title: ST segment elevation by current-to-load mismatch: an experimental and computational study.
abstract: BACKGROUND
  Recently, we demonstrated that ajmaline caused ST segment elevation in the heart of an SCN5A mutation carrier by excitation failure in structurally discontinuous myocardium. In patients with Brugada syndrome, ST segment elevation is modulated by cardiac sodium (I(Na)), transient outward (I(to)), and L-type calcium currents (I(CaL)).
  
  
  OBJECTIVE
  To establish experimentally whether excitation failure by current-to-load mismatch causes ST segment elevation and is modulated by I(to) and I(CaL).
  
  
  METHODS
  In porcine epicardial shavings, isthmuses of 0.9, 1.1, or 1.3 mm in width were created parallel to the fiber orientation. Local activation was recorded electrically or optically (di-4-ANEPPS) simultaneously with a pseudo-electrocardiogram (ECG) before and after ajmaline application. Intra- and extracellular potentials and ECGs were simulated in a computer model of the heart and thorax before and after introduction of right ventricular structural discontinuities and during varying levels of I(Na), I(to), and I(CaL).
  
  
  RESULTS
  In epicardial shavings, conduction blocked after ajmaline in a frequency-dependent manner in all preparations with isthmuses ≤ 1.1 mm width. Total conduction block occurred in three of four preparations with isthmuses of 0.9 mm versus one of seven with isthmuses ≥ 1.1 mm (P<.05). Excitation failure resulted in ST segment elevation on the pseudo-ECG. In computer simulations, subepicardial structural discontinuities caused local activation delay and made the success of conduction sensitive to I(Na), I(to), and I(CaL). Reduction of I(to) and increase of I(CaL) resulted in a higher excitatory current, overcame subepicardial excitation failure, and reduced the ST segment elevation.
  
  
  CONCLUSIONS
  Excitation failure by current-to-load mismatch causes ST segment elevation and, like ST segment elevation in Brugada patients, is modulated by I(to) and I(CaL).
authors.affiliation: Department of Experimental Cardiology, Heart Failure Research Center, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands. m.g.hoogendijk@amc.uva.nl
authors.forename: Mark G
authors.initials: MG
authors.lastname: Hoogendijk
authors.forename: Mark
authors.initials: M
authors.lastname: Potse
authors.forename: Alain
authors.initials: A
authors.lastname: Vinet
authors.forename: Jacques M T
authors.initials: JM
authors.lastname: de Bakker
authors.forename: Ruben
authors.initials: R
authors.lastname: Coronel
mesh_terms: D000404:Ajmaline / Q000494:pharmacology; D000818:Animals; D000889:Anti-Arrhythmia Agents / Q000494:pharmacology; D053840:Brugada Syndrome / Q000503:physiopathology*; D003198:Computer Simulation; D004562:Electrocardiography; D006329:Heart Conduction System / Q000187:drug effects / Q000503:physiopathology*; D066298:In Vitro Techniques; D008297:Male; D013552:Swine
chemical_list: D000889:Anti-Arrhythmia Agents; D000404:Ajmaline