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J Mol Cell Cardiol. 2005 Mar;38(3):475-83.

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

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Departments of Medicine, Surgery and Physiology, University of Wisconsin Hospital and Clinics, University of Wisconsin, 600 Highland Avenue H6/349, Madison, WI 53792, USA.


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 alpha subunit isoforms (NaV1.1, 1.3, 1.5) and for the beta1 and beta2 subunits. This suggests neither alpha subunit isoform switching nor altered beta 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.

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