title: Heart failure enhances susceptibility to arrhythmogenic cardiac alternans.
abstract: BACKGROUND
  Although heart failure (HF) is closely associated with susceptibility to sudden cardiac death (SCD), the mechanisms linking contractile dysfunction to cardiac electrical instability are poorly understood. Cardiac alternans has also been closely associated with SCD, and has been linked to a mechanism for amplifying electrical heterogeneities in the heart. However, previous studies have focused on alternans in normal rather than failing myocardium.
  
  
  OBJECTIVE
  This study sought to investigate the hypothesis that HF enhances susceptibility to arrhythmogenic cardiac alternans.
  
  
  METHODS
  High-resolution transmural optical mapping was performed in canine wedge preparations from normal (n = 8) and HF (n = 8) hearts produced by rapid ventricular pacing.
  
  
  RESULTS
  HF significantly (P < .004) lowered the heart rate (HR) threshold for action potential duration alternans (APD-ALT) from 236 +/- 25 beats/min to 185 +/- 25 beats/min. In dual optical mapping of action potentials and intracellular Ca experiments (n = 16), HF lowered the HR threshold for Ca-ALT (beat-to-beat alternations of cellular Ca cycling) from 238 +/- 35 to 177 +/- 26 beats/min (P < .005). Importantly: (1) Ca-ALT always either developed at slower HR or simultaneously with APD-ALT in the same cells, and (2) the magnitude of Ca-ALT and APD-ALT were closely correlated (P < .05). HF similarly lowered the HR threshold for Ca-ALT in isolated myocytes under nonalternating action potential clamp, indicating that HF enhances susceptibility to cellular alternans independent of HF-associated changes in repolarization. Importantly, HF significantly (P < .02) lowered the HR threshold for spatially discordant arrhythmogenic alternans (different regions of cells alternating in opposite phase, DIS-ALT). Ventricular fibrillation (VF) was induced in 88% of HF preparations, but only 12% of normal preparations (P < .003) and was uniformly preceded by development of DIS-ALT.
  
  
  CONCLUSIONS
  Heart failure increases the susceptibility to arrhythmogenic cardiac alternans, which arises from HF-induced impairment in calcium cycling.
authors.affiliation: Heart and Vascular Research Center, MetroHealth Campus, Case Western Reserve University, Cleveland, Ohio 44109-1998, USA.
authors.forename: Lance D
authors.initials: LD
authors.lastname: Wilson
authors.forename: Darwin
authors.initials: D
authors.lastname: Jeyaraj
authors.forename: Xiaoping
authors.initials: X
authors.lastname: Wan
authors.forename: Gregory S
authors.initials: GS
authors.lastname: Hoeker
authors.forename: Tamer H
authors.initials: TH
authors.lastname: Said
authors.forename: Matthew
authors.initials: M
authors.lastname: Gittinger
authors.forename: Kenneth R
authors.initials: KR
authors.lastname: Laurita
authors.forename: David S
authors.initials: DS
authors.lastname: Rosenbaum
mesh_terms: D000200:Action Potentials; D000704:Analysis of Variance; D000818:Animals; D001145:Arrhythmias, Cardiac / Q000503:physiopathology*; D002118:Calcium / Q000378:metabolism; D002304:Cardiac Pacing, Artificial; D016009:Chi-Square Distribution; D004198:Disease Susceptibility; D004285:Dogs; D006329:Heart Conduction System / Q000503:physiopathology*; D006333:Heart Failure / Q000503:physiopathology*; D006339:Heart Rate / Q000502:physiology; D032383:Myocytes, Cardiac / Q000502:physiology; D016276:Ventricular Function
chemical_list: D002118:Calcium