Cardiomyocytes isolated from normal and explanted failing human hearts express INaL characterized by an ultraslow voltage-independent inactivation and reactivation.
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: τ = 659 ± 16 vs. 529 ± 21 ms; n = 16 and 4 hearts, respectively; mean ± SEM; p b 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 b 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 = 62 nM) 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.
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