Biomarkers and endogenous determinants of dofetilide-induced torsades de pointes in α(1) -adrenoceptor-stimulated, anaesthetized rabbits.
OBJECTIVE
Torsades de pointes (TdP) liability is a stochastic event, which indicates that unidentified factors have an important role in facilitating the initiation of TdP by increasing the probability of TdP occurrence. We sought to identify factors that facilitate drug-induced TdP.


METHODS
We studied dofetilide-induced TdP in pentobarbital-anaesthetized, phenylephrine-sensitized rabbits, seeking biomarkers that discriminated between the animals that experienced TdP ('TdP+' animals) and those that did not ('TdP-' animals). As novel variables, the beat-to-beat variability and instability of ECG intervals were measured at preset times, irrespective of whether or not hearts were in stable sinus rhythm ('absolute' variability and instability). Autonomic activity was also determined.


RESULTS
Dofetilide delayed repolarization and induced arrhythmias prior to TdP. The variability of the coupling interval and shape of arrhythmic beats before TdP were significantly greater in the 'TdP+' group than in the 'TdP-' group. Accordingly, the 'absolute' variability and instability of the ECG intervals were significantly elevated in the 'TdP+' group. Phenylephrine increased significantly the up-baroreflex sensitivity in the 'TdP+' group before dofetilide administration.


CONCLUSIONS
'Preceding' arrhythmias have characteristics that permit prediction of TdP occurrence: the more chaotic the ventricular rhythm, the greater the probability of TdP initiation. This suggests that complexity of the arrhythmic beats may play an important mechanistic role in TdP genesis. The electrical instability quantified by the novel 'absolute' variability and instability parameters correlates with the probability of TdP occurrence. Baroreflex may contribute to TdP genesis in vivo.
Farkas
Attila S
AS
2nd Department of Internal Medicine and Cardiology Centre, University of Szeged, Szeged, Hungary.
Rudas
László
L
Makra
Péter
P
Csík
Norbert
N
Leprán
István
I
Forster
Tamás
T
Csanády
Miklós
M
Papp
Julius Gy
JG
Varró
András
A
Farkas
András
A
D058646:Adrenergic alpha-1 Receptor Agonists / Q000494:pharmacology; D000818:Animals; D000889:Anti-Arrhythmia Agents / Q000494:pharmacology / Q000633:toxicity*; D001145:Arrhythmias, Cardiac / Q000139:chemically induced; D017704:Baroreflex / Q000187:drug effects; D015415:Biomarkers; D004562:Electrocardiography / Q000187:drug effects*; D005260:Female; D006321:Heart / Q000187:drug effects* / Q000503:physiopathology; D010627:Phenethylamines / Q000494:pharmacology / Q000633:toxicity*; D010656:Phenylephrine / Q000494:pharmacology; D011817:Rabbits; D018340:Receptors, Adrenergic, alpha-1 / Q000378:metabolism*; D013449:Sulfonamides / Q000494:pharmacology / Q000633:toxicity*; D016171:Torsades de Pointes / Q000139:chemically induced* / Q000503:physiopathology
D058646:Adrenergic alpha-1 Receptor Agonists; D000889:Anti-Arrhythmia Agents; D015415:Biomarkers; D010627:Phenethylamines; D018340:Receptors, Adrenergic, alpha-1; D013449:Sulfonamides; D010656:Phenylephrine; C063533:dofetilide