Cadmium exposure, intercellular adhesion molecule-1 and peripheral artery disease: a cohort and an experimental study

OBJECTIVES Cadmium exposure has been found to be associated with atherosclerotic plaques in the carotid arteries and with circulating levels of the proatherogenic intercellular adhesion molecule-1 (ICAM-1). The research questions were (1) if blood and urinary cadmium levels are associated with low ankle-brachial index (ABI) as a measure of peripheral artery disease in a longitudinal study and (2) if ICAM-1 mediates proatherogenic effects of cadmium exposure. DESIGN A prospective, observational cohort study with a 5-year follow-up and an experimental study of cultured human aortic endothelial cells exposed to cadmium. SETTING Research unit at a university hospital. PARTICIPANTS A cohort of 64-year-old women (n=489) recruited by stratified sampling of similarly sized groups with normal, impaired and diabetic glucose tolerance as assessed in a population-based screening examination. PRIMARY AND SECONDARY OUTCOME MEASURES ABI (ratio of the systolic blood pressures in the tibial and brachial arteries ≤0.9 in any artery) in relation to cadmium exposure; ICAM-1 concentrations in the cell culture medium after cadmium incubation. RESULTS High (tertile 3 vs 1) concentrations of blood (B-Cd) or creatine-adjusted urinary cadmium (U-Cd) at baseline were found to predict low ABI after adjustment for smoking and other cardiovascular risk factors at baseline. For U-Cd the OR was 2.5 (95% CI 1.1 to 5.8). After exclusion of participants with ultrasound-assessed femoral atherosclerosis at baseline the OR for U-Cd was unchanged, and for B-Cd it was 3.7 (95% CI 1.05 to 13.3). Inclusion of serum ICAM-1 levels did not affect the cadmium-related ORs in multivariate analyses. The experimental study did not show any cadmium-induced increase of the production of ICAM-1 from human endothelial cells. CONCLUSIONS Cadmium exposure was associated with future peripheral artery disease, supporting the concept that cadmium exposure in the population has proatherogenic effects, although ICAM-1 mediated effects do not seem to be involved.