Increased Short-Term Variability of Repolarization Predicts d -Sotalol–Induced Torsades de Pointes in Dogs

Abstract

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. Methods and 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 (410Ϯ37 to 475Ϯ60 versus 415Ϯ47 to 484Ϯ52 ms, respectively). BVR was quantified by Poincaré 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 (3.5Ϯ1.5 to 5.5Ϯ1.6 versus 3.0Ϯ0.7 to 8.6Ϯ3.8 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.

Arrhythmogenesis in a catecholaminergic polymorphic ventricular tachycardia mutation that depresses ryanodine receptor function

“…Remarkably, there was a strict correlation between the prolonged phase of Ca 2+ release and the induction of EADs: the longer the sustained phase of Ca 2+ release, the longer the action potential duration at 90% decay (APD 90 ) and the greater incidence of EADs. Poincaré plots (22) of APD 90 and resting potential for WT cells (Fig. 3A, Middle and Right, respectively) showed no variability of either parameter during the corresponding 20-s train of stimulation, but the former was typically erratic in RyR2-A4860G +/− cells (Fig.…”

Pharmacological characterization of <i>microminipig</i> as a model to assess the drug-induced cardiovascular responses for non-clinical toxicity and/or safety pharmacology studies

“…The cardiovascular variables were expressed as the mean of 3 consecutive complexes. Also, Poincaré plots with QT n versus QT n+1 were prepared using total of 51 consecutive beats of electrocardiogram for each of analysis time points, of which short-term variability was calculated by the following equation: Σ|QT n+1 −QT n |/[50×√2]) Thomsen et al, 2004Thomsen et al, , 2006.…”

“…Increase in net inward currents during early repolarization phase has been known to induce early afterdepolarization, leading to the onset of torsade de pointes (Aiba et al, 2005;January and Riddle, 1989;Wu et al, 2008). Also, we assessed another proarrhythmic surrogate marker, beat-tobeat variability of repolarization, which has been used for quantifying the drug-induced temporal dispersion of ventricular repolarization Thomsen et al, 2004Thomsen et al, , 2006.…”

Reduction in Kv Current Enhances the Temporal Dispersion of the Action Potential in Diabetic Myocytes: Insights From a Novel Repolarization Algorithm

“…Moreover, the protracted AP predisposes myocytes to the occurrence of early afterdepolarizations, which may trigger extrasystoles and tachyarrhythmias and/or aggravate the dispersion of repolarization of the myocardium in the presence of local nonpropagating responses 21. Similarly, beat‐to‐beat variability of repolarization, which is observed at the single‐cell level and in the whole heart,22, 23 has detrimental consequences on myocardial electrical stability by facilitating the development of reentrant arrhythmias 15, 16, 21, 24. Importantly, these defects may be equally operative in the diabetic heart, representing important variables in the propensity to develop ventricular arrhythmias and sudden death in the presence of this disease.…”