Role of Sodium Channel Deglycosylation in the Genesis of Cardiac Arrhythmias in Heart Failure*

We investigated the cellular and molecular mechanisms underlying arrhythmias in heart failure. A genetically engineered mouse lacking the expression of the muscle LIM protein (MLP− /−) was used in this study as a model of heart failure. We used electrocardiography and patch clamp techniques to examine the electrophysiological properties of MLP− /− hearts. We found that MLP− /− myocytes had smaller Na+currents with altered voltage dependencies of activation and inactivation and slower rates of inactivation than control myocytes. These changes in Na+ currents contributed to longer action potentials and to a higher probability of early afterdepolarizations in MLP− /− than in control myocytes. Western blot analysis suggested that the smaller Na+ current in MLP− /− myocytes resulted from a reduction in Na+ channel protein. Interestingly, the blots also revealed that the α-subunit of the Na+ channel from the MLP− /− heart had a lower average molecular weight than in the control heart. Treating control myocytes with the sialidase neuraminidase mimicked the changes in voltage dependence and rate of inactivation of Na+ currents observed in MLP− /−myocytes. Neuraminidase had no effect on MLP− /− cells thus suggesting that Na+ channels in these cells were sialic acid-deficient. We conclude that deficient glycosylation of Na+ channel contributes to Na+ current-dependent arrhythmogenesis in heart failure.