Chronic heart failure significantly slowed late sodium current decay in human ventricular myocytes compared to normal hearts (659 vs 529 ms, p<0.002), increasing total Na+ influx.
Does chronic heart failure alter late sodium current gating and affect action potential repolarization in human and canine ventricular myocytes?
Chronic heart failure leads to larger and slower late sodium current, contributing to increased sodium influx and action potential duration variability, suggesting I(NaL) inhibition as a potential cardioprotective mechanism.
Absolute Event Rate: 659% vs 529%
p-value: p=<0.002
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 degrees C (human hearts: tau=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 degrees 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 muM), 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.
Maltsev et al. (Wed,) conducted a other in Chronic Heart Failure (n=59). Chronic Heart Failure vs. Normal hearts was evaluated on Late Na(+) current (I(NaL)) decay time constant (tau) at 24 degrees C in human hearts (p=<0.002). Chronic heart failure significantly slowed late sodium current decay in human ventricular myocytes compared to normal hearts (659 vs 529 ms, p<0.002), increasing total Na+ influx.