title: Rate-dependent action potential alternans in human heart failure implicates abnormal intracellular calcium handling.
abstract: BACKGROUND
  Alternans in action potential voltage (APV-ALT) at heart rates <110 bpm is a novel index to predict ventricular arrhythmias. However, the rate dependency of APV-ALT and its mechanisms in failing versus nonfailing human myocardium are poorly understood. It is hypothesized that APV-ALT in human heart failure (HF) reflects abnormal calcium handling.
  
  
  OBJECTIVE
  Using a modeling and clinical approach, our objectives were to (1) determine how APV-ALT varies with pacing rate and (2) ascertain whether abnormalities in calcium handling explain the rate dependence of APV-ALT in HF.
  
  
  METHODS
  APV-ALT was analyzed at several cycle lengths (CLs) using a dynamic pacing protocol applied to a human left ventricle wedge model with various alterations in calcium handling. Modeled APV-ALT was used to predict APV-ALT in left ventricle monophasic action potentials recorded from HF (n = 3) and control (n = 2) patients with the same pacing protocol.
  
  
  RESULTS
  Reducing the sarcoplasmic reticulum calcium uptake current < or =25%, the release current < or =11%, or the sarcolemmal L-type calcium channel current < or =43% of control predicted APV-ALT to arise at CL > or =600 ms and then increase in magnitude by >400% for CL <400 ms. In HF patients, APV-ALT arose at CL = 600 ms and then increased in magnitude by >500% at CL <350 ms. For all other model alterations and for control patients, APV-ALT occurred only at CL <500 ms.
  
  
  CONCLUSIONS
  APV-ALT shows differing rate dependence in HF versus control patients, arising at slower rates in HF and predicted by models with abnormal calcium handling. Future studies should investigate whether APV-ALT at slow rates identifies patients with deranged calcium handing, including HF patients before decompensation or at risk for arrhythmias.
authors.affiliation: Department of Biomedical Engineering and Institute for Computational Medicine, Johns Hopkins University, Baltimore, Maryland, USA.
authors.forename: Jason D
authors.initials: JD
authors.lastname: Bayer
authors.forename: Sanjiv M
authors.initials: SM
authors.lastname: Narayan
authors.forename: Gautam G
authors.initials: GG
authors.lastname: Lalani
authors.forename: Natalia A
authors.initials: NA
authors.lastname: Trayanova
mesh_terms: D000200:Action Potentials / Q000502:physiology*; D000368:Aged; D001145:Arrhythmias, Cardiac / Q000209:etiology / Q000503:physiopathology*; D002118:Calcium / Q000378:metabolism; D002128:Calcium Metabolism Disorders / Q000150:complications / Q000503:physiopathology*; D002304:Cardiac Pacing, Artificial; D006333:Heart Failure / Q000150:complications / Q000503:physiopathology*; D006339:Heart Rate / Q000502:physiology; D006801:Humans; D008875:Middle Aged; D008955:Models, Cardiovascular
chemical_list: D002118:Calcium
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