title: Transmural dispersion of repolarization as a key factor of arrhythmogenicity in a novel intact heart model of LQT3.
abstract: BACKGROUND
  Congenital and acquired long QT syndrome (LQTS) are caused by abnormalities of ionic currents underlying ventricular repolarization. For a better understanding of the mechanisms by which functional electrical instability at the level of the whole heart leads to torsade de pointes (TdP), a novel model of LQT3 was developed and the role of transmural dispersion of repolarization for the development of proarrhythmia was evaluated.
  
  
  RESULTS
  In 11 Langendorff-perfused rabbit hearts, veratridine (0.1-0.5 microM), an inhibitor of sodium channel inactivation, led to a concentration-dependent increase in QT-interval and simultaneously recorded monophasic ventricular action potentials (MAPs) (p<0.05) and thereby mimicked LQT3. Veratridine reproducibly induced early afterdepolarizations (EADs) and TdP after lowering potassium concentration. In bradycardic (AV-blocked) hearts, the increase in MAP duration showed marked regional differences. It was significantly more pronounced on the left endocardium as compared to left or right epicardium. This resulted in a significant increase in dispersion of repolarization (24% at 0.1 microM, 92% at 0.25 microM, 208% at 0.5 microM; p<0.01). Left ventricular transmural dispersion of repolarization increased significantly more than interventricular dispersion (104 to 33 ms at 0.5 microM veratridine; p<0.05).
  
  
  CONCLUSIONS
  By inhibition of sodium channel inactivation, veratridine mimics LQT3 in this intact heart model. In bradycardic, hypokalemic hearts, it reproducibly induced EADs and TdP in the setting of significantly increased left ventricular transmural dispersion of repolarization. Based on these experimental data, reduction of transmural dispersion of repolarization may be considered an important target for the prevention of TdP in patients with LQT3.
authors.affiliation: Hospital of the Westfälische Wilhelms-University, Department of Cardiology and Angiology, Münster, Germany. milbergp@uni-muenster.de
authors.forename: Peter
authors.initials: P
authors.lastname: Milberg
authors.forename: Nico
authors.initials: N
authors.lastname: Reinsch
authors.forename: Kristina
authors.initials: K
authors.lastname: Wasmer
authors.forename: Gerold
authors.initials: G
authors.lastname: Mönnig
authors.forename: Jörg
authors.initials: J
authors.lastname: Stypmann
authors.forename: Nani
authors.initials: N
authors.lastname: Osada
authors.forename: Günter
authors.initials: G
authors.lastname: Breithardt
authors.forename: Wilhelm
authors.initials: W
authors.lastname: Haverkamp
authors.forename: Lars
authors.initials: L
authors.lastname: Eckardt
mesh_terms: D000200:Action Potentials / Q000187:drug effects; D000818:Animals; D004305:Dose-Response Relationship, Drug; D004562:Electrocardiography / Q000187:drug effects; D004699:Endocardium / Q000187:drug effects / Q000378:metabolism; D008133:Long QT Syndrome / Q000378:metabolism* / Q000503:physiopathology; D008297:Male; D023421:Models, Animal; D009206:Myocardium / Q000378:metabolism*; D010477:Perfusion; D010496:Pericardium / Q000187:drug effects / Q000378:metabolism; D011817:Rabbits; D026941:Sodium Channel Blockers / Q000494:pharmacology*; D014701:Veratridine / Q000494:pharmacology*
chemical_list: D026941:Sodium Channel Blockers; D014701:Veratridine