title: Mechanisms linking electrical alternans and clinical ventricular arrhythmia in human heart failure.
abstract: Mechanisms of ventricular tachycardia (VT) and ventricular fibrillation (VF) in patients with heart failure (HF) are undefined.
  
  
  
  The purpose of this study was to elucidate VT/VF mechanisms in HF by using a computational-clinical approach.
  
  
  
  In 53 patients with HF and 18 control patients, we established the relationship between low-amplitude action potential voltage alternans (APV-ALT) during ventricular pacing at near-resting heart rates and VT/VF on long-term follow-up. Mechanisms underlying the transition of APV-ALT to VT/VF, which cannot be ascertained in patients, were dissected with multiscale human ventricular models based on human electrophysiological and magnetic resonance imaging data (control and HF).
  
  
  
  For patients with APV-ALT k-score >1.7, complex action potential duration (APD) oscillations (≥2.3% of mean APD), rather than APD alternans, most accurately predicted VT/VF during long-term follow-up (+82%; -90% predictive values). In the failing human ventricular models, abnormal sarcoplasmic reticulum (SR) calcium handling caused APV-ALT (>1 mV) during pacing with a cycle length of 550 ms, which transitioned into large magnitude (>100 ms) discordant repolarization time alternans (RT-ALT) at faster rates. This initiated VT/VF (cycle length <400 ms) by steepening apicobasal repolarization (189 ms/mm) until unidirectional conduction block and reentry. Complex APD oscillations resulted from nonstationary discordant RT-ALT. Restoring SR calcium to control levels was antiarrhythmic by terminating electrical alternans.
  
  
  
  APV-ALT and complex APD oscillations at near-resting heart rates in patients with HF are linked to arrhythmogenic discordant RT-ALT. This may enable novel physiologically tailored, bioengineered indices to improve VT/VF risk stratification, where SR calcium handling and spatial apicobasal repolarization are potential therapeutic targets.
authors.affiliation: Electrophysiology and Heart Modeling Institute (LIRYC), Bordeaux University Foundation, Bordeaux, France; Institute of Mathematics of Bordeaux (U5251), University of Bordeaux, Bordeaux, France. Electronic address: jason.bayer@ihu-liryc.fr.
authors.forename: J D
authors.initials: JD
authors.lastname: Bayer
authors.affiliation: Kaiser Permanente, San Diego, California.
authors.forename: G G
authors.initials: GG
authors.lastname: Lalani
authors.affiliation: Electrophysiology and Heart Modeling Institute (LIRYC), Bordeaux University Foundation, Bordeaux, France; Institute of Mathematics of Bordeaux (U5251), University of Bordeaux, Bordeaux, France.
authors.forename: E J
authors.initials: EJ
authors.lastname: Vigmond
authors.affiliation: Stanford University, Palo Alto, California.
authors.forename: S M
authors.initials: SM
authors.lastname: Narayan
authors.affiliation: Institute for Computational Medicine, Johns Hopkins University, Baltimore, Maryland.
authors.forename: N A
authors.initials: NA
authors.lastname: Trayanova
mesh_terms: D000200:Action Potentials / Q000502:physiology*; D000328:Adult; D000368:Aged; D001145:Arrhythmias, Cardiac / Q000378:metabolism / Q000503:physiopathology; D002118:Calcium / Q000378:metabolism; D002304:Cardiac Pacing, Artificial; D022062:Electrophysiologic Techniques, Cardiac; D005260:Female; D006329:Heart Conduction System / Q000503:physiopathology*; D006333:Heart Failure / Q000209:etiology / Q000503:physiopathology*; D006339:Heart Rate; D006352:Heart Ventricles / Q000503:physiopathology; D006801:Humans; D008297:Male; D008875:Middle Aged; D008955:Models, Cardiovascular; D018570:Risk Assessment; D012519:Sarcoplasmic Reticulum / Q000378:metabolism; D017180:Tachycardia, Ventricular / Q000503:physiopathology*; D014693:Ventricular Fibrillation / Q000503:physiopathology*
chemical_list: D002118:Calcium
keywords: Alternans; Arrhythmia; Computational modeling; Heart failure; Simulation