Increased late sodium current in myocytes from a canine heart failure model and from failing human heart

• Published in: Journal of molecular and cellular cardiology Vol. 38; no. 3; pp. 475 - 483
• Main Authors: Valdivia, Carmen R., Chu, William W., Pu, Jielin, Foell, Jason D., Haworth, Robert A., Wolff, Mathew R., Kamp, Timothy J., Makielski, Jonathan C.
• Format: Journal Article
• Language: English
• Published: England Elsevier Ltd 01.03.2005
• Subjects: Animals; Arrhythmia mechanism; Arrhythmias, Cardiac - etiology; Arrhythmias, Cardiac - metabolism; Base Sequence; Cardiomyopathy; Cardiomyopathy, Dilated - complications; Cardiomyopathy, Dilated - genetics; Cardiomyopathy, Dilated - metabolism; Disease Models, Animal; DNA - genetics; Dogs; Heart Failure - complications; Heart Failure - genetics; Heart Failure - metabolism; Humans; In Vitro Techniques; Kinetics; Membrane Potentials; Myocytes, Cardiac - metabolism; NaV1.5; Protein Subunits; RNA, Messenger - genetics; RNA, Messenger - metabolism; Saxitoxin; SCN5A; Sodium channel subunits; Sodium Channels - chemistry; Sodium Channels - genetics; Sodium Channels - metabolism; Sodium channel subunits; Arrhythmia mechanism; Saxitoxin; SCN5A; Cardiomyopathy; NaV1.5
• ISSN: 0022-2828; 1095-8584
• DOI: 10.1016/j.yjmcc.2004.12.012

Electrophysiological remodeling of ion channels in heart failure causes action potential prolongation and plays a role in arrhythmia mechanism. The importance of down-regulation of potassium currents is well-known, but a role for Na current ( I Na) in heart failure is less well established. We studied I Na in heart failure ventricular cells from a canine pacing model of heart failure and also from explanted failing human hearts. Peak I Na density was significantly decreased by 39% and 57% in the dog model and in human heart failure, respectively. The kinetics of peak I Na were not different in heart failure. Late I Na was measured 750 ms after the initial depolarization as the saxitoxin (STX)-sensitive current and also as the current remaining after contaminating currents were blocked. Late I Na as a percentage of the peak I Na was significantly increased in both conditions. In dogs, STX sensitive late I Na was 0.5 ± 0.1% n = 16 cells from eight normal hearts and 3.4 ± 1.4% n = 12 cells from seven failing hearts; in humans, it was 0.2 ± 0.1% n = 4 cells from two normal hearts and 2.4 ± 0.5% n = 10 cells from three human failing hearts (–40 mV). Quantitative measures of mRNA including RNase protection assays and real time quantitative PCR in the dog model showed no differences for different α subunit isoforms (NaV1.1, 1.3, 1.5) and for the β1 and β2 subunits. This suggests neither α subunit isoform switching nor altered β subunit expression is a mechanism for increased late I Na. We conclude that a peak I Na is decreased, and non-inactivating late I Na is increased in heart failure and this may contribute to action potential prolongation and the generation of arrhythmia.