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

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• 作者：Victor A. Maltsev ; Norman Silverman ; Hani N. Sabbah ; Albertas I. Undrovinas
• 关键词：Heart failure ; Late Na⁺ current inactivation ; Action potential ; Early afterdepolarizations
• 刊名：European Journal of Heart Failure
• 出版年：2007
• 期刊代码：90_13889842
• 类别：med
• 出版时间：March 2007
• 卷：9
• 期：3
• 页码：219-227
• 文件大小：812 K

摘要

>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 < 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 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 (IC₅₀ = 62 nM) or tetrodotoxin (IC₅₀ = 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 Ca²⁺ overload and improvement of repolarization.