Mild hyperhomocysteinemia increases atrioventricular nodal conduction: Role of the cardiac NMDA receptor

Abstract

Hyperhomocysteinemia (HHcy) is a pathological condition resulting in elevated plasma concentrations of homocysteine (Hcy). Patients with HHcy have been reported to be at risk of sudden cardiac death (SCD). In previous electrophysiological (EP) studies in mice with HHcy, we observed an increase in atrioventricular (AV) nodal conduction rate. The mechanisms responsible for this alteration are unknown. Recent studies in mammals have shown that NMDA receptors (NMDARs) are present in heart, and Hcy is known to activate NMDARs. We hypothesize that in HHcy, cardiac NMDARs are hyperstimulated increasing both calcium transient currents in nodal cells and AV nodal conduction rate. To test this hypothesis two groups of C57BL/6 mice were treated with either Hcy in the drinking water or just water for 12 weeks. Standard EP studies were conducted using an octopolar catheter placed in the right ventricle. Surface and intracardiac ECGs were recoded and analyzed. A baseline EP study was conducted in all mice, followed by a second EP study, performed 30 min after IP administration of 20mg/Kg of magnesium sulfate (MgSO4) to block NMDARs. MgSO4 slowed AV nodal conduction in mice with HHcy but had no effect on control mice. These results suggest that acceleration of AV nodal conduction in HHcy may involve the cardiac NMDAR. Further studies using transgenic animals deficient in NMDAR are needed to confirm the role of this receptor.