Chronic heart failure slows late sodium current in human and canine ventricular myocytes: Implications for repolarization variability

Background: Late Na + current (I NaL ) 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. Aims: To test how altered gating affects I NaL time course, Na + influx, and action potential (AP) repolarization. Methods: I NaL 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. Results: I NaL decay was slower and I NaL density was greater in failing hearts than in normal hearts at 24 °C (human hearts: τ659±16 vs . 529±21ms; n =16 and 4 hearts, respectively; mean±SEM; p <0.002; dog hearts: 561±13 vs . 420±17ms; and 0.307±0.014 vs . 0.235±0.019pA/pF; n =25 and 14 hearts, respectively; p <0.005) and at 37°C this difference tended to increase. These I NaL changes resulted in much greater (53.6%) total Na + influx in failing cardiomyocytes. I NaL was sensitive to cadmium but not to cyanide and exhibited low sensitivity to saxitoxin (IC 50 =62nM) or tetrodotoxin (IC 50 =1.2 μM), tested in dogs. A 50% I NaL inhibition by toxins or passing current opposite to I NaL , decreased beat‐to‐beat AP variability and eliminated early afterdepolarizations in failing cardiomyocytes. Conclusions: Chronic HF leads to larger and slower I NaL generated mainly by the cardiac‐type Na + channel isoform, contributing to larger Na + influx and AP duration variability. Interventions designed to reduce/normalize I NaL represent a potential cardioprotective mechanism in HF via reduction of related Na + and Ca 2+ overload and improvement of repolarization.