Blood homocysteine levels mediate the association between blood lead levels and cardiovascular mortality

Lead is a heavy, toxic metal and its exposure to humans can lead to increased risk of cardiovascular disease development and mortality. Lead exposure has been shown to induce hyperhomocysteinemia (HHCy ) which further increases the risk of cardiovascular diseases. We aimed to investigate the mediation effect of blood lead induced HHCy on cardiovascular mortality in a national cohort. A total of 17,915 adults aged ≥ 20 who participated in the National Health and Nutrition Examination Survey (1999 to 2006). Information on mortality was ascertained via probabilistic matching to the death certificates from the National Death Index recorded up to December 31, 2015. Cox proportional hazards regression was performed to assess the association between blood lead levels and mortality. Mediation via HHCy was examined using a logit model. During a mean follow-up of 11.6 years, the incidences of CVD mortality were 0.73, 2.18, 3.03 and 4.94 per 1000 person-years across quarterlies of blood lead levels from low to high. Following multivariable adjustment, blood lead levels were strongly associated with CVD mortality in all mortality models (p trend < 0.001). This association remained statistically significant after further adjusting for quartiles of homocysteine (model 3; HR 1.38 (95% CI 1.01 - 1.89) p trend < 0.001). Furthermore, blood lead levels increased the odds of CVD mortality via homocysteine (indirect effect) (OR 1.42 (95% CI 1.30 - 1.55)), demonstrating the mediatory effect of homocysteine. This the first study that demonstrates that increased homocysteine mediates more than half of CVD mortality related to blood lead levels.