Abstract 17871: Brugada Phenotype in Cardiac-Specific GPD1-L Knockout Mice
Introduction: A Brugada syndrome (BrS) mutation (A280V) in Glycerol-3 Phosphate Dehydrogenase-1 Like (GPD1-L) decreases SIRT1 deacetylase activity, surface expression of Nav1.5, and Na+ current (INa) in heterologous expression systems. Targeted disruption of GPD1-L in mice was homozygous embryonic lethal; heterozygotes had decreased INa, pharmacologically inducible arrhythmias, and increased Nav1.5 acetylation. We hypothesized that cardiac specific GPD1-L knockout mice (cGPD1L-/-) would closely model the BrS phenotype.
Methods: We engineered cGPD1L-/- mice (GPD1Lflox/flox x αMHC-cre), and recorded electrocardiograms (ECGs), echocardiograms (echo), and ambulatory telemetry from cGPD1L-/- mice, cGPD1L+/- mice and littermate controls (Cre -; WT).
Results: Cardiac specific disruption of GPD1-L led to a dilated cardiomyopathy (Fig. 1A). Echos showed dilation and reduced ejection fractions (EFs) compared to WT controls that was mild in cGPD1L+/- mice and severe in cGPD1L-/- mice (~9 month old; WT, n=6, EF=0.76± 0.06; cGPD1L+/-, n=3, EF=0.55± 0.06, p=.002 vs. WT; cGPD1L-/-, n=3, 0.21± 0.06, p<0.001 vs. WT, p=.003 vs. cGPD1L+/-). ECG recordings from ~8 month-old anesthetized cGPD1L-/- mice showed widening of the QRS interval compared to littermate GPD1Lflox/flox controls (19±2 vs. 16±1 msec; n=3 each; p=0.02) with a right bundle branch morphology and ST-segment elevation in the right precordial leads consistent with a BrS phenotype (Fig. 1B). Ambulatory telemetry showed spontaneous runs of nonsustained ventricular tachycardia in cGPD1L-/- mice (Fig. 1C). Surprisingly, premature sudden death was more common in cGPD1L+/- than in cGPD1L-/- mice.
Conclusions: Our data demonstrates that cardiac expression of GPD1-L in the mouse is necessary for both for normal contractile and electrical function. Disruption of GPD1-L yields a mouse model of Brugada syndrome with conduction abnormalities, a BrS-like ECG phenotype, and ventricular arrhythmias.
Author Disclosures: H. Mehdi: None. J. Yoon: None. G.M. Morgan: None. T. Hameed: None. A. Vikram: None. X. Zhu: None. R.M. Weiss: None. B. London: None.
- © 2014 by American Heart Association, Inc.