Objective: The T2238C ANP gene molecular variant has been related to increased risk of cardiovascular events. In-vitro investigations of its pathogenetic mechanisms demonstrated that the 2238C allele variant induced detrimental effects on endothelial cells through increased ROS production. Based on these observations we hypothesized that T2238C ANP gene variant could exert a pathogenic impact on endothelial function in-vivo.

Design and methods: We enrolled 10 double mutant CC2238/ANP healthy subjects and 10 healthy subjects carrying the 2238TT wild type genotype. NT-proANP levels were measured in a fasting venous sample. Endothelial-dependent vasodilation was assessed through FMD procedure at brachial level and endothelial endothelial-independent vasodilation was evaluated by means of FMD after sublingual nitrate administration. All subjects underwent carotid ultrasonography.

Results: No significant differences were observed between the two groups in terms of prevalence of cardiovascular risk factors. NT-proANP plasma levels were comparable in double mutant and in wild type subjects (2200±190 vs 2353±340, respectively). Endothelial-dependent vasorelaxation was significantly lower in 2238C as compared to 2238T allele carriers (6.97±2.4 vs 9.31±1.6, p=.02). No significant differences were observed regarding endothelial-independent vasodilation (13.4±3.4 vs 14.5±5.6, NS). Carotid ultrasonography did not show any significant alteration of arterial wall in either group.

Conclusions: The 2238C ANP molecular variant, responsible for detrimental effects on endothelial cells in-vitro, leads to significant early impairment of endothelial function in-vivo. The functional derangement induced by T2238C ANP gene variant may contribute to the increased predisposition to cardiovascular events observed in 2238C allele carriers. Further studies are needed to fully explore this issue.