Genetic Deletion of NOS1AP Enhances Ventricular Tachycardia and Cardiac Death in Pressure Overload

Abstract

Introduction:GWAS identifies association of NOS1AP (neuronal nitric oxide synthase adaptor protein) with QT interval variations and sudden cardiac death. We aimed to characterize NOS1AP KO mice.Methods:Mice underwent transverse aortic constriction (TAC) procedure to compare the survival rate. Surface electrocardiogram (ECG) and ultrasound cardiogram (UCG) were recorded in baseline condition and 2 weeks after TAC. Implantable telemetry recording was done in subgroup of mice.Results:ECG showed slightly longer QT 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 (32.9% vs. 40.4%). After TAC operation, survival rate was significantly reduced in KO than WT (50% vs. 9.5%). FS was more impaired in KO mice 2 weeks after TAC (16.6% vs. 35.0%). Telemetry recording detected frequent non-sustained ventricular tachycardias and premature ventricular beats only in KO but not in WT.Conclusions:Genetic deletion of NOS1AP induced frequent ventricular tachyarrhythmias, impaired cardiac function, and sudden cardiac death in pressure overloaded condition.