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

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 IN. 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 a subunit isoforms (NaV 1.1, 1.3, 1.5) and for the P1 and P2 subunits. This suggests neither a 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 noninactivating late I-Na is increased in heart failure and this may contribute to action potential prolongation and the generation of arrhythmia. (c) 2005 Elsevier Ltd. All rights reserved.