Abstract 14488: Male Predominant Cardiac Phenotype in Cardiac-Specific Gpd1-l Knockout Mice

Introduction: We reported that a mutation in Glycerol-3-Phosphdate Dehydrogenase-1 Like (GPD1L-A280V) is linked to Brugada Syndrome (BrS). This mutation increases acetylation and reduces surface expression of Nav1.5, and reduces inward Na+ current (INa) in HEK293 cells and rat neonatal cardiac myocytes. Global homozygous knockout of Gpd1-l in mice (Gpd1l-/-) was usually lethal, though we noted increased Nav1.5 acetylation, decreased INa, and pharmacologically inducible arrhythmias in Gpd1l+/- heterozygotes. Cardiac-specific deletion of Gpd1l (cGpd1l-/-) led to ventricular arrhythmias, contractile dysfunction, and a BrS-like ECG phenotype in males. Here, we extend our study to female cGpd1l-/- mice.

Methods: cGpd1l ^-/- mice were generated by crossing floxed (Gpd1l ^fl/fl ) mice with αMHC-Cre expressing mice. ECGs and echocardiograms (echos) were recorded at 6 and 9 months of age in cGpd1l ^-/- mice and Gpd1l ^fl/fl littermate controls.

Results: At 9 months of age, male cGpd1l-/- mice compared to Gpd1lfl/fl controls had increased end diastolic and end systolic volumes (EDV, 108±67 vs 27±3 μL, p=0.02; ESV; 80±66 vs 6±2 μL; p=0.03), and markedly reduced ejection fractions (EF, 33±18% vs. 77±7%, p=0.001). Female cGpd1l-/- mice, on the other hand, had no changes to EDV, ESV, or EF (Figure A). The echo changes in male mice were minimal at 6 months. ECG recordings of ~9-month-old cGpd1l-/- male mice compared to Gpd1lfl/fl controls showed prolonged PR interval (52±1.1 vs. 40±2.7 ms; p=0.05) and QRS duration (17.8±1.5 vs. 15.2±1.1 ms; p=0.01) with no change in heart rate (Figure B). ECG parameters were also unchanged in cGpd1l-/- female mice.

Conclusions: Cardiac-specific disruption of Gpd1l causes ventricular dysfunction, conduction abnormalities and arrhythmias in male but not female mice. Further investigation into the mechanisms underlying the sex-dependent phenotype of Gpd1l-/-mice and whether this impacts the male predominance of BrS in humans is warranted.