Increased short-term variability of repolarization predicts d-sotalol-induced torsades de pointes in dogs.
BACKGROUND
Identification of patients at risk for drug-induced torsades de pointes arrhythmia (TdP) is difficult. Increased temporal lability of repolarization has been suggested as being valuable to predict proarrhythmia. The predictive value of different repolarization parameters, including beat-to-beat variability of repolarization (BVR), was compared in this serial investigation in dogs with chronic AV block.


RESULTS
In anesthetized dogs with electrically remodeled hearts, the dose-dependent difference in drug-induced TdP (d-sotalol, 2 and 4 mg/kg IV over 5 minutes, 25% and 75% TdP, respectively) could not be accounted for by prolongation of QT(c) (410+/-37 to 475+/-60 versus 415+/-47 to 484+/-52 ms, respectively). BVR was quantified by Poincare plots at baseline and immediately before onset of d-sotalol-induced extrasystolic activity. TdP occurrence was associated with an increase in short-term variability (STV) of the left ventricular monophasic action potential duration (3.5+/-1.5 to 5.5+/-1.6 versus 3.0+/-0.7 to 8.6+/-3.8 ms, respectively), which was reversible when TdP was abolished by I(K,ATP) activation. The absence of TdP despite QT(c) prolongation after chronic amiodarone treatment could also be explained by an unchanged STV. In experiments with isolated ventricular myocytes, STV increased after I(Kr) block and was highest in cells that subsequently showed early afterdepolarizations.


CONCLUSIONS
Proarrhythmia is not related to differences in prolongation of repolarization but corresponds to BVR, here quantified as STV of the left ventricle. STV could be a new parameter to predict drug-induced TdP in patients.
Department of Cardiology, Cardiovascular Research Institute Maastricht, Maastricht University, Maastricht, Netherlands.
Morten B
MB
Thomsen
S Cora
SC
Verduyn
Milan
M
Stengl
Jet D M
JD
Beekman
Geert
G
de Pater
Jurren
J
van Opstal
Paul G A
PG
Volders
Marc A
MA
Vos
D000200:Action Potentials / Q000187:drug effects; D000319:Adrenergic beta-Antagonists / Q000633:toxicity*; D000818:Animals; D005117:Cardiac Complexes, Premature / Q000139:chemically induced / Q000503:physiopathology; D002908:Chronic Disease; D004198:Disease Susceptibility; D004285:Dogs; D004305:Dose-Response Relationship, Drug; D004562:Electrocardiography / Q000187:drug effects; D005260:Female; D006327:Heart Block / Q000150:complications*; D006329:Heart Conduction System / Q000187:drug effects / Q000503:physiopathology*; D006352:Heart Ventricles / Q000503:physiopathology; D008297:Male; D011237:Predictive Value of Tests; D013015:Sotalol / Q000633:toxicity*; D016171:Torsades de Pointes / Q000139:chemically induced* / Q000209:etiology / Q000503:physiopathology
D000319:Adrenergic beta-Antagonists; D013015:Sotalol