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

Carmen A. Ufret-Vincenty^§, Deborah J. Baro^¶, W. Jonathan Lederer^**, Howard A. Rockman, Luis E. Quiñones, and L. Fernando Santana^§§§

From the  Institute of Neurobiology, University of Puerto Rico, San Juan, Puerto Rico 00901, the ^¶ Department of Biochemistry, Medical Sciences Campus, University of Puerto Rico, San Juan, Puerto Rico 00936, the ^** Medical Biotechnology Center and Department of Physiology, University of Maryland School of Medicine, Baltimore, Maryland 21201, and the  Department of Medicine and Cell Biology, Duke University Medical Center, Durham, North Carolina 27710

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 -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.