Abstract 11758: NOS1AP Deletion Enhanced Susceptibility to Ventricular Tachyarrhythmias and Cardiac Death in Pressure Overload
Introduction; Genome wide association study (GWAS) identified association of NOS1AP (neuronal nitric oxide synthase adaptor protein) with QT interval variations and sudden cardiac death, the underlying mechanism of which is poorly understood. We used NOS1AP knockout (KO) mouse to elucidate the role of NOS1AP in pathological conditions.
Methods; Wild type (WT; n=60) and NOS1AP KO (n=40) mice were enrolled in this study. Mice were subjected to either transverse aortic constriction (TAC) or myocardial infarction (MI) operation. Surface electrocardiogram (ECG) and ultrasound cardiogram (UCG) were recorded in baseline condition and 2 weeks after the operation. Implantable telemetry recording was done in subgroup of mice. Oxidative products were evaluated by western blotting, and reactive oxygen species (ROS) was evaluated by dihydroethidium staining in histology.
Results; ECG showed slightly but not significantly prolonged QTc interval in KO than WT. This difference was cancelled by infusion of NOS inhibitor, L-NAME. UCG revealed significantly reduced fractional shortening (FS) in KO (32.6±0.8% and 40.2±2.1% in KO and WT, respectively p<0.01). After TAC operation, survival rate was lower in KO than WT (50% and 90.5% at 5 weeks after TAC, p<0.01). FS was more impaired in KO mice 2 weeks after TAC than WT (16.6±3.5% and 35.0±2.5%, p<0.01). Telemetry recording detected frequent non-sustained ventricular tachycardias only in KO (3 cases out of 6) but not in WT (0 out of 5). The survival rate was not different between KO and WT after MI procedure (82% vs. 78% at 5 weeks after TAC, p=0.67). The expression of nitrotyrosine and hydroxynonenal was significantly higher, and the fluorescence of dihydroethidium was greater in KO than WT.
Conclusions; Genetic deletion of NOS1AP induced enhanced oxidative stress, which may underlie frequent ventricular tachyarrhythmias, impaired cardiac function, and sudden cardiac death in pressure overload condition.
- © 2011 by American Heart Association, Inc.