title: Prolongation of minimal action potential duration in sustained fibrillation decreases complexity by transient destabilization.
abstract: OBJECTIVE
  Sustained ventricular fibrillation (VF) is maintained by multiple stable rotors. Destabilization of sustained VF could be beneficial by affecting VF complexity (defined by the number of rotors). However, underlying mechanisms affecting VF stability are poorly understood. Therefore, the aim of this study was to correlate changes in arrhythmia complexity with changes in specific electrophysiological parameters, allowing a search for novel factors and underlying mechanisms affecting stability of sustained VF.
  
  
  RESULTS
  Neonatal rat ventricular cardiomyocyte monolayers and Langendorff-perfused adult rat hearts were exposed to increasing dosages of the gap junctional uncoupler 2-aminoethoxydiphenyl borate (2-APB) to induce arrhythmias. Ion channel blockers/openers were added to study effects on VF stability. Electrophysiological parameters were assessed by optical mapping and patch-clamp techniques. Arrhythmia complexity in cardiomyocyte cultures increased with increasing dosages of 2-APB (n > 38), leading to sustained VF: 0.0 ± 0.1 phase singularities/cm(2) in controls vs. 0.0 ± 0.1, 1.0 ± 0.9, 3.3 ± 3.2, 11.0 ± 10.1, and 54.3 ± 21.7 in 5, 10, 15, 20, and 25 µmol/L 2-APB, respectively. Arrhythmia complexity inversely correlated with wavelength. Lengthening of wavelength during fibrillation could only be induced by agents (BaCl(2)/BayK8644) increasing the action potential duration (APD) at maximal activation frequencies (minimal APD); 123 ± 32%/117 ± 24% of control. Minimal APD prolongation led to transient VF destabilization, shown by critical wavefront collision leading to rotor termination, followed by significant decreases in VF complexity and activation frequency (52%/37%). These key findings were reproduced ex vivo in rat hearts (n = 6 per group).
  
  
  CONCLUSIONS
  These results show that stability of sustained fibrillation is regulated by minimal APD. Minimal APD prolongation leads to transient destabilization of fibrillation, ultimately decreasing VF complexity, thereby providing novel insights into anti-fibrillatory mechanisms.
authors.affiliation: Laboratory of Experimental Cardiology, Department of Cardiology,  Leiden University Medical Center, P.O. Box 9600, Leiden 2300 RC,  The Netherlands.
authors.forename: Brian O
authors.initials: BO
authors.lastname: Bingen
authors.forename: Saïd F A
authors.initials: SF
authors.lastname: Askar
authors.forename: Martin J
authors.initials: MJ
authors.lastname: Schalij
authors.forename: Ivan V
authors.initials: IV
authors.lastname: Kazbanov
authors.forename: Dirk L
authors.initials: DL
authors.lastname: Ypey
authors.forename: Alexander V
authors.initials: AV
authors.lastname: Panfilov
authors.forename: Daniël A
authors.initials: DA
authors.lastname: Pijnappels
mesh_terms: D000200:Action Potentials / Q000187:drug effects; D000818:Animals; D000831:Animals, Newborn; D001896:Boron Compounds / Q000633:toxicity; D002478:Cells, Cultured; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D017629:Gap Junctions / Q000187:drug effects / Q000378:metabolism*; D007473:Ion Channels / Q000187:drug effects / Q000378:metabolism; D007700:Kinetics; D049990:Membrane Transport Modulators / Q000633:toxicity; D032383:Myocytes, Cardiac / Q000187:drug effects / Q000378:metabolism*; D018408:Patch-Clamp Techniques; D010477:Perfusion; D051381:Rats; D014693:Ventricular Fibrillation / Q000139:chemically induced / Q000378:metabolism* / Q000503:physiopathology; D056969:Voltage-Sensitive Dye Imaging
chemical_list: D001896:Boron Compounds; D007473:Ion Channels; D049990:Membrane Transport Modulators; C109986:2-aminoethoxydiphenyl borate