title: Chronic heart failure slows late sodium current in human and canine ventricular myocytes: implications for repolarization variability.
abstract: 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.
  
  
  OBJECTIVE
  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.
authors.affiliation: Heart and Vascular Institute, Henry Ford Health System, Detroit, Michigan 48202-2689, United States.
authors.forename: Victor A
authors.initials: VA
authors.lastname: Maltsev
authors.forename: Norman
authors.initials: N
authors.lastname: Silverman
authors.forename: Hani N
authors.initials: HN
authors.lastname: Sabbah
authors.forename: Albertas I
authors.initials: AI
authors.lastname: Undrovinas
mesh_terms: D000200:Action Potentials / Q000187:drug effects / Q000502:physiology*; D000328:Adult; D000818:Animals; D002104:Cadmium / Q000494:pharmacology; D004195:Disease Models, Animal; D004285:Dogs; D004305:Dose-Response Relationship, Drug; D005260:Female; D006321:Heart; D006333:Heart Failure / Q000378:metabolism / Q000503:physiopathology*; D006352:Heart Ventricles / Q000187:drug effects / Q000503:physiopathology; D006801:Humans; D015640:Ion Channel Gating / Q000187:drug effects; D017136:Ion Transport / Q000187:drug effects; D008297:Male; D008875:Middle Aged; D032383:Myocytes, Cardiac / Q000378:metabolism*; D018408:Patch-Clamp Techniques; D012530:Saxitoxin / Q000494:pharmacology; D012964:Sodium / Q000378:metabolism*; D015222:Sodium Channels / Q000187:drug effects / Q000378:metabolism*; D013779:Tetrodotoxin / Q000494:pharmacology
chemical_list: D015222:Sodium Channels; D002104:Cadmium; D012530:Saxitoxin; D013779:Tetrodotoxin; D012964:Sodium