Date on Master's Thesis/Doctoral Dissertation

12-2012

Document Type

Doctoral Dissertation

Degree Name

Ph. D.

Department

Physiology and Biophysics

Committee Chair

Maldonado, Claudio

Author's Keywords

Homocysteine; arrhythmia; MNDA receptor; cardiac conduction system; electrophysiological study; atrioventricular node

Subject

Arrhythmia; Heart--Diseases; Heart beat; Heart conduction system

Abstract

Introduction: Hyperhomocysteinemia (HHcy) is a pathological condition characterized by excessive levels of plasma homocysteine (Hcy). Patients with HHcy are reported to be at risk for arrhythmias like atrial fibrillation and sudden cardiac death (SCD); however, the causative mechanisms remain unknown. The effects of HHcy on sinus node function, atrioventricular conduction and ventricular vulnerability were investigated by in vivo electrophysiological (EP) analysis, and the role of the cardiac N-methyl-D-aspartate receptor (NMDA-R) in promoting Hcy-induced conduction abnormalities was explored. Materials and Methods: Anesthetized wild-type control mice (WT), mice receiving Hcy in the drinking water for 12 weeks (DW), and heterozygous cystathionine-ß-synthase knockout mice (CBS+/-) were subjected to electrocardiographic (ECG) analysis and programmed electrophysiological (EP) studies. To examine the role of the NMDA-R in eliciting conduction changes in HHcy, animals from the three groups were subjected to paired-design repeat EP studies before and after intraperitoneal injection of magnesium sulfate (MgS04, 20mg/kg), an endogenous blocker of NMDA-R. Another set of studies utilized a specific NMDA-receptor antagonist, dizocilpine (MK-801), in similarly paired-design studies in an acute, intraperitoneal infusion model of HHcy. Expression levels of cardic NMDA-R in all three groups of animals were quantified by immunoblotting, and immunohistochemical identification of cardiac NMDA-Rs at the mouse atrioventricular (A V) junction was undertaken. Results: DW compared to WT had significantly shorter RR, PR, QT, and HV intervals, corrected sinus node recovery times (CSNRT), Wenckebach periodicity (WP), AV nodal effective refractory periods (A VNERP), and right ventricular effective refractory periods (RVERP). No ventricular arrhythmias were induced in either WT or DW. In the paired-design studies, blockade of cardiac NMDA-R with MgS04 had no effect on any ECG or EP variables in WT but significantly prolonged RR, QT, HV, CSNRT, WP, and AVNERP in DW and CBS+/- animals. Immunopositive staining for cardiac NMDA-R at the mouse A V junction was detected. Conclusions: Significant changes in conduction were observed between wild-type mice and mice with diet-induced or genetically-induced hyperhomocysteinemia (HHcy). Low-dose magnesium administration did not alter ECG or EP conduction variables in wildtype mice, but had a profound effect on mice with HHcy. These results suggest that shortened sinoatrial and atrioventricular conduction time in mild HHcy may involve cardiac NMDA-Rs.

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