES analyses, however, adjustment for serum cotinine (an objective biomarker of tobacco internal dose) did not change the association between cadmium and PAD, 21,25 supporting that cadmium is a risk factor for PAD independent of tobacco smoke.


Other reasons could also explain differential associations by smoking status. For instance, potential effect modification of cadmium with other atherogenic components of tobacco smoke could explain stronger associations between cadmium and PAD among smokers compared to non-smokers. Among never-smokers, negative confounding by vegetable intake, a major source of cadmium exposure, is possible. In a recent systematic review of epidemiologic studies, 52 8 studies evaluated associations between cadmium exposure and clinical cardiovascular disease endpoints among never smokers. The clinical endpoints were heterogeneous and could not be pooled, but 7 of 8 studies showed positive associations between cadmium and clinical cardiovascular disease, although only 2 of them were statistically significant. Altogether, cadmium is clearly associated with cardiovascular disease among smokers. Among non-smokers, there is supportive evidence that cadmium is a cardiovascular risk factor, but this evidence is not conclusive. The associations between cadmium and PAD observed in the Strong Heart Study are consistent with experimental evidence supporting a variety of potential mechanisms for cadmium as an atherogenic factor, including promoting the formation of reactive oxygen species,8 interfering with anti-oxidative stress responses,8, 53 promoting hypertension54, 55 and kidney disease,56 and causing endothelial dysfunction and damage.4-6, 57 Cadmium could also act through epigenetic58 and endocrine disruption59-61 pathways. The mechanistic studies add biological plausibility to the evidence from studies in human populations suggesting a dose-response relationship in the association between cadmium exposure and PAD.


Our study has some limitations. First, we used a single baseline urine cadmium determination as a biomarker of exposure. Non-differential measurement error may have thus resulted in an underestimation of the associations. Second, we imputed 191 individuals who were known to be PAD free at the end of the follow-up but did not have ABI measurements during the follow-up as being PAD free also at intermediate follow-up visits. ABI measurements, however, can undergo daily fluctuations. In our study population, only 74 and 59 individuals with measured ABIs between 0.9 and 1.4 range at the 1st and 3rd exams, had values above or below that range, at the 2nd exam, respectively. Accordingly, depending on the PAD definition, we would expect between 2.5 and 5 % of the imputed observations to be misclassified (a total of 5 - 10 individuals). Therefore, the expected number of misclassified participants with imputed data is small and unlikely to impact the findings. Third, 10% of participants were lost during follow-up. However, the distribution of cadmium concentrations and demographic variables at baseline did not differ comparing those who missed and not PAD determinations, making selection bias less likely. Finally,


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American Indian communities have increased burdens of diabetes and obesity as well as of mortality due to non-cardiovascular causes compared to other populations.62 Generalizability to populations with a different cardiovascular risk factor profile is unknown, although cadmium toxicity pathways are likely to be common for human populations. Important strengths of this study include the prospective design and the long follow-up, the high number of events, the availability of detailed information on relevant confounders, and the careful standardization and quality control of data collection, laboratory analyses, and identification of incident cardiovascular events.26, 27 In addition, our study contributed to the characterization of a potentially important environmental cardiovascular risk factor in American Indian populations, an understudied ethnic group.


In conclusion, cadmium exposure was prospectively associated with an increased risk of PAD. Our prospective findings in the Strong Heart Study will add to the evidence-base for cadmium-related peripheral arterial disease, but large studies in never-smokers with adequate evaluation of potential confounders, including vegetable intake, are needed to fully establish the cardiovascular effects of non-smoking related cadmium exposure. Atherosclerotic cardiovascular disease is a major cause of death, functional disability and medical costs around the world.63, 64 The implementation of population-based preventive strategies to decrease cadmium exposure could contribute to reduce the burden of cardiovascular disease, including PAD, in the population.

Supplementary Material Refer to Web version on PubMed Central for supplementary material.

Acknowledgments Funding/Support: This work was supported by the National Heart Lung and Blood Institute (grant R01 HL090863, SHS grants HL41642, HL41652, HL41654 and HL65521). Maria Tellez-Plaza was supported by a Rio Hortega training grant (Funds for Research in Health Sciences, Ministry of Science and Innovation, Spain).

