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 (INa) in heart failure is less well established. We studied INa in heart failure ventricular cells from a canine pacing model of heart failure and also from explanted failing human hearts. Peak INa density was significantly decreased by 39% and 57% in the dog model and in human heart failure, respectively. The kinetics of peak INa were not different in heart failure. Late INa 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 INa as a percentage of the peak INa was significantly increased in both conditions. In dogs, STX sensitive late INa 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 INa. We conclude that a peak INa is decreased, and non-inactivating late INa is increased in heart failure and this may contribute to action potential prolongation and the generation of arrhythmia.