Impact of combined elevations of homocysteine and asymmetric dimethylarginine on all-cause death ― The Tanushimaru Study

•Both homocysteine (Hcy) and asymmetric dimethylarginine (ADMA) induce endothelial dysfunction.•We have measured Hcy and ADMA levels simultaneously in a general population.•The association between elevations of the Hcy or ADMA and all-cause death are shown.•The hierarchical model showed synergistic effect of Hcy and ADMA on all-cause death.•Combined elevations of Hcy and ADMA demonstrated a big impact on all-cause death. Both homocysteine (Hcy) and asymmetric dimethylarginine (ADMA) induce endothelial dysfunction. However, the impact of both elevations on all-cause death is not known. We investigated the association between elevations of Hcy or ADMA and all-cause death in a general population. A total of 517 subjects (224 men, 293 women; mean age, 62.8 years) were recruited from a population-based survey in 1999 in Tanushimaru, and we measured fasting plasma Hcy and ADMA levels. We followed them up for over 20 years and examined the effect on mortality using Cox proportional hazard regression model. The mean follow-up years were 17.7 (1.8-20.8). In this period, 182 subjects have died (35.2%). The correlation between Hcy and ADMA was high (r=0.194; p