Role of sodium channel deglycosylation in the genesis of cardiac arrhythmias in heart failure

We investigated the cellular and molecular mechanisms underlying arrhythmia s in heart failure. A genetically engineered mouse lacking the expression o f the muscle LIM protein (MLP-/-) was used in this study as a model of hear t failure. We used electrocardiography and patch clamp techniques to examin e the electrophysiological properties of MLP-/- hearts. We found that MLP-/ - myocytes had smaller Na+ currents with altered voltage dependencies of ac tivation and inactivation and slower rates of inactivation than control myo cytes. These changes in Na+ currents contributed to longer action potential s and to a higher probability of early afterdepolarizations in MLP-/- than in control myocytes. Western blot analysis suggested that the smaller Na+ c urrent in MLP-/- myocytes resulted from a reduction in Na+ channel protein. Interestingly, the blots also revealed that the a-subunit of the Na+ chann el from the MLP-/- heart had a lower average molecular weight than in the c ontrol heart. Treating control myocytes with the sialidase neuraminidase mi micked the changes in voltage dependence and rate of inactivation of Na+ cu rrents observed in MLP-/- myocytes. Neuraminidase had no effect on MLP-/- c ells thus suggesting that Na+ channels in these cells were sialic acid-defi cient. We conclude that deficient glycosylation of Na+ channel contributes to Na+ current-dependent arrhythmogenesis in heart failure.