Blood cadmium and lead concentrations in association with homocysteine and all-cause and cardiovascular mortality

• Cd and Pb were associated with elevated all-cause and CVD mortality • Homocysteine was positively associated with all-cause and CVD mortality • Homocysteine contributed to the associations between Cd and all-cause and CVD mortality • Homocysteine contributed to the associations between Pb and all-cause and CVD mortality • Pb modified the associations of Cd, homocysteine, and all-cause and CVD mortality Cadmium and lead exposure are reported to associate with elevated plasma homocysteine concentrations. However, whether homocysteine plays a role in the associations of cadmium and lead with all-cause and cardiovascular mortality is unclear. We conducted a cohort study using data from 6,456 participants in the National Health and Nutrition Examination Survey (NHANES) (2003-2006). Cox regression models and restricted cubic splines (RCS) were used to examine the associations between cadmium, lead, and homocysteine and all-cause and cardiovascular mortality. Mediation analysis was conducted to evaluate the indirect effect of homocysteine in the associations between cadmium, lead and all-cause and cardiovascular mortality. During a median of 14.33 years of follow-up, 1,642 (25.43%) all-cause deaths and 575 (8.91%) cardiovascular deaths were observed. When compared with the first quartile, cadmium, lead, and homocysteine levels in the fourth quartile were associated with increased all-cause mortality risk [hazard ratios (HRs) with 95% confidence interval (CI) 1.91 (1.60, 2.29), 1.38 (1.16, 1.64), and 1.74 (1.42, 2.14), respectively] and cardiovascular mortality [1.85 (1.37, 2.50), 1.55 (1.15, 2.09), 1.67 (1.17, 2.37), respectively]. RCS analysis suggested nonlinear associations of cadmium, lead, and homocysteine with all-cause mortality, nonlinear relationships between cadmium and cardiovascular mortality, and linear associations between lead, homocysteine and cardiovascular mortality. Changes in homocysteine levels accounted for approximately 4.11% and 5.81% of the observed associations between cadmium exposure and all-cause and cardiovascular mortality, respectively. Similar observations were made for homocysteine on the associations of lead exposure and all-cause (11.05%) and cardiovascular (7.69%) mortality. Furthermore, lead concentrations modified the associations of cadmium and homocysteine with cardiovascular and all-cause mortality. Our findings suggested that plasma homocysteine was associated with the observed relationships between cadmium and lead exposure and increased all-cause and cardiovascular mortality, potentially reflecting underlying pathways relevant to heavy metal-related cardiovascular risk.