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Figure 1. Hazard ratios for incident peripheral arterial disease (ankle-brachial index 1.4) by urine cadmium concentrations, Strong Heart Study


Abbreviations: PAD, peripheral arterial disease. Solid lines are adjusted hazard ratios and dashed lines are 95% confidence intervals based on restricted quadratic splines for logtransformed cadmium concentrations with knots at the 5th, 50th and 95th percentiles (0.33, 0.94 and 2.65 μg/g, respectively). The reference was set at the 10th percentile of the cadmium distribution. Vertical bars represent the histogram of cadmium distribution. Models were adjusted for sex, age at baseline (restricted cubic splines with knots at 50 and 65 years), education, location, body mass index, postmenopausal status, total cholesterol, estimated LDL-cholesterol, hypertension, diabetes, glomerular filtration rate, smoking status and cumulative smoking dose (restricted cubic splines with knots at 10, 20 and 30 packyears).

NIH-PA Author Manuscript Circ Cardiovasc Qual Outcomes. Author manuscript; available in PMC 2014 October 08.

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Table 1 a,b


Baseline Characteristics of Study Participants by Incident Peripheral Arterial Disease Status

Characteristics

d PAD (N= 470)

No PAD (N= 2,394)

Overall (N= 2,864)

Age, years

57.4 (0.4)

55.6 (0.2)

55.9 (0.1)

Women, %

61.5 (2.2)

61.0 (1.0)

61.1 (0.9)

c Postmenopausal Women , % Location, %

81.3 (2.3)

74.1 (1.1)

75.3 (1.0)

Arizona

38.5 (2.2)

30.6 (0.9)

31.9 (0.9)

Oklahoma

30.2 (2.1)

35.4 (1.0)

34.6 (0.9)

Dakotas

31.3 (2.1)

34.0 (1.0)

33.5 (0.9)

52.1 (2.3)

44.4 (1.0)

45.7 (0.9)

31.7 (2.1)

30.8 (0.9)

30.9 (0.9)

Education < High School, % Smoking, % Former Current Cumulative Smoking, pack-years

36.4 (2.2)

34.9 (1.0)

35.1 (0.9)

11.8 (0.8)

10.5 (0.4)

10.7 (0.3)


Body Mass Index, kg/m2

31.2 (0.3)

30.8 (0.1)

30.9 (0.1)

Total cholesterol, mg/dL

192.9 (1.7)

189.4 (0.8)

190.0 (0.7)

LDL cholesterol, mg/dL

118.8 (1.5)

116.6 (0.7)

116.9 (0.6)

Hypertension, %

45.1 (2.3)

35.3 (1.0)

36.9 (0.9)

Diabetes, %

59.8 (2.3)

43.1 (1.0)

45.8 (0.9)

11.9 (1.5)

7.9 (0.5)

8.5 (0.5)

Urine Cadmium, μg/L

1.03 (0.96, 1.10)

1.03 (1.00, 1.07)

1.03 (1.00, 1.06)

Urine Cadmium, μg/g creatinine

0.96 (0.90, 1.02)

0.94 (0.91, 0.96)

0.94 (0.92, 0.96)

GFR < 60

mL/min/1.73m2,

%

Abbreviations: GFR, glomerular filtration rate; PAD, peripheral arterial disease a Percentages (standard errors) are given for categorical variables or arithmetic means (standard errors) for continuous variables, except for urine cadmium and creatinine-adjusted urine cadmium, for which geometric means (95% confidence intervals) are reported. b

To convert urine cadmium to nmol/L, multiply by 8.896; to convert creatinine-corrected urine cadmium to nmol/mmol creatinine, multiply by 1.006. c Subsample of women (N Overall = 1,749, N PAD = 289 and N no PAD = 1,460). d


PAD defined as an ankle-brachial index 1.4.



NIH-PA Author Manuscript Model 1 HR (95% CI)

0.01

1.93 (1.32, 2.74)

1 (Referent)

0.10

2.07 (1.22, 3.37)

1.32 (0.79, 2.15)

1 (Referent)

0.10

2.10 (0.96, 3.88)

1.13 (0.56, 1.87)

1 (Referent)

0.09

2.32 (0.91, 4.59)

1.36 (0.64, 2.40)

1 (Referent)

0.14

2.10 (1.16, 3.53)

1.32 (0.76, 2.19)

1 (Referent)

0.02

1.96 (1.32, 2.81)

Model 3: Model 2 further adjusted for smoking status and cumulative smoking dose (restricted cubic splines with knots at 10, 20 and 30 pack-years). The sample sizes were N= 2,864 for an ankle-brachial index 1.4, 2,950 for an ankle-brachial index < 0.9 and 2,937 an antebrachial index >1.4.

