title: Ventricular rate adaptation: a novel, rapid, cellular-based in-vitro assay to identify proarrhythmic and torsadogenic compounds.
abstract: BACKGROUND
  Delayed cardiac repolarization is an established risk factor for proarrhythmia and Torsades-de-Pointes (TdeP) that is typically measured in vitro during slow, regular stimulation. We have developed an alternative, novel, and rapid cellular-based approach for predicting drug-induced proarrhythmia that detects changes in electrical refractoriness based on mechanical responses (measured optically) during increasingly rapid trains of stimulation interspersed with pauses (mimicking the clinically observed short-long-short (SLS) stimulation sequence associated with the TdeP initiation).
  
  
  METHODS
  Acutely isolated rabbit ventricular myocytes were superfused and electrically stimulated using an accelerating pacing protocol (APP) consisting of 12 consecutive pacing segments (10 beats per segment) with incrementally faster cycle lengths; trains were separated by pauses to identify loss of stimulus capture as well as to mimic clinically observed SLS sequences. Drug effects were evaluated based on a myocyte's ability to contract during progressively faster pacing segments (rate-adaptation); the earliest rate during which the myocyte fails to respond (longest cycle length with incomplete capture (CLIC)) was used to quantify electrophysiologic effects.
  
  
  RESULTS
  Torsadogenic drugs known to delay repolarization during slow stimulation prolonged CLIC and dramatically limited the ability to respond to progressively rapid stimulation. The recognized proarrhythmic compounds E-4031, cisapride, grepafloxacin, and haloperidol rapidly prolonged CLIC at and above therapeutic concentrations in a concentration-dependent manner, while negative controls (captopril, indomethacin, and loratidine) do not affect rate-adaptation.
  
  
  CONCLUSIONS
  Ventricular rate adaptation represents a novel approach for rapidly detecting drugs with torsadogenic risk using rapid rhythms that are typically not employed when evaluating proarrhythmic risk. This method is well suited for detecting and avoiding potential cardiac liabilities early in drug discovery ("frontloading") prior to final selection of candidate drugs.
authors: Abbott Laboratories, Department of Integrative Pharmacology, R46R, Bldg. AP9, 100 Abbott Park Road, Abbott Park, IL 60064, United States. Jonathon.Green@Abbott.com
authors: Jonathon R
authors: JR
authors: Green
authors: Gilbert J
authors: GJ
authors: Diaz
authors: James T
authors: JT
authors: Limberis
authors: Kathryn A
authors: KA
authors: Houseman
authors: Zhi
authors: Z
authors: Su
authors: Ruth L
authors: RL
authors: Martin
authors: Bryan F
authors: BF
authors: Cox
authors: Stan
authors: S
authors: Kantor
authors: Gary A
authors: GA
authors: Gintant
mesh_terms: D000818:Animals; D004353:Drug Evaluation, Preclinical / Q000379:methods; D064420:Drug-Related Side Effects and Adverse Reactions; D004558:Electric Stimulation / Q000379:methods; D004562:Electrocardiography / Q000187:drug effects*; D005260:Female; D006321:Heart / Q000187:drug effects* / Q000503:physiopathology; D006352:Heart Ventricles / Q000187:drug effects / Q000503:physiopathology; D032383:Myocytes, Cardiac / Q000187:drug effects*; D011817:Rabbits; D016171:Torsades de Pointes / Q000139:chemically induced* / Q000175:diagnosis* / Q000503:physiopathology