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Abstract 504: AAV9-Mediated Overexpression of TRPM4 Increases the Incidence of Ventricular Arrhythmias in Living Mice


 Cardiac conduction disorders are a common cause of lethal cardiac arrhythmias and can be caused by mutations in ion channels. Several studies suggest that mutations in the Transient Receptor Potential subfamily M member 4 (TRPM4) are responsible for hereditary forms of cardiac conduction disorders. The majority of mutations that are described in TRPM4 lead to gain-of-function of channel activity. Analysis of the first identified gain-of-function mutation, p.E7K in a cellular overexpression system suggests that attenuated deSUMOylation of the protein, leads to impaired endocytosis and consequently an increase in the number of functional channels in the plasma membrane. To test the idea that an increased number of TRPM4 channels leads to cardiac arrhythmias, we created a functional overexpression model of the TRPM4 channel in living mice. To this end, we overexpressed TRPM4 in mice using adeno-associated virus serotype 9 (AAV9) particles, which has been described as the most cardiotropic of AAV serotypes. Overexpression of TRPM4 was achieved via tail vein injection of AAV9 particles. Subsequently, we performed telemetric ECG-measurements in freely-moving mice to determine their
 in vivo
 cardiac phenotype. In baseline conditions, the heart rate and ECG-parameters were similar between TRPM4-overexpressing and WT mice. Additionally, the number of arrhythmic incidents in resting mice was not different between TRPM4-overexpressing mice and WT mice. Instead, WT mice overexpressing TRPM4 exhibited more premature ventricular ectopic beats during exercise-induces β-adrenergic stress. Conduction abnormalities were rare and was not increased in mice overexpressing TRPM4. Taken together, mice overexpressing TRPM4 were more prone to develop premature ventricular ectopic beats during exercise-induced β-adrenergic stress.
