Review of cadmium exposure and smoking‐independent effects on atherosclerotic cardiovascular disease in the general population

Abstract Background Exposure to cadmium (Cd) via food and smoking is associated with an increased risk of atherosclerotic cardiovascular disease (ASCVD). Blood and urine levels of Cd are established biomarkers of exposure. Objectives To review (1) the smoking‐independent associations between Cd exposure and ASCVD, including the possible presence of a nonlinear dose–response relationship with Cd exposure and (2) the causal effects of Cd exposure on different stages of atherosclerosis. Methods Narrative review. Results Cd confers increased risk of ASCVD and asymptomatic atherosclerosis in the carotid and coronary arteries above B‐Cd >0.5 μg/L or U‐Cd >0.5 μg/g creatinine, but it has not been shown below a threshold of these exposure levels. Adjustment for smoking does not exclude the possibility of residual confounding, but several studies in never‐smoking cohorts have shown associations between Cd and ASCVD, and experimental studies have demonstrated pro‐atherosclerotic effects of Cd. Cd accumulates in arterial walls and atherosclerotic plaques, reaching levels shown to have proatherosclerotic effects. Suggested early effects are increased subendothelial retention of atherogenic lipoproteins, which become oxidized, and endothelial dysfunction and damage with increased permeability for monocytes, which in the intima turn to macrophages and then to foam cells. Later, Cd may contribute to plaque rupture and erosion by endothelial apoptosis and degradation of the fibrous cap. Finally, by having prothrombotic and antifibrinolytic effects, the CVD risk may be further increased. Conclusions There is strong evidence that Cd causes ASCVD above a suggested exposure level via mechanisms in early as well as the late stages of atherosclerotic disease.