Model 2: Model 1 further adjusted for body mass index, postmenopausal status, total cholesterol, estimated LDL-cholesterol, hypertension, diabetes and glomerular filtration rate

Model 1: Sex, age at baseline (restricted cubic splines with knots at 50 and 65 years), education and location

0.11

2.12 (1.08, 3.84)

55/ 954

> 1.23

68/ 906

1 (Referent) 1.14 (0.60, 1.84)

79 / 875

0.71 – 1.23

Linear p-trend

Model 3 HR (95% CI)

1.27 (0.87, 1.74)

Ankle brachial index > 1.4 in at least one leg

≤ 0.71

Tertiles

0.12

2.07 (1.27, 3.32)

> 1.23

119 / 872

1 (Referent) 1.33 (0.83, 2.14)

74 / 910 85 / 890

0.71 – 1.23

Linear p-trend

1 (Referent) 1.23 (0.86, 1.70)

Ankle brachial index < 0.9 in at least one leg

≤ 0.71

Tertiles

0.01

2.02 (1.42, 2.91)

163 / 777

> 1.23

154 / 797

1 (Referent) 1.29 (0.92, 1.78)

153 / 820

0.71 – 1.23

Linear p-trend

Model 2 HR (95% CI)

Ankle brachial index 1.4 in at least one leg

Cases / Non cases

≤ 0.71

Tertiles

Urine cadmium, μg/g

Hazard Ratio (95%CI) for Incident Peripheral Arterial Disease by Urine Cadmium Tertiles


Table 2 Tellez-Plaza et al. Page 16



NIH-PA Author Manuscript 289 / 1460

Women

470 / 2394

1.41 (1.05, 1.81)

1.50 (1.05, 2.05)

1.25 (0.83, 1.80)

1.44 (1.01, 1.99)

1.32 (0.84, 1.90)

HR (95% CI)

0.45

0.73

P-int

Hazard ratios and associated P for interaction were obtained from Cox proportional hazard models with log-transformed cadmium as a continuous variable.

Models were adjusted for sex, age at baseline (restricted cubic splines with knots at 50 and 65 years), education, location, mass index, postmenopausal status, total cholesterol, estimated LDL-cholesterol, hypertension, diabetes, glomerular filtration rate, smoking status and cumulative smoking dose (restricted cubic splines with knots at 10, 20 and 30 pack-years).

The 80th and 20th percentiles of urine cadmium distribution were 1.62 and 0.55 μg/g, respectively.

Overall

150 / 822 320 / 1572

Never Smokers

Ever Smokers

Smoking

181 / 934

Cases / Non Cases

Men

Sex

Subgroups

Hazard ratio (95% confidence interval) for incident peripheral arterial disease (ankle brachial index 1.4) comparing the 80th to the 20th percentile of urine cadmium distribution, by sex and smoking


Table 3 Tellez-Plaza et al. Page 17


Lipoprotein-Associated Phospholipase A2 and Incident Peripheral Arterial Disease in Older Adults: The Cardiovascular Health Study.

Peripheral arterial disease.

Atherectomy for peripheral arterial disease.

Evaluating peripheral arterial occlusive disease.

Fibrinogen genes and peripheral arterial disease.

Uric Acid and Peripheral Arterial Disease.

Metabolic syndrome and peripheral arterial disease.

Arterial stiffness in patients with peripheral arterial disease.

Reply to arterial stiffness in patients with peripheral arterial disease.

Laser angioplasty of peripheral arterial occlusive disease.

Surgical intervention for peripheral arterial disease.

Bioresorbable scaffolds in peripheral arterial disease.

Treatment of hypertension in peripheral arterial disease.

Antithrombotic therapy in peripheral arterial occlusive disease.

Spatiotemporal Changes Posttreatment in Peripheral Arterial Disease.

Advances in peripheral arterial disease endovascular revascularization.

A compendium on peripheral arterial disease.

Below-knee amputation in peripheral arterial disease.

Patterns of disease distribution of lower extremity peripheral arterial disease.

Audible handheld Doppler ultrasound and peripheral arterial disease.

[Peripheral arterial disease and diabetes mellitus(author's transl)].

Atherosclerosis, peripheral arterial disease and the vascular response to ketanserin.

Hyperuricemia in coronary, cerebral and peripheral arterial disease: an explanation.

Endothelial shear stress and blood viscosity in peripheral arterial disease.