© 2007 European Society of Cardiology
Chronic heart failure slows late sodium current in human and canine ventricular myocytes: Implications for repolarization variability
Heart and Vascular Institute Henry Ford Health System, Detroit, Michigan, United States
* Corresponding author. Henry Ford Hospital Cardiovascular Research Education and Research Bldg, Room 4015 2799 West Grand Boulevard Detroit, MI 48202-2689, United States. Tel.: +1 313 916 1321; fax: +1 313 916 3001. E-mail address: aundrov1{at}hfhs.org
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Abstract |
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Background: 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.
Aims: To test how altered gating affects INaL time course, Na+ influx, and action potential (AP) repolarization.
Methods: 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.
Results: INaL decay was slower and INaL density was greater in failing hearts than in normal hearts at 24 °C (human hearts: 
659±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 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=62nM) 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.
Conclusions: 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.
Key Words: Heart failure • Late Na+ current inactivation • Action potential • Early afterdepolarizations
Received January 26, 2006; Revised August 1, 2006; Accepted August 29, 2006
1 Current address: Gerontology Research Center, National Institute on Aging, NIH, 5600 Nathan Shock Drive, Baltimore, Maryland 21224, USA.
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