Late Na+ current (INaL) in human and dog hearts has been implicated in abnormal repolarization associated with heart failure (HF). HF slows inactivation gating of late Na+ channels, which could contribute to these abnormalities.
To test how altered gating affects INaL time course, Na+ influx, and action potential (AP) repolarization.
INaL and AP were measured by patch clamp in left ventricular cardiomyocytes from normal and failing hearts of humans and dogs. Canine HF was induced by coronary microembolization.
INaL decay was slower and INaL density was greater in failing hearts than in normal hearts at 24 °C (human hearts: τ = 659 ± 16 vs. 529 ± 21 ms; n = 16 and 4 hearts, respectively; mean ± SEM; p < 0.002; dog hearts: 561 ± 13 vs. 420 ± 17 ms; and 0.307 ± 0.014 vs. 0.235 ± 0.019 pA/pF; n = 25 and 14 hearts, respectively; p < 0.005) and at 37 °C this difference tended to increase. These INaL changes resulted in much greater (53.6%) total Na+ influx in failing cardiomyocytes. INaL was sensitive to cadmium but not to cyanide and exhibited low sensitivity to saxitoxin (IC50 = 62 nM) or tetrodotoxin (IC50 = 1.2 μM), tested in dogs. A 50%INaL inhibition by toxins or passing current opposite to INaL, decreased beat-to-beat AP variability and eliminated early afterdepolarizations in failing cardiomyocytes.
Chronic HF leads to larger and slower INaL generated mainly by the cardiac-type Na+ channel isoform, contributing to larger Na+ influx and AP duration variability. Interventions designed to reduce/normalize INaL represent a potential cardioprotective mechanism in HF via reduction of related Na+ and Ca2+ overload and improvement of repolarization.